Transcript : ImmunityBio, Inc. - Analyst/Investor Day

Published: 2025-04-15 13:00:00 ET IBRX

Published on 04/15/2025 at 13:00 - Modified on 07/16/2025 at 17:06

Hello, and welcome to the 2025 ImmunityBio KOL and Investor Day. [Operator Instructions] Please note that this call is being recorded. [Operator Instructions]

I would like to turn the conference over to Dr. Hemanth Ramaprakash, Chief of Staff and Head of Investor Relations at ImmunityBio. Please begin.

Welcome, everyone, and thank you for joining us this morning for ImmunityBio's first KOL and Investor Day. We are here today to discuss the progress made over the past year since the launch of ANKTIVA in May of 2024. On the call today are Dr. Patrick Soon-Shiong, Executive Chairman and Global Chief Scientific and Medical Officer; and Rich Adcock, the company's President and Chief Executive Officer. Also joining us today are several key opinion leaders who will participate in today's call. The call is being broadcast live at www.immunitybio.com. A playback will be available for at least 3 months on ImmunityBio's website.

Before I continue, I'd like to take a moment to read the company's safe harbor statement. Certain statements contained in this Investor Day program that are not historical information contain forward-looking statements. The forward-looking statements involve risks and uncertainties, and actual results may differ materially from those projected or implied. Further, certain forward-looking statements are based on assumptions of future events, which may not prove to be accurate.

For details regarding factors that may impact such forward-looking statements and risks that may impact the company's business, please refer to the Risk Factors section of the company's Form 10-K filed with the Securities and Exchange Commission on March 3, 2025, and in subsequent filings made by the company with the SEC as well as press releases.

In a moment, Dr. Soon-Shiong and Rich will discuss the recent developments of ImmunityBio, including discussing the latest on ANKTIVA approved for BCG-unresponsive non-muscle invasive bladder cancer, carcinoma in situ. They will also unveil and provide details on the cancer Bioshield. During today's call, they will discuss a range of ongoing efforts at ImmunityBio with our panel of KOLs. Finally, they will provide an update on the company as a whole before we open the call for questions.

With that said, I will now turn the call over to Dr. Soon-Shiong.

If you could put the first slide on, do I control it from a top or do you have. I just sort of control, okay? So I think today, what we want to do is really -- okay. While we're waiting for the first slide. So what we're going to do today is really there's been such a groundswell of interest on the cancer BioShield. And it really was an opportunity that we had planned this Investor Day way in advance of this. And we thought that this would be a real opportunity for me to expose work that has been going on for 20 years. So this cancer Bioshield is such an important concept.

I thought we would take this opportunity for most of this discussion. And first, I want to really thank the key opinion leaders who really traveled all the way here and we'll meet them individually to really talk about the science behind the cancer BioShield.

So you will hear a little bit about this concept of lymphocytes. When we talk to some of these KOLs and immuno-oncologists, this thing called absolute lymphocyte count, is almost a foreign name or word, yet it's been look -- staring us in the face. We talk about NKs and T cells because that matters. We talk about how duration of complete response matters. We talk about how survival matters. We're going to talk about quality of life matters. And in a sense, that really is the vision that we've been pursuing almost for 25, 30 years now to say that we will think back a decade from now of how barbaric our standards of care have been with high-dose chemotherapy.

Some of you may recall at one point for breast cancer patients, they wanted really intense high-dose chemotherapy. And we will show you today how sadly and inadvertently that's actually killed the cancer BioShield.

So let's start with that on the next slide, where I want to, as I said, introduce the -- let me get away from this slide. The leadership that is present today and obviously, time doesn't permit, but you will see and have a chance to meet with some of the leadership, and I'm so proud that we have an amazing leadership team that will take this, what we think, to the next frontier.

Next slide. And this is what we are going to be talking about today very much so. When we did the IPO of a company called NantKwest many years ago that this natural killer cell that is -- this is a real live sort of [indiscernible]. The oncologists and doctors to this team. And some of you know that in the right-hand corner there, you will see this thing 2016 January, where during the Vice President Biden timeframe, I launched the Cancer Moonshot 2020. And the concept here was for us to really explain this really, and we'll come back to this quantum effect. When I talk about quantum effect, it gets all lost. And every one of those little images is a cell.

Next slide. And this is quite literally an Oxford developed time lapse. This is what's happening in your body. These are real cells, natural killer cells that are quantumly trying to kill the cancer cell while the cancer cell is trying to hide and block. And this is where you have granules and you have T cells so that it acts as the vaccine to your BioShield to use the tumor itself in your body, what we call the neoadjuvant and then do the surgery to remove the tumor. And the non-muscle invasive bladder cancer, next slide is the first opportunity to pursue the science.

[Presentation]

The scientific details of the results, which bladder cancer first, the first armamentarium with the first output of the BioShield. But your natural killer cell doesn't care whether it's a bladder cancer, breast cancer, pancreatic cancer, liver cancer because that's the cancers that all natural killer cells would kill. More importantly, it actually kills any infected cells, so HBV, hepatitis, HIV, which were in trials and even COVID. So we'll talk about that as we proceed, but let me start in a methodical way and go through bladder cancer because as investors, I think you focus on very much on our very first approval and then how these really fall through the platform of the BioShield.

Now just to set the stage, the BioShield of this NK cell T cell can be given through this one shot, the jab where you activate the NK cells. So when I say 1 shot, I don't mean 1 single shot. I mean, one shot, then you go home and you come back and you have a shot. That's what we call in vivo activation. We also need to activate your memory through a regular adenovirus, which you'll speak to. But then we can also through an ex vivo, take your blood grow these NK cells and there's different kinds of NK cells, iNKT cells, NK T cells and ex vivo infuse that.

So there's a whole component of this BioShield that we now, for the first time, have at our fingertips. But let's start with bladder cancer.

Next Slide, please. So in April 2024, this was a turning point. For us, the first approval of ANKTIVA plus BCG and many people didn't understand why would we keep on using the BCG because the BCG is an immuno stimulating agent. You need to activate the body's immune system and ANKTIVA is a proliferating agent of that immunostimulation. So this is the first chemo free. If you look at those 2 boxes, there's no chemotherapy. It doesn't mean we don't need to use chemotherapy, but you need to use it in a very different way. So we need anything that would stimulate the tumor and wake it up and stress it. And in this case, it was BCG. In another case, it could be some other therapy, which we'll discuss.

Next slide. And yes, the results. I mean the take-home message here is we've now updated this and we'll be presenting some of this at the AUA -- upcoming AUA. And the remarkable nature we went from 77 to which the FDA reviewed to 100 patients, and we completed it. And the data is consistent. We now have, in these 100 patients, a 71% complete remission. This is not a response, this is a complete remission. What's exciting is the duration of this complete remission is now 53 months and ongoing. So this Bioshield, so to speak, not only is important, but I think the next most important part of that slide is the avoidance of removing the bladder. The cystectomy-free rate at 12 months and 95%, 90% at 24 months, 84% at 36 months with an overall survival of 93% of these patients. So what we've done in my mind, we've changed the course of bladder cancer.

Next slide. And here is a graphical example of exactly what we talked about. And for us now we'd be able to say with a high level of probability that there's a long-term overall survival and complete response duration.

Next slide, which then takes us to -- as I said, there's 2 types of bladder cancer, there is CIS which got approved and now papillary, I think my level of frustration, it's heads and tails of the same coin. When we published this data in 2022, now one may think theoretically, you should get both approvals simultaneously. We did not, and we've now submitted that as a supplement to this -- to the FDA that existed before. And hopefully, the new administration will recognize the urgent need.

But more importantly, rather than the urgent need, let me show the slides.

Next slide. And here are the results on papillary. And again, the cystectomy avoidance rate, 92% at 12 months, 81% at 36 months. The overall survival rate is 91% at 36 months. That means patients with papillary disease, which, by the way, is a larger number of bladder cancer, 80,000 bladder cancer patients a year and then the prevalence of these who resort sadly to chemotherapy to anything to avoid having their bladder removed. And unfortunately, chemotherapy is very toxic to the bladder.

Chemotherapy doesn't allow the bladder to heal, the pain and suffering from the patient receiving chemotherapy. And worst of all, chemotherapy kills the BioShield.

But let's talk about the results of the comparator on the next slide. Before I go there, we took the CIS and the papillary and combined them in terms of safety. So here now, we have 180 patients and look at all the zeros. That's remarkable for a treatment that gives you a complete remission without any toxicity and is biologically rational because this is what your body has. And the 3% is consistent with just the BCG alone.

Next slide. So if you combine that toxicity and safety and you look at these 2 issues. So this is what I mean by the heads and tails. CIS with or without papillary is approved. Papillary alone, which is just the heads without CIS is not approved. I scratch my head about that. And I think I'm now at the stage where I do need to speak out. I do need to speak out on behalf of patients because all we do is follow the science. And I want to show you the science on the next slide.

And on the left is the approval. And if you look at 36 months on the left, 93% overall survival and 84% saving the bladder. On the right, papillary, 82%, 92%. Same bladder disease, same therapy, same treatment. And on the far right, when you combine it to the safety is no different. In fact, it's combined. So I am very hopeful that on behalf of patients, that this current FDA recognizes the inconsistency of why you approve one and don't approve the other yet. And this is what we call a supplemental BLA, and we've just announced today that we've submitted it to the FDA. It's sitting in their hands. We submitted it. We talked about it in 2022 when the paper got published. So now it's 2025, we submitted it again after a January meeting where finally we convinced some of the leadership that this is -- doesn't make any sense. And they said, go ahead and submit it, which we did. And now it's sitting there.

Now look, I had a long talk for the first time in my career with a nonscientific long, what I call, podcast discussion with Dr. [ Carlsen ]. And that received remarkable responses from the general public. And I'm not here -- and this is not the right audience to talk about what goes on behind the scenes, how people make decisions on what basis they make decisions. But I do need, again, I suppose, at some level of risk from -- to the academia and I'm an academic. I was professor at UCLA of how decisions are made, what we call the NCCN. NCCN provides guidelines for drugs that are not approved but should be made medically accessible. And so obviously, papillary is not approved by us. Papillary is not approved by Merck. Papillary is not approved by Ferring.

So let me show you the next slide. So here, we have the NCCN guidelines. And if you look at the data for papillary, cystectomy free rate of Ferring's is 86%. Merck's Pembro 76%; and for ANKTIVA 92%. If you look at the treatment-related AEs, which is the toxicity, 3.8%, 14%, 3% with no immune-related, all 3 of us are not FDA approved. To our knowledge, both Ferring and Merck have not filed the BLA. Obviously, I say unknown because I don't really know but to our knowledge is not. We're the only ones submitted the BLA.

And the NCCN, the Chairman, Vice Chairman and the committee met last year after the New England Journal Medicine paper is already published on papillary. And those guidelines said papillary is okay for Ferring and Merck, but not for ImmunityBio. And so we asked this question why? And to this day, I don't have an answer. So I view that as it may be of how decisions are made and what's behind some of these decisions. But I think this is a struggle where really we are here to talk and speak on behalf of, 1, science and 2, of the patients. And we recognize this struggle, and we will take it on.

But I think as long as we present good science with good results that really help the patients, we'll continue speaking out now. I've kept this very quiet for 1.5 years, but I don't think we can afford not to speak out when there's no basis for this kind of inconsistent policy.

Next slide. So let's talk about the next level. So what we just presented to you was the BCG unresponsive. But really, we want to get to patients at the earlier stage, meaning once they diagnosed with bladder cancer, which we call BCG-naive. They never received BCG yet. So the current standard of care to these patients is to get BCG and we -- as we will discuss this with some of our key opinion leaders of the fireside chat about BCG. So we've initiated a trial with BCG naive, and I'll show you some data today, which I've said spent I don't know, 3 other scientific episodes presenting that data. And yet at the European meeting, our competitors said there's no data presented yet on the naive and I scratch my head and I said maybe I should just present it yet again. So let me do that yet again. And not only there is data, it's published data.

So here, the patients with BCG naive published that received our drug, whether it be papillary or CIS. And in this publication, 6 years complete remission. We then went to the FDA and said, we want to follow this up. And now 9 years, as we sit here today, and you'll see some videos, complete remission. So again, I worry very much about the misinformation that our competitors are willing to say. And it's not a criticism in terms of we holier-than-thou. I understand competition is good. But it really it's important for us to really present truthful scientific information. And again, I've been asked to give several keynotes at the AUA. I'll probably still a lot of noise by saying, yes, the truth. But here we are.

Next slide. Most importantly, the FDA, next slide, asked us to give an interim analysis. And this is what I presented multiple times. Now when you do this trial, which is ongoing, it's a randomized trial. It's BCG alone versus BCG plus ANKTIVA. And the goal, obviously, is to beat BCG because in 40%, 50% of cases, BCG fails, and that's what you call BCG-unresponsive. So the FDA made an unusual request to say unblind even though you don't normally unblind a randomized trial. And we said, fine, we'll unblind if you ask us to. I wonder internally whether they didn't really believe that ANKTIVA could really change the course of cancer therapy because they asked us to do this because they asked what they call the contribution of effect.

Now let me show you the results.

So we unblind it, next slide. And here it is. By 9 months, the response with N-803 plus BCG, ANKTIVA plus BCG, 85%, 85%, 84%. BCG really began to fail. And the statistic level, [ P 0.045 ], it was really statistically significant with a small number of patients, unblinded at the request of the FDA. What bothers me a lot is when our competitors go out to large plenary sessions and so we don't have any data on naive when this data has been presented at many conferences, but more importantly, look at the value of what we can now in this form of a BioShield bring to patients.

And so therefore, the randomized trial is now enrolling rapidly as we speak, in U.S.A., India and South Africa. One of the problems, however, was availability of BCG, which then took us to the next step because Merck was making the BCG. And as some of you may know, the shortages of BCG. And the way they were making BCG, believe it or not, is growing with in potatoes. I know that sounds crazy, but that's how the BCG is currently manufactured.

Next slide. Which then said we needed to address that. So which brought us then to this recombinant BCG, and we met with the Serum Institute of India and said we want to address the shortage.

Next slide. And most importantly, what was really exciting to me was this recombinant BCG was engineered so that it would activate the CD4, CD8 T cells, exactly the cells that I wanted to cross talk to the NK cells, exactly what we just showed you. So not only is it a BCG that would be available now to the world, thousands and thousands of vials could be made very rapidly. But more importantly, it would appear to have a higher immunogenic effect, but most importantly, it appeared to have a higher tolerability than the current BCG.

So again, to me here was this combination that I think we're now going to reveal at the upcoming AUA.

Next slide. And when they did the trial in Europe, just with BCG alone, remarkably, they had this 4-year duration of 42%. I've not seen a BCG do that. So what's exciting is that, imagine then that combination, which we are now instituting of that BCG without ANKTIVA and that trial is now ongoing. And again, you have some thought leaders yet to speak a little bit to that.

Next slide. So we went to the FDA and said, again, look, we really have the shortage. We need to address the shortage and thank goodness in February 2025, the FDA authorized what we call this access to BCG, which through the expanded access.

Next slide. And the first dose, and again, one of the thought leaders are here today, that to speak to how the first dose is given, how we activate the 60 sites and you'll hear a little bit about the response and reaction to that. And I think this is an important point is when the FDA needs to move, they can move. We filed for that request for that expanded access. And within weeks, it was granted. I think we face the same issue now for the supplemental BLA, why would we not allow the bladder cancer patients to receive the same drug that's already approved for CIS with and without papillary and then papillary with and without CIS, doesn't make any sense. So that is where we stand with regard to the bladder cancer.

Next slide, which then, am I ahead of time? It's amazing which then says we're going to really have an opportunity to talk about. And I want to really introduce Dr. Pieczonka, if you could come up to the fire side here and Dr. Reddy, if you're in the audience, I'm not sure where he is, there he is, you could have a seat and we can just have a chat a little bit about your experience with recombinant BCG.

And I don't know what the next slide would be? So Dr. Pieczonka, first of all, thank you for joining us.

If you don't mind, giving introduction to yourself and your background.

That's a much younger version myself up here. But apart from that, so by way of introduction, we've had an opportunity to work in the bladder cancer space in clinical research for the last 10 years or so. My company is part of a larger private equity-based platform called U.S. Urology Partners that recently had an investment from a company called General Atlantic. And they have really done an Yeoman's job of supporting our research endeavors within our organization.

And to that end, I am the Chief Executive Officer of our practice in Syracuse, New York but serve as the Corporate Research Director for all of U.S. Urology Partners. And that's how I became introduced to Dr. Soon-Shiong and Dr. Reddy probably 12 or 18 months ago. We were not part of the original clinical studies that were presented on the TV, but are actively engaged in participating in the ongoing clinical studies now and including having one of our sites, the first place to actually use the recombinant BCG.

Thank you very much. So what I'd like to do is combine this discussion with commercial launch discussion. So if I could put up the next slide and invite Richard Adcock, the CEO; and Matt Hilman and then I'll moderate from here, and then we can have a -- please have a seat, Matt, and we'll moderate the commercial launch discussion and get into that. Maybe a few slides first about where we are on the commercial launch?

[indiscernible] surgeon spoke to me. I think there's a possibility to [indiscernible] I don't know how to react. My wife was sitting. The biopsies came back nonmuscle invasive [indiscernible].

[Presentation]

All negative results. Now there was no complete remission again. I learned that the N-803 combination with BCG therapy was given a boost to the NK and T cells, which are cancer fighting cells and that was eliminating the growth of the tumor cells. My friends say, how far do you run? I can do 6 miles, 7 miles. You're 70 years old, you shouldn't be able to do that. I said I will do this until I can't do it anymore. I'm not going to stop. Everything [indiscernible] until we see the cytology, then that's the single cell that may have escaped, we can't see that's negative, then you can go part be happy. So I'm looking forward to look at yesterday's results. No cancer cells in the...

So the wonderful news is that he's now 9 years. So maybe, Rich, you want to then take on this discussion of the commercial launch.

Certainly. First of all, I just want to thank everybody for being here and for those that are online listening as well. I think if you look at ANKTIVA and there's 1 message you get, it's duration matters. And this slide here really talks about it and while this was not a head-to-head study, it tells you the results of A versus B versus C. And no one -- and Dr. Soon-Shiong has talked about this as to the why, and it was the original design. And you heard from physicians that online, that duration of 47 months and as he announced in the prior one we had previously announced at the end of 100, we're at 54 months of ongoing duration is what really sets ANKTIVA apart, not in just bladder cancer, but across all cancer types.

Next slide. As we started with ANKTIVA and this 1 and many of you have seen this before, I think what matters most in this one is that we've progressively and I was just having this conversation with somebody at the back of the room, been checking off check boxes one at a time. We got it approved. We got it launched and we had our initial sales going, and that was good. It was really the J code that was needed, and you saw with today's announcement, the rapid increase in sales happened.

And it was really the physicians that needed this the J-Code that allowed them to have that confidence of permanent billing. And that allowed them to see that. And so we saw 129% revenue, 150% increase quarter-over-quarter of our sales on those. And so now Q1, we really started to see these, but we're also incredibly excited about the submission and the work that we're doing with Europe. We're the first to our knowledge and only that have submitted to Europe for that one for both U.K. as well as EMA, and we're in the process of that review right now.

Next slide. One of the things that I always try to identify for folks and for those of you that know my background, well, I'm not a physician, I worked in helping to enable physicians in my entire career work in building very large practices of those. And I had a group of doctors that I was presenting to and they said, you kind of almost Amazon the drug delivery to us because we order it and you ship it direct to us in 1 day. There's no middlemen that we have to go through, we can order through our normal distribution but everything comes directly from you. And we have 36 months of shelf life. It's a normal refrigerated product. So you take it out of refrigerator. For some reason, the patient shows up with a fever or UTI, you just put it back in the refrigerator as opposed to another product that you actually may not be able to do that with. And so it's very different. But in Dr. Pieczonka, I'd ask you to talk about this as well, maybe there's no change in the BCG workflow. Maybe you wouldn't mind talking about what does that mean to you guys in your practice?

That's a big deal. The reality is in our practice, we struggle with keeping our staff employed just like any other different industry within the country. And in particular, the nursing staff and the medical system staff, fairly high turnover staff. And so keeping things as simple as possible is very important. We've had the opportunity of participating with several of your competitors' clinical studies. And suffice to say is the usage of ANKTIVA and BCG is easy. And the usage of some of the other medicines are not easy, just relative to procedures, physician time, and the freezer thing is actually a real issue. So where I practice, we have a catchment of patients that may drive from 3 to 4 hours away and taking something out of the freezer and then having the patient not show up because of weather, literally or some other thing is a real problem for us logistically.

And as a business, we can't be on the wrong end of wasting any medicine. So the practical aspect of this independent of the science and the benefit makes it a lot easier for us to operationalize in our clinic. And we've been able to successfully do that. Once the J-code thing was an important thing at the beginning of the year. And since that's happened, that's been a pretty easy thing for us to operationalize.

I was -- Dr. Reddy and I were with a large group of physicians, and they were smart because they actually brought the BCG nurses with them. And as we were talking and Dr. Reddy was explaining, here's how it works and pretty soon, one of the BCG nurses she raised her hand, she said, "So you mean exactly what I do today, I do tomorrow with ANKTIVA except I just add mix it." And Dr. Reddy said, that's exactly right. She goes Okay. I love that. I think there's another component on here that we need to look at. So as easy as it is for the staff, it's easier for the patient.

So an ANKTIVA patient can come in, and I've personally given ANKTIVA and BCG to patients, it takes exactly 90 seconds. And the patient comes in, they check in and then they leave. And some of the other things that are on the horizon are not bad at all, hours of patient time. And then independent of that particular product. There are other products that require instrumentation by the urologist. And part of the problem on that is the logistics for the patient in terms of cost. So one of the dirty realities of just the way that the Medicare system is Medicare is now making it near impossible for urologists to be able to do cystoscopies in office setting.

So there's a continued push to decrease the reimbursement and in Medicare's infinite wisdom, that's going to shunt patients to surgical centers. And surgical centers are much higher cost for the patient. So with some of the other medicines that are going to potentially coming out, the cost toxicity for the patient is going to go way up relative to the procedural aspect of it. So I think there's a social thing for the patient time and there's a real concern about additional cost toxicity for some of the other things that are going to require procedures as they go in and out of the patients for are readthrough.

Thank you. Dr. Pieczonka, could I just ask you, I think I hear about the cost and I hear about the logistics and I hear about the ease. But really what concerns me as a physician and a scientist is the toxicity. And while we don't really want to compare ourselves to any competitors, what Big Pharma seems to be wanting to do is go back to chemotherapy. And there is now a molecule that is put into a little pretzel device that actually releases this chemotherapy. You will hear through the course of today that chemotherapy kills these natural killer cells. Chemotherapy kill the T cells, which doesn't make actually rational scientific sense.

Could I ask you your experience of or your knowledge of this, not yet approved. I get that is in clinical trials, but they'll have massive marketing power of trying to induce patients to receive chemotherapy rather than this natural product. Could you share with us some of your experience with regard to that?

I think that this is a real concern for patient care because part of it is how does the patient's bladder feel. So anecdotally, I can tell you in a handful -- a couple of handfuls of patients that we have that the tolerability of ANKTIVA plus BCG and a lot of patients report that it's better than BCG alone. So that's one aspect. That's not quite what you asked. The thing that I think that you're getting at is are we making these patients bladders effectively crippled the bladders that the bladder simply can't work, store urine, be able to have an opportunity to go to a movie, go watch whatever the new Disney movie is coming out and not have to go to the bathroom midway through it.

And the sheer fact of chemotherapy effectively being somewhat indiscriminate in terms of how it destroys both cancer cells as well as the collateral damage to the bladder is a real concern. And so I think what's going to be really interesting to look long-term as some of these chemotherapeutic options actually potentially become to market is what the side effect profile and that's going to be and the tolerability for the patient on a minute-to-minute day-to-day basis.

I think the other thing that's important on that is the durability that we have with some of the data that you're showing is really intriguing. We don't have that near in any of the other studies that are out there. And I get concerned about long-term what the quality of life will be for the bladder for patients who may be successfully responding to chemotherapy, but what's the downstream implications for that in year 2 or year 3 or even year 4.

Well, we've spoken like a real urologist. I look at the patient, he looks at the bladder. And what's a wonderful -- it's the first time I heard from a healthy bladder to crippled bladder to remove bladder. And if you look at it that way in a realistic sense, what we drive to give is a healthy bladder and you just see these patients' quality of life where you can run for 6 miles, it makes me jealous to a crippled bladder when you get chemotherapy to remove bladder when you have long -- no duration.

So -- and you put that in the context of a whole human being, when we get to pancreatic cancer, lung cancer, breast cancer, triple-negative cancer, you also see the same effect. So what we're actually seeing is truly this paradigm change of how we really need to think and our struggle is going to be to actually educate both scientists, and thank you for being here as a doctor who is not involved in the trials, but now seeing experience in the real world with your patients. That it's intriguing.

We are now hearing reports after reports that when you give ANKTIVA plus BCG, it's better than BCG alone because we know that this modulating effect of your immune system. And as you have this BCG and gets inflamed, that you have a modulating effect of the NK cells is a very exciting phenomenon which we will continue to study. I think the other exciting phenomenon is that this BCG you were still using with TICE BCG, you've now used the first recombinant BCG, if you may want to speak to that.

I think that I always get concerned with -- well, first of all, on the BCG shortage front, we have offices in 5 different states, and one of our states actually cannot get BCG. And as a consequence for that, we have something that we call BCG Tracker and our physicians in that office have to review and literally rationing care because there's not BCG available. So -- and that's just a horrible thing to be told as a patient you simply can't get medicine even though the doctor wants to give it to you.

So that's one aspect for it. The second aspect is, I always worry about the variability that you get with -- I didn't know actually BCG was made in potatoes until you said that earlier. I mean, when I look at potatoes, I think that there are nice-looking potatoes and ugly-looking potatoes. So my concern would be is their variability with the BCG based on how cute the potato looks compared to the ugly potato. So the recombinant aspect takes that completely out of the equation and makes that very serene and calm in terms of the BCG effect, I believe in terms of the dosing and what you expect to get out of the BCG should be consistent based on it being made in a very controlled setting, where there's quality control rather than coming from a potato.

Yes, more than the potato, it's actually made in potatoes and then in roller bottles, quite literally roller bottles that has a roll long way. But anyway, I think that really speaks really not owing to the science with the quality of life. And this is what's really important to us as ImmunityBio, I understand that investors look at revenue, and I think revenue is going to be important. But the purpose of our revenue and our growth is not to spend from the sake of spending.

And then some of you had the ability to do a tour this morning with Rich Adcock, and really see the enormous amount of investment we've made in capacity building because really, I often say that when companies fail because they plan for failure. They really fail because they don't plan for success, meaning that once you actually have this breakthrough and the knowledge of the breakthrough, I think it would be immoral not to have patients who really deserve it to have access. So we have invested for success, and some of you have seen not only the clinic but also the manufacturing facilities.

But with that, I'll ask Rich then go to the next slide to speak to what's happened since the J-code.

Yes. And maybe actually, I'll turn this 1 over to Matt first. If you want to talk about what's really happening. Matt Hilman, heads up our entire commercial operation.

So you can clearly see that where we received our J-code was the true catalyst for us. But there are a couple of other things that were kind of that we speak to. I think we had a core structure and recognizing that the sales team we brought in-house had a strategy with Rich. And we decided to bring everybody into that first, we started with a contract sales organization recognized senior leadership decided to invest and bring everybody in-house and that allowed us to bring in at different kind of talent.

So that continued sales momentum. You can clearly see January the receipt of the J-code when that kind [indiscernible] of the chart was completely up. But I will tell you the most important thing, when we train these new representatives, a lot of people have had the ability to speak to a complete response that Dr. Soon-Shiong and Rich spoke to -- the complete response is super important, but we've never had that ability to tell someone when you tell someone in complete response, they'll be there for up to 4 years. Plus remember, we haven't hit our duration yet based on academia that is what resonates the most, and that's why duration matters.

It's messages like that, that will allow [indiscernible] cystectomy that you see on the chart, because nothing else can do that. That's something we're really proud of. That's what the sales force really proud of.

The other 1 I would add in here, this sales growth is using all types. So none of this was with the recombinant BCG. And while we're not selling the recombinant BCG, we're now able to deliver that. As Patrick said, we've had our first centers and first patients, we actually have almost 90 centers that are in process of being signed up, and there's many, many more that are going through those. It's a pretty light process to get going on those, but it takes just a minute to work through that process. I think that's what I'm most hopeful for in Q2, but really Q3 and Q4 is that now there are no encumbrances.

The J code is fully in place, BCG, we effectively have an unlimited supply of. And so it gives us the ability to truly meet patients where they are. Doctors don't have to rationalize care. They don't have to make a trade-off to say this one gets it and this one doesn't get it or this one gets a partial dose. And this one will be able deliver it for everybody. The other one I would add to that is it's not just the BCG, but the diluent. If you remember, in October of this last year in 2024, there was a hurricane that hit, took the largest sterile saline plant offline for the United States. So now not only in October and November and December was there a BCG shortage.

Now there was a saline shortage. And one of the things and Dr. Soon-Shiong has always emphasized this, we have to control every element of the supply chain. If we don't do that, then we're incumbent upon somebody else. So as we sit here today, we have the ability to produce immense number of ANKTIVA. We have more that is available than all of sales across all of ours that are needed. We have the BCG, but we also have the diluent and that's our very strong feeling, couple that with the J code, and you see this chart that's headed straight up.

We believe it's going to continue that way.

Well, thank you for that. And I think the supply chain, look, I learned my lesson and some of you may know or not know, that I ran a company called American Pharmaceutical Partners in 2001 for about 10 years. In 2008, there were 87 deaths in the United States from heparin, the show came on in Nightline, and we were the only company in the United States that control the supply chain of safe heparin. Heparin comes from the intestine of pigs. And we're able to actually monitor and make sure that the -- we had [indiscernible] from the pigs to the intestines to the heparin in our hands, and that's what really changed the ability for patients to have heparin, otherwise, literally 100,000 patients a day require heparin in the United States.

So that was a lessons learned that we said it would not happen here. And the massive amount of investment that ImmunityBio has made is to ensure that we have access to the entire supply chain. And when we knew that Merck had this issue with regard to BCG shortage, not only did we want to control that supply chain, we wanted to make sure that patients would have access to this therapy that would give them this long duration.

So with that, I want to thank this -- okay, well, amazingly, I'm literally by the minute on time, which really gives us time now to talk about this. I really want to introduce this concept which is crazy that I have to introduce called lymphopenia. And what lymphopenia means is that you lose your NK cells and T cells, the very cells that is necessary to kill cancer. So again, I went to the FDA in January and presented the concept.

Look, we have a therapy that could change the course of cancer forever. So a test I do and one of our thought leaders, I'll -- I did this test on, if you do -- you speak to your oncologists today, they will say, when you do a CBC, which is a complete blood count, you measure for anemia. And because we know that when you get chemotherapy, you get anemic because we have a drug called Epogen that's made by Amgen, and we give that.

But red blood cells don't kill cancer cells, but we have a treatment for that. Then the next thing you measure is platelets because platelets drop when you give chemotherapy, but we have a treatment for that because we can give you a platelet transfusion. The next thing we measure is called neutrophils, and that's called ANC and neutrophils prevent infection. So we have a treatment for that because we call NEUPOGEN former Amgen.

So you asked 90% of the oncologists, do you measure a thing called absolute lymphocyte count or ALC? And they would say, no, what's that? Well, that happens to be the only cells in that CBC that actually kills cancer, i.e., the natural killer cells and the T cell. That has been staring us in the face for 15 years. I would challenge you to go to PubMed or Google and hit the word lymphopenia and overall survival in all cancers. And it makes rational sense. If you have no NK cells and no T cells in your body, you have a reduced overall survival.

So that's what I want to introduce today. And in January, I had the privilege to be able to be invited to the FDA to meet with the leadership there. And we had a 2-hour session, no minutes, just presenting the signs of how we could change the course of cancer by giving patients the ability to overcome lymphopenia and prolong overall survival. So today is the opportunity for me to present the data before the fireside chat. And I think I'm going to present the data and speak to this lymphopenia reversal or treatment. But before I do that, let me show you what we're activating. You will see soon, I'll put up a video soon, of a video that we put together maybe 10 years ago, think about that, in which we had a breast cancer cell that we could light up as a green cell. And then we would have our natural killer cell and our T cells kill this breast cancer cell and we'd watch it die and it would go blue.

We showed this video around and it was -- it's sort of a nice video, except that was the paradigm change that we've been pursuing. So if I may show that video. So what you're seeing are the red cells and look at the blue cells happening dying, and the green cells of the breast cancer cells. And the attack is enormous. These are your lymphocytes. This is what a chemotherapy kill. Imagine that. You give chemotherapy, you destroy those exact cells that are fighting so hard. You give radiation, you destroy those cells that are fighting so hard. You give steroids when you give docetaxel and with chemotherapy you destroy those cells that are fighting so hard. Give checkpoint inhibitors, you actually destroy those cells that are fighting so hard.

That's what makes no rational sense. And for me as a surgeon from UCLA, I want to create cancer into a surgical disease so I can capture it as early as possible so you don't actually destroy these cells, we now call thank you for Tucker Carlson who says, don't call it a vaccine, we call it the cancer BioShield, which it really is. It is your BioShield. Every one of you in your -- sitting here today have a cell that's about to transform because you're having stem cells that's growing every one of you, and every one of you have these cells in your body that's killing those transform cells that you don't have cancer. You are in equilibrium because of these cells that's happening now called lymphocytes.

So the fact that I have to now introduce this concept of lymphopenia and it is independent of tumor type and the ability to create this BioShield is the next slide. There's what I call this missing link. So I now really have to go on an educational campaign, but it's really been staring us in the face that after many, many years of spending literally millions, maybe tens of millions, actually hundreds of millions of dollars on genome sequencing and of the largest genome sequencing lab and having a genome test to look at your mutations that cost thousands of dollars, we are reduced to a $20 test called a CBC. If I show you the next slide, all of you have this test called CBC.

And the single blood test on the one hand, measures your anemia, which a doctor gives you Epogen, measures the thing called ANC, absolute neutrophil count. So everybody understands ANC that gives you neutropenia. But if you ask 99% and some of you should go away and ask your oncologist, do you measure or look at the same test that gives you the thing called ALC or absolute lymphocyte count. And if it's less than 1,000 lymphocytes per microliter, it's called lymphopenia. And if it's between 1,000 to 4,000, you have normal lymphocytes. In most cases, and this is not a disparagement to the doctors, by the way.

The reason they largely ignore it is because there was no treatment. And that is why they largely ignored this because there was no treatment available to overcome lymphopenia. But there was treatment called Epogen and Neupogen, next slide. And then there was this missing link. So I want to show you now the fact that I actually monitor and make sure that this missing link has now been fold. I call this a missing link, and I said to Tucker Carlson a little bit is like finding the lost arc. These are the only cells in our body that kill cancer. We can now measure that.

If you go into the literature, as I said, and type in lymphopenia or type in absolute lymphocyte count or type in a thing called neutrophil lymphocyte ratio, you will begin to see that no matter what cancer you pick up, is that in the presence of lymphopenia, you have a reduced overall survival, and it makes rational sense. So this missing link, next slide, is the ability for us to really understand what we're doing with our standard of care. And this is why you will hear some support leaders today, and I won't name him until I bring him up, who I called and said, you do radiation. And would you mind looking at your patients, please do identify them for the next first 20 patients that you've done radiation on and look at the ALC and the question is what is ALC? No, the lymphocyte count, not the neutrophil count.

And you'll see that discussion when we get to the fireside chat when we talk about not only radiation, but chemotherapy steroids. This is a difficult conversation actually because what it actually implies inadvertently, and I must say it's inadvertent. There's no bad -- I believe 99.999% of doctors want to do the best thing for their patients. And it's this educational need not only to the medical community, the thought leaders, the Sloan Kettering, MD Anderson, the UCLAs, the Cedars-Sinai and Johns Hopkins of the world to say, wait a minute, should we really rethink if we kill the NK cells and T cells and we get a lower median overall survival, which is logical, should we be doing something differently? Is that why we've not won the war in cancer? Is it because we win the battle but lose the war?

Well, what's crazy is this information of lymphopenia has been in the literature for 10 years, 12 years, 15 years, 20 years. And now I'll show you a few papers are just select papers. Next slide. Guess what? Lymphocytes is a new organ at risk, can you imagine? It's not a new organ at risk. It is the only cells in our body that protect us from cancer. And we've put it at risk. So that, again, is a very, very difficult conversation because we'll be curious of all kinds of stuff, nonscience, hype, whatever. But this is a science, not from me, but from papers, I'll begin to show you, and we couldn't stop finding these papers when we did the search. 10s, 20s, 30s, 40s, 50s of these papers from different parts of the world.

Next slide. And then they even have Kaplan-Meier plots in these papers. And that is exactly how it is in this paper, meaning not lymphopenic and lymphopenic, and the red line shows the overall survival reduced statistically. Next slide. And this is even with checkpoint inhibitors. It's remarkable that this has been the biggest breakthrough and rightly so that T cells and checkpoint inhibitors that's generated billions and billions of revenue for pharma companies that followed each other, whether it be Merck, Bristol-Myers, AstraZeneca, Roche, they all follow each other because it was a large revenue generator, except this is what you're getting.

And in 2017, I presented myself to the FDA and says, listen, there's no question in my mind that checkpoint inhibitors are good, but they're going to fail because we're actually inducing what we call, you heard from the doctors on the video that the T cells pull in the receptors. But think about that. If you have no T cells, the checkpoints are supposed to accelerate T cells. But you have no T cells, I'm not sure what you're accelerating.

And then we spend billions of dollars in patients where we take a checkpoint and you combine another checkpoint on top of the checkpoint to see if it actually work and they all failed, TIGIT, et cetera. So the idea of following rational science is so difficult that we just had to pursue this on our own. And that's why if you ask why the Cancer Moonshot didn't progress, none of the Big Pharmas really wanted to participate, and we'll get into that to some other time.

Next slide. But this was the most telling slide. On the right-hand side are the references in the blue of all different papers. On the left-hand side, let's look at them every cancer you can think of. If you look on the middle side of lymphopenia, look at them, all lymphopenic. And if you look at the statistics and overall survival, they all decreased. [indiscernible] is paper 2019. So what we're revealing today is not some revelation.

It's been staring us in the face. And the way they now present this is a prognostic factor back then that if you have lymphopenia, we know you're going to have a lower survival. But this was really prescient, and I don't know these authors. This is for combination with cytokines. It turns out that every lymphocyte has a receptor on it called IL-15, and that's what ANKTIVA does. It actually binds to that receptor, next slide, and kills it -- and proliferates it.

And here is the lung cancer and we'll speak to lung cancer today because we took patients who failed this, failed the checkpoints, progressed on the checkpoint. We gave them nothing more plus the same checkpoint plus ANKTIVA, and you'll see the overall survival because we reversed lymphopenia.

And this became sort of incredulous both to a large group called SWOG, again, thought leaders, the biggest thought leaders of lung cancer, who, again, it's not pejorative, didn't understand the science that what we're trying to drive is prolonged overall survival. And think about that, you have a patient on a checkpoint inhibitor who have had chemotherapy radiation, second line, third line, fourth line, for which there's no treatment left. These patients die sadly within 7 months. That's the duration. They get docetaxel as the standard of care afterwards, which is very toxic. It turns out that docetaxel has to be given with steroids. So both docetaxel and steroids wipe out your lymphocytes.

So now you have a checkpoint failure. Now you think about this in a logical way, and I'll walk it through in a logical way. And I tried at multiple meetings to explain it, but it didn't sound scientifically reasonable that if you're going to give a patient a checkpoint, trying to accelerate the T cells and it works and then it fails.

And the reason it fails because there's no more T cells. And so giving back another -- that same checkpoint shouldn't work. And the truth it shouldn't unless you reactivate those T cells, and that's well the treatment of lymphopenia. That's the BioShield. And our treatment plan was to combine that checkpoint. And by the way, you will hear today from BeiGene representative because we're agnostic to the checkpoint, any checkpoint because it's a biological activation of that T cell.

But if you proliferate your NK cells and T cells with this IL-15 stimulant or superagonist or the BioShield, whatever you want to call it, you now have the reactivation of these checkpoints and you prolong the survival. I will show you data for the first time today. I will show you data for that, not only for lung cancer, I will show you the data for that for pancreatic cancer. I'll show you data for that in -- let me see what I've got on this list, for all tumor types actually.

We've never shown this data. I'm in the process of putting it together as a paper. I hope it doesn't jeopardize the paper. But I think it's important for this to be exposed now. So with that, if I can show the next slide. I really want us to now go into this BioShield and talk about why lymphocytes matter. And this is the first introduction and all you see have the little buttons of the cancer BioShield, why NK and T cells matter, and you will hear from some thought leaders coming here today to talk about NK and iNKT cells.

Why duration matters, as you just heard, in our bladder cancer patients and more importantly, in our lung cancer patients, pancreatic cancer patients, why survival matters, but most importantly, why quality of life matters because all of this therapy is given as an outpatient. And some of you who visited the clinic this morning know or seen, it's all given as an outpatient. That's a remarkable basis of this and why all of this matters in this cancer BioShield.

I think we're on track still for me to go through this now for the next 30 minutes, okay? So let's go to the next slide. And this is the missing link. I apologize for getting technical. I can't help myself, but I have to. On the left-hand side, you will see that on the top of that, every cell that is a lymphocyte, whether it be NK cells, CD4, CD8 and T cell has a receptor called the IL-15 receptor.

That's the key. That receptor is what has been waiting for some molecule to come into your body and activate that receptor, and this is called the IL-15 superagonist down below. This IL-15 is in your body. It's not an unnatural product, but it only lasts for 2 minutes. And it does that because that's how your body works. It needs to give you balance. And that's why -- that's what alluded the scientists, even the NIH for 15 years.

They could not create a system where not only it could last for more than 15 minutes or 2 minutes, but it could bind with great strength to that receptor called the beta receptor and proliferate on the right-hand side, the natural killer cells, the T cells and with the adenovirus to all by itself generate the dendritic cells and the memory T cells.

So this is what we call a new class of immunotherapy called the lymphocyte-stimulating agent. So for the first time, we are now nominating this as a new class of immunotherapy called LSA. So this lymphocyte stimulating agent is what we've put in front of the FDA as we speak. We have shared with the FDA in January the importance of this. That molecule's already approved. And we've received thousands, literally thousands -- the most painful thing about the Tucker Carlson interview is the pain and the suffering that's out there, and we received literally thousands of requests for what they call the BioShield, and we can't do that because we needed to get what we call emergency or expedited or expanded access.

So we filed that with the FDA as we've just announced for the first time today. I'm awaiting a response. I'm not sure what the response would be, but I'm hopeful it is, next slide, the opportunity for them to understand that for the first time, and it's more than 50 years, radiation was done 100 years that, next slide, a link is available for patients. So this drug is now approved for bladder cancer. And we chose bladder cancer early on because it was what you call non-muscle invasive as early as you can, even though it had failed BCG.

But now the goal in my mind is to find patients or to treat patients the moment they're diagnosed, whether you have pancreatic cancer, brain cancer, lung cancer, the moment they're diagnosed and be able to actually institute, what I call, the neoadjuvant therapy. But there are patients sadly that have gone through the ravages of every treatment today, and they can still be rescued.

And that's what I'm going to show you now the next slide. So the first thing I needed to do was to actually prove to ourselves that the ANKTIVA actually stimulates NK cells and T cells in normal human beings. So in 2022, this trial was done in healthy volunteers. And again, I don't -- I'm not going to go too technical, but it's published now. Next slide. And here it is. On the top right in column A is the absolute lymphocyte count with 2 different doses, and you begin to sort of see it actually able to actually stimulate and maintain.

On the -- in C, you will see the NK cells, CD4, CD8 T cells. And in F, you'll see how it peaks at Day 7. And then in D, you'll see how at the end of the treatment, it's maintained. So the exciting thing is not only can we stimulate it, proliferate it and maintain it, but it's also safe because it doesn't go beyond what your normal levels are. You don't get what we call lymphocytosis. I know this sounds a little crazy, but it's not. But this could even be involved with aging, what we call senescence.

When you age, these NK cells and T cells all deteriorate. So there is a possibility, and I say that is a possibility because you've not done this trial that this has an effect on aging. Why I'm so excited about this in healthy volunteers is because we have been chosen to be the first trial using this molecule in patients without cancer called Lynch syndrome, and you'll hear about that in the fireside chat, where you will see that patients who have Lynch syndrome, which is 1 in 280 Americans have this thing called Lynch syndrome, a genetic disposition to cancer and an 80% increased risk of colon cancer, breast cancer and lung cancer.

And we've now recruited this nationally across the country like wildfire in which these patients are getting a shot of this ANKTIVA, this BioShield plus an adenovirus to generate the memory and T cells, which you'll hear today from some of our keynote speakers. So the proof that it actually works in healthy volunteers, next slide, was emphasized by this very detailed analysis, what they call the flow cytometry on the right-hand side, where all the cells proliferate.

Next slide. And as I said, at the end of the cycle, it maintained. What was really disturbing, I listened to a talk at the European Urology Association given by either the thought leader or competitor, who said there was no clinical evidence of ANKTIVA actually proliferating NK and T cells. And I don't know how to react to that when you actually have this all published. And this is what I worry about.

As I said, competition is fantastic. Competition is good, but misinformation is bad, especially for patients. So this is the data that is out here, and this, again, I will be presenting the AUA to correct some of these statements that actually pervades for whatever purpose. So next slide. And so this is the missing link that would then take us if you can go to the next slide to what I want to now show is that this -- I now call this a lymphocyte-stimulating agent or the BioShield or LSA.

It not only treats lymphopenia, but it prolongs overall survival across all tumor types. Nobody has seen this data. We submitted this data to the FDA. We submitted the data as part of the expanded access request, and we will be submitting this data as part of a -- whether it be a supplemental BLA or RMAT discussion. We got the RMAT authorization, which is very rare, which is regenerative medicine advanced therapy. And this is the work of this "trials" was this Quantum Oncotherapeutics of this discussion I had across second-line non-small lung cancer patients that failed everything.

In these patients, the only chance today would be docetaxel or something else and some other molecule. And then third-line patients and fourth-line patients for which there's no treatment. And the overall survival and every time you do a docetaxel, there's hundreds of docetaxel patients that receive docetaxel in tons of clinical trials where it's been approved, I think, 20 years, 40 years ago, in which the median overall survival is 7 months.

We'll show you data of how we change that when we rescue lymphopenia. And then we have renal cell carcinoma, hepatic cell carcinoma and some of the thought leaders here speaking to some of that, colon cancer, breast cancer, et cetera, what I call multiple tumor types, I call that tumor agnostic. And that makes biological sense because this natural killer cell was not a surgeon and didn't get surgical training, so it doesn't know whether it's a breast cancer or lung cancer. It actually works wherever you have cancer.

And then finally, a cancer that I spent my life trying to overcome, i.e. metastatic pancreatic cancer. And if we can get that cancer early on before it has a tumor burden, we think we can change the course even of pancreatic cancer. So let me now show you this data. I'm going to show you very snapshots of it. I'm not able to show you the full wholly approved glory of it because otherwise, I won't be able to get this paper published. I'm in the process of drafting it. But here it is.

In these patients, where on the left-hand side, you see the docetaxel median overall survival. I understand that's a historical data, but it's not changed 5 to 7 months. When we're able to reverse lymphopenia in some patients beyond severe, we get 11 months. But really, when we're really able to get them into this 1,500 range, which is closer to your normal, what I call mild lymphopenia, we get 21 months. And the probability of these patients living 5 years is 20%, for which there's no other treatment.

And these patients, all they received was a checkpoint plus ANKTIVA. This speaks to this BioShield. And I hope the -- both academia, NCCN, the regulatory bodies, the FDA recognize why this is a paradigm change. There's no chemotherapy in these patients. Next slide. When we did the same -- in the same trial, which is called a basket trial, we had 147 patients, including these lung cancer patients. So it's not a small trial, 21 months, regardless of tumor type.

These patients in order to be eligible for the trial must have failed everything. Imagine if we got them before, they failed everything. So this is what I mean about why this is so exciting because it is tumor agnostic. Next slide. And then finally, we were only allowed to do these in pancreatic cancer patients at a third line, fourth line, fifth line, sixth line, think about that, that literally would have weeks left.

So when we actually be able to capture even these patients at fifth, sixth line, not only do we give them -- not weeks, we gave them months, 6.6 months. And for those who understand the tumor burden, think of CA19-9, the normal level is about 30, in our lab, 40. The median, not even the range in these patients was 3,000, huge tumor burden. And yet with that huge tumor burden, we were able to get this.

Next slide. So on that basis, we went to the FDA and it's still sitting there, and we'll see where that goes. To ask for this RMAT, which we got granted, but we now wanted to get also the request for emergency use while we're getting this RMAT designation BLA filed because that has to go through the process rightly so. But if we -- I don't know how our single unit can manage 2,500 patients just in the last few weeks requests. We need to make this available to the entire country where every doctor could actually give the shot if needed before they get radiation, before they get chemotherapy, before they get steroids, before they get docetaxel, before whatever the standard of care. That's the EU designation that we put through. So on that basis, if you show me the next slide, I'm not sure where we are now. Before we go to the fireside chat, which I think we're going to take a little break of lunch, but we are quite literally half an hour early, right. So I'm happy to take questions, and then we can take a break and then we can continue with the fireside chats with all the rest.

There you are. I tell a lot of people, you've got to read the instruction book. The first thing is you've got to plug it in. Second thing you have to do is turn it on. So first of all what we're going to do. I want to really, again, thank these are really amazing key opinion leaders. They would want to participate in this. So I'll be bringing them up and having a chat where we will speak to the science. But really talk about, in my mind, I really wanted outside scientists who are really steamed in their work to speak about the science that affect all of us today.

And it really is important because the subjects will be covering things like what happens when we get our standard of care. How do we know what happens to our immune system, things like what happens if you have a genetic disease, which affects 1 in 280 Americans, things like what happens when you get COVID, things like why do we have long COVID. And most concerning, and I wanted to do that today, because last year, I was invited to Washington by the Hinge Jackson Foundation to speak to the CEO thinking that I'd have a meeting with just a CEO and in a room, bigger than this, maybe twice the size of this, it puts me up on the stage, and there's about 20 people in the room, the head of NIAD, the Walter Reed Institute, all the thought leaders, I had no slides and the time frame was unlimited.

So we spoke about 2 hours, 3 hours maybe, and I decided it was time and I shared my concern. And my concern was, is this virus or was this virus, something we never anticipated. And could it act like HPV. Some of you may know about HPV, is it oncogenic. And when I brought that up, the first response by one of the members in the audience, that's impossible. At the end of 3.5 hours, he said, this is so important, you have to publish it. And we have the science and information and I was fearful of publishing it because I don't want to create panic in the country.

However, we now have a glimmer of an opportunity to treat it, to face it. And because we have an opportunity to treat it, you needed to first understand how and why it occurs. And that's why we're going to have some of these KOLs speaking today about long COVID. And the -- what I call the oncogenic potential of it, is not to scare us but as a nation and as a humanity, we have to be prepared. And the thing about countermeasures and how to prepare ourselves against radiation exposure not from a nuclear war, but radiation exposure that we're getting as treatment, how to prepare ourselves against long COVID. And how do we prepare ourselves for 5 to 10 years from now to address why we're seeing cancers in younger people. Today, I have a call of a 21-year-old that had a recurrence, as I shared with -- on the interview 8-year-old, 10-year-old with colon cancer. How is that possible, a 13-year-old metastatic pancreatic cancer, how is that possible?

So we can't put our head in the sand and I've taken this opportunity to have these key opinion leaders come and share not only the experience, but the unvarnished opinion based on science so that not only we could be exposed, but you could ask them and feel free to ask them any questions you want. There's as I said, microphones on either side and maybe you want to put microphone in the center so that the audience and online audience can really interrogate this in a very transparent way. I think one of the important opportunities now for us as scientists and as biotech and pharma is to be as transparent as possible about the knowledge we learn in real time so that you can really adapt to it, accept it or not. I got in big trouble with the early times when I said I want to create a bias meter, but we have that. It's not a bias meter, it made us perspective of your opinion. But I don't think science is about opinion. I think science is about data. And if you have data that is validated then you really need to accept it.

So this data, we talked about the lymphopenia was staring us in the face for 30 years. It was in literature for 25 years, but nobody did anything about it. So with that, if I could look at my list of fireside chatters, I think it was Dr. Steven Finkelstein. So Phil, if you could put the slide on. And let's talk about the platform maybe first, if I may, the BioShield platform. So before I bring the -- next slide, please. This next slide, on the BioShield platform. Here we go. I think you've got -- there we go. Thank you.

So what you saw this morning is ANKTIVA. By ANKTIVA, we mean we either give it into the bladder or we give it subcutaneously. So it's literally as a jab or in infused through the catheter. And that's what we call the fusion protein. And it's what we call in vivo lymphocyte rescue by activating the NK & T cells. But we need to treat -- train your human body to have a T cell that is specific to the cancer or specific to COVID or specific to the protein that the tumor is putting out.

And that's what we have created, and you will hear from Beth this next-generation adenovirus that's been tested now extensively by the National Cancer Institute to be very safe, injected and, more importantly, teach your T cells, the memory they need so that you can have long-term memory. This is a T cell vaccine that I was talking about from COVID and we'll talk a little bit about that. And you will hear these words when you see a CEA, MUC1, Brachyury, PSA and HPV, these are all the proteins that the tumor expresses.

And if we teach a T cell, how to do that, how to go after that tumor and then activate it with ANKTIVA, you now have a combination of the fusion protein and the DNA vaccine as what we call in vivo stimulation, 1 jab, 2 jabs, that's it. That's the treatment. 2 subcutaneous injections.

But on the other hand, you have in your body NK cells. You have in your body T cells. So we can pull out of your body, these NK cells. But we have developed an off-the-shelf NK cell that we can target to the tumor. And here is a PD-L1, CD19 in K cell that is targeted, that is infusing 30 minutes as an outpatient. Now you have a what we call a CAR-NK cell, and that's already in clinical trials. And then the final one, where we can have these cells and now we're getting very technical, cell called an NK cell and cell called an iNKT cell that is both an NK cell and the T-cell. You all have that in your body. By the way, what's exciting about that, we can extract that from your body and give it to somebody else. There's no blood matching needed because it's universal. So the ability -- don't you got something on the slide there. Dr. Yang, I think.

So the idea is on the left is the in vivo and on the right is the ex-vivo. So with that, this fireside chat is going to try and go through these and explain to the audience what we call this cancer BioShield. It's more than a cancer BioShield, by the way. I believe it's also infectious disease BioShield. We are very much deep into clinical trials for HIV. In clinical transfer for HPV cancers. And we hope soon to be in clinical trials, we are beginning and one of the doctors are here for the treatment of long COVID.

So with that, I'm not sure what the next slide is for, if there is next slide. So with that, let me start the fireside chat and Dr. Steven Finkelstein and Alan Portella, if you could both come up and introduce yourselves.

Okay, yes. Please have a seat, Alan, good seeing you. Where is Dr. Finkelstein. So I'll sit out here, so you don't just strain your neck. So let me ask -- first if you don't mind introduce yourself, Dr. Finkelstein.

Hi, it's a pleasure. I'm Dr. Steven Eric Finkelstein. I'm the National Director of Radiation Oncology for U.S. Urology Partners and the Chair of British Oncology for AMP in Syracuse in New York. It's been an interesting journey. As I talk today about our fireside chat, I think for me, it's personally, how did I get in front of all these nice folks, and it's about Steve Rosenberg taught me, 3 patients, 3 patients who've got to sit here today and be with you and with you as we've talked before.

My background is, my grandmother had colon cancer, node-positive colon cancer when I was about 12 years old, and she was treated with surgery in high-dose chemotherapy. And she was cured of that, but the chemotherapy impaired her life to such a degree that she never lived the quality of life that she had before. And for me, it triggered -- it was a trigger for me to want to do something different. And that building a difference is pretty much what I think we'll talk about for the remainder of the hour about trying to help patients to get better therapies that were different than we were currently doing.

So I ended up becoming a surgeon because I knew that the chemotherapy was not what I really wanted to do for a living, I wanted to do, be a surgeon and find a better way to do surgery to solve the problem. I became -- I did my fellowship at the National Cancer Institute with Steve Rosenberg, who taught me about the immune system and all of the intricacies that I can know at that time.

And won the Presidential Award for that from what you guys now know as society for biologic therapy of cancer, SITC and then ultimately, I found in my lab as a surgeon and an immunotherapist that radiation was cool. That radiation can trigger immune responses against cancer. And I went back to school after 10 years of a career in surgery and immunotherapy to take national leadership roles in which I have several in the United States.

But it's been a pleasure to join U.S. Urology Partners in the last 6 months to be partnered with Chris Besanko, who you met earlier today, who is a dear friend, who -- as we're building new therapies for cancer to help patients to physically see new exciting therapies that occur.

Alan, do you want to just introduce yourself briefly and then we'll get into the discussion.

It's Alan, I'm a prostate cancer survivor. And I'm very honored to be here. I'm cancer free thanks to ANKTIVA. That's it.

[Operator Instructions]

I am Heath Cunningham. Before you submit the BLA for lymphopenia, will you have to do additional trials?

The trials were done.

So now?

So that's what I just showed you the results of those 3 trials. We did the trial in healthy volunteers, as you could see. We did a trial in first-line randomized control in first-line lung cancer, where we did ANKTIVA alone versus ANKTIVA plus checkpoints and looked at the results of that to show that we can [indiscernible]. We did this in third-line lung cancer. We did this in multiple tumor types. We did this in metastatic pancreatic cancer. So the trials have done, the results are -- we literally have to now put all this massive amount of data into the BLA. And we just completed what we call a briefing book and submitted to the FDA yesterday, actually -- no, actually tomorrow. Tomorrow, I think, is the date in which we have a physical meeting with the FDA in May. Any other questions right here?

My name is Dr. Gregory Howard. I was wondering if you had combined ANKTIVA with histotripsy or high-intensity focused ultrasound. And so for those of you that don't know high intensity focused ultrasound, it was just FDA approved last October. It breaks out the tumor and the fragments can be seen as [ foreign ] and about 20% of the patients, the cancer goes away and never comes back because the body will continue to see this [ foreign ]. And I did this 15 years ago on my dad, and he lived to age 90 after advanced lung cancer.

Well, not only thank you for that question. You have now basically enunciated what we've been trying to say. So this is how it works. If you took, for example, those patients with high intensive ultrasound, whether it be high intensity ultrasound or whether it be a small dose of radiation, what that does, it exposes the tumor to the body's natural killer cells and T cells. So the tumor has this amazing capability of hiding. And in order to expose it to the receptors of your body, you need to disrupt it slightly and that's what we call immunogenic cell death.

And by disrupting it slightly, you release a thing called damps. So now I'm getting very technical, but you need to -- you've asked a question, so that allows me the opportunity to give you some really technical which damps means damage associated molecular patterns. So when you give high intensity ultrasound or even a tiny dose of SBRT or even a tiny dose or even a chemo, I call these immunomodulators. So that exposes the tumor. And the moment you expose the tumor, that little slide that I showed you of all these cells coming in and say, "I found you, I'm going to kill you."

And because it disrupts the tumor, it also disrupts the antigens, then it becomes its own vaccine to create memory T cells. And now remember you, and that's why you have patients cell free of disease. It's not complicated. It's really the biology of the human process why all of you are in equilibrium without cancer because that's how the body works. We just needed to be enlightened enough to understand it and more importantly activate it.

So these preactivation molecules or immunomodulators that induce or expose the tumor could be anything. It could be a little bit SBRT. It could be a little bit of radiation, which we'll talk about. It could be literally a, what we call, metronomic low-dose touch of chemo, not to hurt the patient and hurt the immune system but to expose the tumor. It's a different way of thinking. And the answer is yes. All these opportunities now even in lung cancer, now where they have these nodules and patients now can be able to give directly towards the tumor the ability to stimulate and expose that tumor. So the answer is absolutely.

And that's why all these treatments that we've created has not gone to waste for the last 40 years. We just need to rethink how to use them. And then in -- with that concept, create this missing link of this BioShield to activate the cells that are already in your body. That's why I said I want to treat -- to convert cancer to a surgical disease or interventional radiological disease, meaning that you could use a tumor in your body as the vaccine so that you can kill it with your own cells, and it's tumor agnostic.

So when I say the word, we need to treat the host rather than the disease, it goes sort of over the head because you're not sure what you're talking about, what we're trying to do by treating the host is to activate the patient's tumor system, the immune system and use the tumor itself as the BioShield, the vaccine, whatever you want to call it and create memory. And then we get a complete response. We've seen this in bladder cancer. We're seeing this now, we should be able to see this in all cancers as long as we capture them early.

The sad news is our standards of care now sees this tumor once a sort of short-term satisfactory effect by giving high-dose chemotherapy, high-dose radiation, checkpoint inhibitors, you see tiny reduction, and then you see a response, you see a failure. If you think about it, our regulatory bodies, now again, I don't want to disparage the FDA. It's a dangerous thing for me to do. But our first opportunity was response rate. Now what's the response rate. The response rate is merely a short-term effect.

Then the next endpoint that the FDA gave us was progression-free survival, PFS, it's called. Now you think about that, it means that we are accepting at the regulatory body that you will have progression. So it doesn't make any sense to me. I said progression-free survival is not the right end point. And then there's another thing that FDA asked us to do in the Phase I is what we call maximum tolerated dose, MTD, what that means? Let's give you enough chemo that doesn't kill you, but it kills the tumor to get the response rate and progression-free survival. That's what we pursued for 50 years.

If I put that logic out to you and so that's craziness, and we keep on doing the same thing. And then President Nixon says, we're going to win the war against cancer, and you don't because you wiped out the very cells that kill cancer and you're surprised. Well, I'm not sure why you're surprised. So a long answer to your question of, should we use high-dose ultrasound, should we use SBRT, should we use low-dose chemotherapy, should you use anything, you'll soon see there's another molecule called -- it even get worse than that epigenetic modulation where the cancer hides through its genes, it actually prevents you itself from being exposed, but we can now outtrick that by exposing those genes and making them express the receptors, so we can see the T cells. And we'll hear that from a thought leader that you'll speak to today. So you gave me an opportunity to give you a long answer to a question. The next question?

We have online questions, so I'm going to pick 2 here. The first one is some providers believe the neutrophil lymphocyte ratio is more important. Can you explain why that could be misleading?

So thank you. We're getting questions from, obviously, the viewers listening into this. So here's another unexpected effect. You have in your body called neutrophils. And we have a drug called GM-CSF that is given to upregulate these neutrophils. What we haven't realized is that because is the cat alive, is the cat dead, it has a dynamic effect. These neutrophils could be killers, and immediately, they could change to become suppressors. So this thing called myeloid-derived suppressor cells, stimulated by the very drug that we give to upregulate the neutrophils called GM-CSF. So when you have high suppressors, which is the neutrophil and the low killers, which is the lymphocytes, and you put then the ANC, which is the neutrophil count divided by the ALC, which is a lymphocyte count, and you have a double whammy of high suppressors, a high ANC and low ALC, you have a high neutrophil lymphocyte ratio and now you're in trouble.

And that's why if you go into the literature and look at neutrophil lymphocyte ratio, you will see in pancreatic cancer, any other cancers when you have this high ratio, you have a lower survival. Again, it is such a logical science. Why are we giving GM-CSF to patients? Why are we upregulating the suppressor cells because you're going to end up with the lower survival.

Sadly, these molecules are out there. There's like an IL-2 that stimulates these Treg cells. And there is now soon be another bladder cancer gene therapy that is tied to up-regulating GM-CSF, i.e., these suppressor cells. So you watch the industry, doing things that it makes no biological sense, but it makes marketing sense. And this is why I think we have to exist as ImmunityBio to keep on fighting the fight and talk about the science on behalf of the patients and then show how the science has a major impact on the longevity of patients with cancer.

We have one more online. This one is, can BioShield be given as a preventative, especially in past cancer patients who are in remission, but have gone through radiation and/or chemotherapy?

I didn't hear you, Hemanth.

Can BioShield be given as a preventative, especially in past cancer patients who are in remission but who have gone through radiation and/or chemotherapy?

The answer is, could we give it for patients who are in remission? It depends on your ALC count. And we haven't looked at that in terms of long term. I can tell you that if your ALC count is in the lymphopenic range, we can help you get it out of that range. And I think that's going to be important. You will see a few slides soon on the patients with prostate cancer and patients with ovarian cancer, how we've done that before they had surgery. If you are in remission, what I worry about today, and we'll talk about that when you talk about Long COVID is that Long COVID is immunosuppressive. And if you have your low lymphocyte count and you have immunosuppression from this virus, would you then end up with a very rapid recurrence of your cancer when you've been in remission for a long time and would ANKTIVA help. That's something we have to actually explore now very urgently.

And then Patrick, we've got a couple more questions.

I'm Joel Shapiro. I'm trying to wrap my head around autoimmune disease as a back or mirror image of the cancer and looking at maybe if ALC is too high, is that perhaps an inducement to an increase in autoimmune, of course, in diabetes and other considerations?

That's a good question. So you have a balance in your body called the yin and the yang and the Chinese have taken this for thousands and thousands years because it's a basis of truth. So while on the one side, the NK cells and the T cells activate to go kill; on the other side, if they're overreacting, you have what you call autoantibodies, they will then actually kill the cells. And this is when you start getting these autoimmune disease. I always believe that type 1 diabetes was autoimmune disease.

I think even Alzheimer's is an autoimmune disease. So you begin to sort of see then how do you then go to the other side, how do you then induce suppressors. And now you could see people with psoriasis, et cetera, there's drugs out there. What it's doing? It's inducing the opposite side of the suppressors. But you have to be careful. As you induce the suppressors then you actually activate the -- you induce then the cancers. So there is this balance, and it's a great question, Joel. And the idea would be is there the opposite to IL-15, which is called IL-2 that stimulates these suppressor cells. But that's not what we're doing at this point in time. I think there's one more question.

I'm Dr. Michelle Howard. I was wondering if you had ever looked at measuring the circulating tumor cells before and after giving ANKTIVA.

That's a great question. And you'll see one of our patients with ovarian cancer that we're now measuring the circulating tumor cells beforehand and then giving ANKTIVA and measuring circulating tumor cells after and there's none left after that. So the beauty is that we now have really these early diagnostic markers of the circulating tumor cells, cell-free DNA and now even believe it or not, a simple CBC that will measure a lymphocyte count.

So the answer is yes. And now we can actually capture what we call minimal residual disease and really truly drive what I've been trying to say, the earlier you catch, the lower the tumor burden, the more maximum activity of your immune system, we can actually drive towards. I call this long-term complete remission. I don't want to say the word cure because we'll be slapped about. But I do believe we are on this path, any questions?

You spoke about scratching your head on why the FDA approved ANKTIVA for the carcinoma in situ, but not for the papillary alone. And then you showed some of the data for the naive, BCG naive. And the results look similar? Are you similarly scratching your head there? And can you give us some sense of specificity of time line for when you expect that FDA might approve ANKTIVA for BCG naive? And similarly for the lymphopenia, the results seem great. Is there any sense of when the time line might be for when the data might be strong enough to get an approval in that sense?

I can see you want to get me into trouble, but, well, I have been scratching my head for the last 4 years, almost at the point I've got bald, but seriously, you're absolutely right, right? I think when you end up in some level of bureaucracy where you have a check box, and I don't want to be political, but the last 4 years has been horrific for us, where for no unknown reason, whether you talk about COVID, let me speak a little bit about that, where we had a T cell vaccine completed Phase I, and then we're put -- told by the FDA to stop. We have CIS plus papillary approved, but papillary without CIS with the same results is not. So you begin to ask yourself why?

And I said on Tucker Carlson'’s show, it's not a conspiracy if it's true, but there's some things going on behind the scenes that we're not privy to. So I'm really hopeful that by having this Investor Day and showing the science in a very public way that both on behalf of the patients as well as the scientists and the investors, I know this Investor Day, and I'm not -- I'm cognizant of the fact, but more importantly, for the regulators to start to really just adopt what you just said, common sense, but not common sense without data.

And now we have data with hazard ratios of [indiscernible] some of those with statistical, [ 3.001, 3.0001 ], I don't know how much more significant you can get with regard to that. And we're showing this over and over and over again. And I'm just hopeful that this current administration, this current FDA recognizes that. I do understand there's now a patient groundswell on behalf of patients that may take that up and maybe that's what should happen anyway if it doesn't go forward. But I'm really encouraged and hopeful that common sense will now prevail.

And I hope I didn't get into trouble. Any other questions?

Okay. So I think we should take a break a little bit.

Yes. So the restrooms are all the way at the end of the hallway over here. They're setting up lunch now, and you'll be able to grab that, and then we'll start back shortly. Thank you all. We do have about 1,000 plus people that are online.

What time should we start back? Just so I'm clear. It's 12:00, so what time are we starting back, Rich?

It's 12:00, should we start back at 12:30?

12:30.

Just for everybody, we will start back at 12:30.

We will start back at 12:30.

[Break]

Before we start, again, I think Steven just reminded me about Dr. Rosenberg, an amazing work that you did at the NCI, as you all you know, he pioneered cell therapy. And the growth of the CAR-T and the T cells that you work with. But let me take you down this path, even with the most amazing scientists and science at the NCI that if we sort of create an assumption that gets locked in to a drug called IL-2. In order to do that, you use IL-2 to stimulate the T cells, grow the T cells. This is where it gets confusing and difficult for many to understand.

The IL-2 is a protein just like the IL-15 in our body. It happens to exceed the exact same receptor on T cells that IL-15 does. Except IL-2 when it goes on to the T cells cause suppressor cells. It induces the suppressor cells. IL-15 when it goes in T cells induces the killer cells.

So for years and years and years, people are pursuing IL-2 in proliferation of T cells. And it was -- even a drug approved for IL-2, which itself has toxicity. So by and not fully -- and there's not -- again, a disparaging thing about anybody. It's just how science works because this is so confusing.

It's called the IL-2 receptor that actually sees IL-15. And by not fully understanding and having an enlightenment that actually what we're doing is going in favor of the tumor by creating the suppressive T cells. So even today, there's a company that just got approved for the first TIL, which is a tumor-infiltrated lymphocytes and using IL-2 to proliferate them.

So this is why science is complex. This is why we really need to go deep, deep, deep, deep into the receptor level and truly, truly understand it and then develop drugs in that vein. So that was just a sidebar that I'm not sure you were going to plan to discuss, but I wanted to -- you just show that if you have IL-2 and you have GM-CSF, very important molecules approved, both drive one on one hand to a neutrophil that is suppressor and the other one to T cell that is suppressor.

And then as Steven just shared a chemotherapy that wipes out all the killers. So if you're going to war and before you start the fight, all your killers are gone and all your suppressors are there, I think no one will be losing the war.

So with that, Steven, I maybe you want to recall the conversation and then you called me back on the call while I was driving and said you're going to make me really happy at this conversation we had about, Steven, do you mind looking at your -- what happens with radiation.

Yes. So how do I get from a surgeon like Patrick got from being a surgeon to be an radiation oncologist, right, because surgeons are cool, right? Okay. So...

You noticed, I didn't see anything. There's a lot of MDs in the room.

All right. So my grandmother gets cancer, I knew I want to do something different. I was in medical school 16, like some people I know, and I -- to do surgery before I could drink legally. And I'm at the National Cancer Institute, and we're playing with using ways to try to stimulate the immune system.

We had, as Patrick said, IL-2, and I started playing with radiation in my lab as a way to trigger those kind of immune responses. And in doing so, I found that, first of all, I think for the audience and those who are watching outside, when we think about radiation, you can't just think about the word radiation. It's kind of like if you're doing surgery, the difference between taking a little mole off and Patrick doing a Whipple is completely different, right?

Everybody would say that those 2 things are generally a small thing and a big thing. With radiation therapy, I could be doing a little radiation to a small spot or I could be radiating the entire person to be trying to get them preconditioned for bone marrow transplants. It's very different.

So when we use the word radiation, we have to be -- and put words in that clarify what is it that you're actually radiating, what is the size of it, how much energy you're getting. So there's all these nuances. So radiation, does it work? Well, maybe, but it has to be the right kind of nuance thing, as Patrick has discussed previously. So from my standpoint, I was working in the lab with radiation therapy, and one of the things that was striking to me in animal models was we spent 15 years of 3 fellows in MCI working on to create a mouse that could make a cell that could go after a specific cancer.

And we injected that animal after 15 years of 3 people's hard work, I was the last 5 years of it. And the cancer grew in that mouse where every single T cell would know to go after that cancer. And that was kind of a bummer, right? And then we realized that if we were able to give certain medications, IL-2, IL-15 and couple that with radiation therapy, for the first time in a very, very, very, long time, in vivo in animals, we were able to impact those tumors. We always wanted to take that to humans. But we never could because no one had an IL-15 construct that could give to humans until now.

And so with that, I was interested in something that was in the textbook. In the textbook when I convert it from being a surgeon to a radiation oncologist, the first thing was radiation is immunosuppressive. Yes, if we drop an atomic bomb on someone and you're right next to it, that's probably very bad. If we radiate an entire person, right, that's going to be tremendously immunosuppressive.

But what would happen if you radiated specific things, specific small things? Would it be immunosuppressing, would there be lymphopenia. And that was early in my career, something we went after, and I think we have slides to talk about that next.

So I call Steven, 3 weeks ago, 2 weeks ago. When I said, Steve, you published this paper, how long ago, 12 years ago?

It was in 2015.

And I said, Steven, well, after you radiated, what happens to these patients? They are fine. He said the ANC doesn't change. I said, no, no, I'm not talking about ANC, which is the neutrophils. Tell me what happens to the ALC. What's that. And we went back into the paper, which we will show you today. And again, this is not a disparaging of Steven. This is what happened with the entire industry because it wasn't a treatment, as you said, and people did not look at ALC. So we went back into the paper to look at that paper.

And the ALC did drop. So let me just show a few slides, and I'll ask him to react to them, so if I may. So here it is, the -- what he talks about and we'll talk about that when you speak to Alan, is that could you combine immunotherapy in radiation? And the answer is absolutely, but you need to understand how to combine it because we would know in the next slide, what radiation does in terms of, as Steve would say, if you [indiscernible] you get radiations, it's probably not a good thing.

And this is what happens because it basically kills your cells. Next slide. So we asked Steven, does your paper, to look at ALC, and if you look at the slide, low and behold, the median, when you start is 1,700 and on day 1, it dropped to 970. And I think that was a surprise because nobody looked at it. But that paper was published 12 years ago?

Yes. And when we thought about this in 2015, think about the world. So when I went back to school, I was told that there was no role for immunotherapy in cancer that when I said I was going to go through the NCI, my friends all said, that is one of the stupidest ideas you've ever had, right? Because immune things don't have anything to do with cancer. And so 20 years later, everything that this audience might know about checkpoint inhibitors and things of all that nature, right? So when we did this, there was just the creation of Provenge, right, and what we were looking for was ALC counts that were able to potentially support harvesting lymphocytes to some degree.

And so when we looked at it, we said, it goes down, but there are some lymphocytes. But this is very specific. This was a specific form of radiation therapy given to a very, very, very small area just to prostate in low and intermediate risk patients. So this was not the kind of things that Patrick and I are talking about today. This was talking about, could you radiate very, very small targets.

So as Patrick was right and I was wrong in my interpretation is the lymphocyte counts fall. They don't fall as dramatically as we're about to see. But they do fall in a way that you could harvest T cells and other things if you need it to. But they fall in a way that is probably not great for taking care of your cancer.

So just to play what Steven just shared with us here. This was his very important experiment to test whether you do really localize shot, as you said, without invading the lymph nodes in the pelvic area around. And I think to his surprise, even with a single shot locally, it goes from 1,700 to 970 and look what happens after 1 year, it never gets back. It's 1,350. And what's happening here is what people don't realize is that no matter when you radiate the circuitry events of the systemic event of this lymphopenia occurs, but you can protect that.

You can project that by actually making sure that you have an activator and recover that. So I then went to the next step and said, Steven, would you do me a favor? And this was what? 2 weeks ago. Would you go into your database and get the IRB approval to de-identify because I know this was done just with the localized, what if you actually expose to the pelvis and in different areas. And I think you looked at that.

So when we're talking about radiating high-risk patients, classically what we do is we radiate the prostate and we rate the regional lymph nodes. God did not put the lymph nodes on the planet for me to radiate them, right? But what would you imagine would happen with your lymphocytes. That data is from a very, very small target. I think we're going to see on the next slide, here's what happens the same number of patients if you actually radiate the prostate and what we would think important in high-risk patients, significant prostate cancers, the kind of people that we need to cure in the world. And you can see it's a significant drop.

So I got this call from Steven as I was driving and he said, it's very exciting, and you're going to be happy for it. And I said, I'm not happy about it because this is exactly why Steven, I need you to educate us or educate radiologists with your therapists that, that drop can be prevented, more importantly, you could change the course of treatment, which then turns me to Alan because Alan was a CEO of one of my companies, he has then move to another company and basically was going to retire and I've got a call.

And Alan said, Patrick, I have a -- he's allowing me, by the way, very openly to share his history, and I'll ask him to share it himself directly. And this was in December last year. I'm about to go for radiation because my prostate cancer as recurred.

And knowing what I know and I said, Alan, please stop, before you do that. I want to give you ANKTIVA plus an adeno, the educational tool to educate your body about the T cell and prevent this from happening. He spoke to his radiotherapists and I think I'll ask Alan himself to share with you what his radiologists or radiotherapist said. And in most cases, when you give radiation to these patients who recur high risk, the PSA drops 6 months over time. Maybe, Alan, you can then react by sharing and this is, I think, normal now. What did your radiation oncologist say that we're going to do beforehand on should we, should we not? Maybe get your reaction?

Perfect. Thank you, Patrick. So after my radical proctectomy, and biochemical recurrence, the oncologists at UCSD Medical Center recommended that we watch over time and see if it was going to increase significantly, but every month actually was increasing by 20% my PSA. So I reached very quickly what is the 0.2 number where you have to start radiation.

And at that time, they recommended radiation and hormone therapy. Of course, they told me to do both at the same time and the hormone therapy for 6 months. I mentioned that I did not want to go through the standard treatment for hormone therapy. But yes, I will do the radiation. That's when I called Patrick. And immediately, the thing that the radiologists mentioned is that my PSA was not going to drop for a while if I was just doing the radiation, and I started the treatment a few days before the radiation. And within 5 days, preradiation, my PSA dropped from 0.2 to 0.16. And in 12 weeks, it went completely undetected.

What was the reaction of your radiotherapists or your oncologists?

Well, first, they told me not to do this. And that there is absolutely no role of immunotherapy in prostate cancer. And since I started going through the radiation, every week, I had a team at UCSD that met with me every Wednesday just to see what was happening to me and they did a number of blood tests to see how this was dropping. So they are amazed. They are amazed. They said this was a miracle. So the last day of my radiation, when you ringed the bell, I was like a movie star, and I didn't realize I was going to be doing this.

Well, I think it's not a miracle. I think it's actually just what God gave us, right? So if you look at the next slide. So this is Alan. And thank you for Alan. Alan produced this slide for me. He did some of those magnificent slide productions, where if you look at the left hand side, you see January 3, 2024. And as he says, although it's time that these PSAs started rising, rising, rising, rising, as I said stop.

At that point, he got the ANKTIVA, that's adenovirus vaccine. So that is March and then he had the radiation. As you said, within weeks his PSA started to drop. And by March 10, I think, that is 10/3, I read things differently the English way. 10 to me is October, but that's the tenth of March, right, his PSA was basically undetectable. And by the time it's finished, is undetectable at the end.

And you see the dotted line, he now has trained memory T cells. This is the promise of radiation chemotherapy -- immunotherapy. And the opportunity for us now to take this in the clinical trials, which we've now initiated about initiated with Dr. Finkelstein at U.S. Urology and other places in the country is overcoming this barrier of insight, that in fact, you can train your immune system, and it's not a miracle. What we see here is basically the biology that exists.

I worry when people say we're going to do a lymph -- remove your lymph nodes in surgery. As you said, the lymph nodes were there because that's where your memory T cells reside. Imagine now -- you've given chemotherapy, knocked out your NK cells, knocked out your T cells. You've given radiation, you've gotten yourself in lymphopenia, then you go to surgery and you move the lymph nodes.

And you ask yourself all these little steps do they make logical sense when you have this particular insight? The next slide is the protocol that we're about to institute now in prostate cancer. So the opportunity to take what we call high-risk patients. And I think also the questions can you avoid hormone therapy, which you see, maybe, Stephen, you can speak to this a little bit.

So I said in the beginning that this is very personal. It's about patients who have guided. This is my dad. My dad had high-risk prostate cancer. And when he was -- the average age showing up is like 69, he was about that age. And he basically had 2 choices. He could have radiation therapy or he could have surgery. And those are felt to be equivalent.

As you get older, a lot more men based on American Cancer Society statistics get radiation about 300% more but they're equal in outcome. And so he had a choice between what we see on this slide and what we'll see on the next slide. And this is, if you look behind me, they have...

We can do the surgery one first.

So this is the -- so for me, what I do is personally now is the radiation piece, which is, basically, we would normally offer someone radiation therapy to the prostate. And before that, they would usually get androgen deprivation therapy as an option to go along with it. But what if we could actually use the immune system to do the heavy lifting.

And so what this does is add innovative immunotherapy before getting their radiation therapy and then afterwards, something that, if my father had been alive to get back 12 years before, he would have -- I would have told him that this is something that was rational and reasonable. But it didn't exist. And my dad got radiation therapy, the way that it's described on here. He lived 12 years before he ended up passing away of COVID.

Now today is 2025. I think if we could add innovative immunotherapy to both approaches in high-risk prostate cancer, a disease which 1 out of every 3 patients, despite our best work in surgery or radiation therapy will have to come back would be a huge blow for freedom.

And so what this does is, does all the usual what we do to classify the stage of the patient, imaging, blood work, all those things beforehand, patients get, as Patrick can talk about the innovative BioShield approach and then get their radiation therapy and then see how they do and then get more BioShield outback as a boost.

Thank you, Stephen. And that's what we're trying to do to get what we call this emergency use access because we cannot, as I said, address this across the country now. And the only way we can think about it is get the FDA to give us this emergency access. And I'm announcing we are willing to provide this drug free literally to anybody about to get radiation is the doctor wants to use it until we get this approved as a lymphopenia rescue agent.

So I want to thank you. Maybe are there any questions before I let Alan and Steve go. I want to thank you, Alan, for sharing your story with us.

Are there any questions? If not -- there is a question.

It looked like from your slide, you gave 33 treatments of radiation. Is that right?

So what you're talking about in this trial. This trial is innovative in it. So when you think about radiation therapy, that classically is this much energy broken up into small pieces. Why do we do that? Because we've always done that. And every time we've tried or wanted to try changing the way we do radiation therapy, it comes back to what we have standardly done with radiation, doing the heavy lifting to deal with the problem. What if you didn't, what if you used innovative radiation therapy?

And as Patrick talks about exposing a tumor which is in you, it's you, cancer is you and yet it grows in you. What if you could use it to expose as Patrick said in the interview with Tucker Carlson, expose the truth, expose things where the immunotherapy gets to do the heavy lifting, and I don't have to do as much to potentially cause side effects.

And so that -- for that trial is -- can be done with standard fractionation if patients wanted to go this way we've done it for 60 years or they could use stereotactic body radiation therapy, the new hot kid on the block for radiation therapy.

And I think that allows some innovative approaches to radiation that we've never been able to do before.

I think one of the most important, if you look at the total gray in the standard of care, what's the total gray?

Yes. So for high-risk prostate cancer, that would be 81 grays for years. And now we've shortened it to about 28 treatments based on some work that was done within the cooperative groups. But now we're able to do it in as fast as 5 days and now we lowered the dose to what was called 40 gray, but the biologic effectiveness, we think is equal to doing 81 grays. So it's complicated, right?

But the point is that radiation is not all radiation. If I do something a certain way to radiate just this target or if I'm radiating this plus the entirety of the lymph nodes, that's got to be somewhat different, right? In this way, people can get radiation just to the prostate without radiating all the lymphocytes, potentially in the lymph nodes to go all the way up to the pelvis. So it's a great question you ask. It basically sets the tone that when you say hear the word radiation, ask how am I going to get radiated, not I got radiation.

Let me explain the difficulty for you. You hear 80 gray, some people -- for other forms of radiation goes 100 gray, 200 gray, huge numbers. The gray, by the way, is the amount of exposure to radiation, just to give you some idea what that means. For [indiscernible] we said we're going to give you 30 gray who had pancreatic cancer over the course, not over 5 days, once a week because the idea is not to kill the tumor or kill you NK cells or T cells, is to really stress the tumor, what I call cyto stress.

If you look at that little wiggly map that I did in 2016, the word cyto stress, stress the inners of the tumor so exposed it outside. That is such a revolutionary idea that when I said to Stephen and Stephen, can you go put that in the protocol, he says, no, we will do that, number one. Two, you'll never get reimbursed, number two. And I said, oh my God, how do we break through this.

So your question is a perfect question that not only do we have to break through Dogma, and I see [indiscernible] wrote this book on blind spots. We have a lot of blind spots in medicine. And but the blind spots are biologically rational. So why the heck are you radiating so much? Why the heck are you radiating this large area? Why the heck are you radiating lymph nodes? Why the heck are you killing NK cells?

When all you really want is to expose the tumor. That's why I said all these therapies that we've created don't go to waste. We just have to figure out how to use them as immunomodulators and unblind the blind spot. That's going to be the challenge for us. I get it.

There you see that trial, it says 40 gray, we negotiated. If some of you wanted to know how I got to the dose of Abraxane, it would blow your mind. When the Taxol was approved, it was 240, 260 milligrams high dose. We completed the study at MD Anderson. It showed that you'd be given that MTD what FDA wants maximum tolerated dose at 360. Finished the Phase I, I said to MD Anderson. We're now going to do Phase II at 100. They said, if you don't do it at 360, we're going to ask you to leave. I said, I'm leaving, we left.

I then went to Northwestern, Dr. Bill Gradishar, and I said, listen, can we negotiate? He said, fine, let's take 100 off. That's how we negotiated. It became 260. That was the dose. Think about this empiric craziness. It took maybe 5 years finally to get the dose of 100, which it is now of a vaccine for pancreatic cancer.

It is this kind of blind spot that is not understood of why we have to do what we're doing. And this conference today, I think is the first time I'm speaking of this publicly, I've been railing like this quietly with my academic friends for 10 years. So your question is so pertinent about why are we giving what dose we're giving.

Yes. That was my point is I think it's just Dogma that we're giving so much radiation and Dr. Finkelstein, I think that we've talked in the past, by the way, and I've read some of your articles and to achieve the abscopal effect, I think you were talking about using much less radiation, is that right?

So I think there's so much undiscovered country. And as a radiation oncologist, I'm not encouraging that anybody just go out and do radiation whatever dose they want. But when they're -- it will allow for the ability to work in synergy with immunotherapy, it creates the ability to start doing things we've never really been able to do before, which is start to change the fields and change the amount of dose that we give because the immune system is probably what can do the heavy lifting. It's not just on me. if there's no other possibility, surgery can't solve the patient and Patrick isn't here, there's no such thing as immunotherapy as a radiation oncologist we're going to cover where the cancer is and treat the cancer.

But that's not what we're talking about today. What we're talking about today is what if we could combine the benefits of the immune system with the benefits of radiation and figure out what that right pace is. We're not -- I don't think we're there yet. I think we've built history based on radiation by itself, but never been able to build history because these drugs didn't exist before.

Just so for the audience, when you heard this abscopal effect, what he's talking about is when you give radiation to, let's say, one spot in the thigh, just making that up, and you have a cancer in your lung, you're not radiating the lung, that lung cancer disappears. That's called the abscopal effect. It turns out that, that effect is based on your natural killer cells. So if you wiped out a natural killer cell, you will not get abscopal effect and cancer is a systemic disease. It's not a localized disease. So that is why this is so important, what's been brought up here. Lower the radiation dose, believe it or not, can't intuitively the better because you do not want to wipe out your natural killer cells.

Kelly Xu from Jefferies. Curious across various tumor types, how does lymphocyte counts vary at a baseline in patients. So if we think in the future [indiscernible] moving to frontline treatment, would you prioritize certain tumor types for patients to achieve the best benefit? Or you'd rather think this is more like a universal mechanism of action for lymphocytic reversal?

Thank you for that question. It's a great analyst question. So it's -- you're right, it's very complicated because your lymphocyte counts whether you're a healthy or with cancer, varies depending on your age. So the younger you are and the different lymphocyte count and then the older you get the different lymphocyte count. And cancer itself reduces the lymphocyte count. Cancers figure out a way to reduce lymphocyte count.

Worse than that is your chemotherapy reduces lymphocyte radiation and all the things we do that reduces lymphocyte count. So there's a definition of a cutoff that we've seen from all the data that when you go below 1,000, you're really in trouble. And if you get to 1,500, you're a little better but you get greater than 1,500, you're in great shape. So there's a normal range from 1,000 to 4,000. Crazy as it may sound. It depends on which lab you are. Some labs say 700 is a normal range when it's not, some labs say 1,000.

So we have then taken what we call the median. We've taken the [indiscernible] and looked at the entire proposition and looked at a level. And the medium is usually around 1,000 because they've all had this said chemotherapy. You see that median that Stevens' patients has 20 patients. And that was just literally pulled out the first 20 patients. So it's quasi universal sadly that all cancer patients, whether de novo or more importantly, after whatever has happened to them treatment-wise, they end up with lower than 1,000.

So we use a cutoff as a primary endpoint of less than 1,000, and we want to hope to capture all these patients and get them above. What we have shown and we provided in our meeting package yesterday, that it's linear. When you get to 1,000, you beat 1,000, you get this kind of survival. You beat 1,200, you get this survival; 1,400, you get a longer survival; 1,500 and greater, you get even the longer survival. So your lymphocytes matter.

So when I say lymphocytes matter, your count matters, survival matters, duration matters and quality of life matters. So these aren't just sound bites. These are biologically intentional to really explain in sound bites why this is all important. So it is universal. And we will use an ALC count of 1,000, which by the way, is a $20 test now. As I said, ironically, after years and years of hundreds of millions of dollars of genomic analysis, all you need is the CBC and look at your lymphocyte count.

My name is Leona Oliver, and I had no intention of speaking to that. I'm not a medical professional. But my question has to do with being that this chat. Centers on immune disease, immuno -- I should say, immunocompromised disease and the BioShield. I'm wondering if there has been any thought given to conditions like myasthenia gravis, in that regard and with this type of immuno disease be a good candidate for the BioShield.

It's a complicated question. So it's very much like what we talked about and we may be talking about when we get to cell therapy on myasthenia gravis and even lupus where there are treatments of the NK cell therapy, but it has to be very targeted under those circumstances because each of these, I consider autoimmune disease have a specific error in one of the cell types, which we can correct or the cells themselves in your body has an error. So we'll get into that when we talk about the NK cell therapy.

Okay. Well, thank you very much, Stephen and Alan. Okay. So I hope it's a long time. I think we're good. So this time, I'd like Dr. David Kerr and [indiscernible] to come up, and we're going to talk -- and I don't know what [indiscernible] please have the seat. Good to see you, David.

So I can't tell you how honored we have -- to have David here with us and we'll introduce Beth. David is one of the most foremost oncologists in the world, and I mean that. And he's the head at Oxford and he's considered such a thought leader that is invited by literally every country, I know of to not only give advice, but give his opinion. So David, thank you for coming and being with us.

And Beth and I know each other now for years and years and years and decades and Beth used to be at one of the government facilities, which she will share. And really has been the innovator of pursuing this what we call this next-generation adenovirus will train all our T cells. And we'll sort of explain that and Beth is now the head of cell therapy adenovirus program and science program and process science program at ImmunityBio.

So with that, maybe, David, you may want to introduce yourself and then your background, we'll start from there.

No, no. Thank you, Patrick. So I'm a Professor of Cancer Medicine at Oxford. So warm words of welcome from the [indiscernible] still a practicing physician. I mean, given the tenor of the discussion this morning, I probably should say, "I'm David, I use chemotherapy, hide my head in shame. There's sort of a balance to be made. And I think the only other thing is, as I say, is still busy in the clinic and so on.

But in terms of what Stephen was saying, I think we're forming an elderly [indiscernible] and I think I went to university when I was 16 also. So I think there was a small group of us describing that phenotype, but delighted to be here and, of course, contributing to this fantastic seminar. We see what we can do to explain the basis of immunotherapy, but perhaps most importantly, it's future and where we're going next.

I am Beth Gavich. My background, I was trained in microbiology and focused on virology, where I actually served a tenure at the Center for Disease Control, researching different viral vectors to be used against primarily first infectious disease. And over the last couple of decades, especially working with Patrick, really taken advantage of this T cell inducing technology against cancers.

And there is Dr. Mark Lanasa. So -- and he is -- can we expose a little more than that little thumbnail -- that's it -- so he's -- so maybe, Mark, thank you for being here. Mark was at AstraZeneca, is now at BeiGene. And one of the most important things that we're going to need to partner is a combination with the checkpoint. As I said, the checkpoint inhibitors upregulate the T cells and if we can actually proliferate T cells and up-regulate them and then train them with best technology and expose the tumor with what David will share with us.

I'm so grateful for BeiGene or BeOne now for agreeing to partner with us as we provide -- they will provide the checkpoint inhibitor throughout the course of these trials that we will be undertaking. So Mark, if you don't mind, just introducing yourself.

Sure. Thank you very much for that introduction. Very glad to be here this afternoon. My name is Mark Lanasa, also a physician and medical oncologist by training. I went to school at the University of Pittsburgh. Subsequently went to Duke where I was on faculty, took care of patients with acute and chronic leukemias, decided to move to industry. So I could stop giving chemotherapy and really focus on targeted therapies, so it would be better tolerated for patients.

As Patrick kindly mentioned, I was at AstraZeneca for the best part of the decade. My current role is that I'm the Chief Medical Officer for solid tumors at BeiGene, now BeOne medicines. And again, very glad will be here today.

Thank you, Mark. So with that, maybe do we have a few slides for us to talk about. So if you look at what we're talking about in this section of the fireside chat, we spent the morning on ANKTIVA, but imagine the combination of the fusion protein plus the DNA vaccine. And those are both the 2 jobs, giving you lymphocyte rescue and it's one component of the BioShield. David will speak a little bit deeper because as you could see, soon these tumors hide and he has found a way to expose them with yet another molecule. So with that, we're going to spend some time now. I'm not sure which slide you got coming up next. On the end of -- so Beth, maybe we can speak to adenovirus, where we've done this clinical trial where you combine the IL-15 plus adenovirus with the ADCA, MUC1, and brachyury. We have a lynch syndrome but maybe you can give a little background before the lynch syndrome and this was, are we coming to the colon cancer slide, after this? So just to speak to this a little bit, we -- this is a trial to prevent colon cancer. Think about that. This is the first trial now in patients who do not have cancer.

These patients have the thing called adenomatous polyps in their colon and an 80% increased risk of getting colon cancer. And they are born with this genetic defect, so to speak, that allows, frankly, the body not to protect itself against cancer. So if we can actually create this BioShield, so to speak, train the body to see what they call CEA-specific T cells or MUC1 specific T cells or brachyury T cells and go after these cancer cells before they become cancer, that's the goal.

And so far, as of today, 101 subjects have been enrolled. And if you look at the logo, what I'm grateful about is the entire country. whether it be MD Anderson, Mayo Clinic, UCSF, Northwestern and Fox Chase, Dana-Farber are in this fight together to prevent cancer. And I'm really privileged and honored to say that the only 2 treatments for these patients that they are trying now is the ANKTIVA plus the adenovirus. Maybe Beth, you can speak a little bit about the adenovirus.

Absolutely. So I've been working on this specific platform for a couple of decades. So you'd say I'm a believer. But really, it comes down to the power of the T cell. And this agent, we're kind of dancing around the word vaccine. It's gotten a negative connotation. And really, I'd like to use the specific T cell inducing agent here. And what you're doing here is using this virus, which is a common cold and flu virus that most of us have encountered while we were children to actually use that as a very elegant delivery system that we have co-evolved with for centuries tens of years -- millions of years. And essentially, to deliver a payload to your immune system to your T cells to specifically educate them against your protein of choice. And so what you see listed here on the screen, such as MUC1 brachyury, CEA the are our antigens of choice. A very common one that I think a lot of us have been exposed to is PSA or prostate-specific antigen that we just spoke about. And so in the context of that vaccine or T cell inducing agent, we are presenting that protein to your immune system to now allow the education of your T cells to go and destroy cells that are expressing this protein, so prostate-specific antigen specific to prostate cancers.

We have been working with the National Cancer Institute on these targets for about 15 years, and that's for some of our more unique targets such as brachyury, which is actually a cancer stem cell target. So when your cancer is metastasizing and moving through your body, it will just fix display or express brachyury. And if we have pretrained your T cells to see that target and recognize it as it is a foreign as an invader or something to clear. We now have that army of white blood cells that's circulating through your blood that will seek and destroy those cells. So it's a very important part of this overall BioShield. It's one of these extremely powerful killers that you need to actually go in and destroy a cell. So that being a tumor cell or an infectious disease riddled cell, so it's all that's producing more virus, so it's a very powerful technology, which we have harnessed and now been able to apply to multiple oncology as well as infectious disease indications to essentially train those T cells to go out and do their job and kill its target.

So I think, as I said, the sequence of events is to expose the tumor. We just talked about that. But then you need to find and kill. You can't just find and kill whether you have the NK cell. But you imagine you have an educated T cell that could actually seek out and be targeted to kill, and this is exactly what we did. That has not spoken about that, but you have seen that we have actually treated patients with not -- in the animal models as well as some patients. It's lots of fever and all the infectious diseases, SIV and as well as cancer. These trials will be done in cancer patients. So if you look, see Jeffrey Schlom the last author and I want to give him credit, he's been at the National Cancer Institute for decades, pursuing the cancer vaccine or cancer immunotherapy. If you look at the date of this slide, it's 2015, think about that, a decade ago. So this has been a decade in the making, and when COVID came around, not only were we already in patients, safely in patients, but we have generated these T cells. So when you get into this paper, you will see that the investigators drew the blood of these patients after having given you these vaccines, and there were specific T cells to each of these targets, which meant that if we created a T cell to the nucleic acid of the COVID, it will kill the COVID virus and clear the virus. We actually showed we did that. We'll get to that when you speak to long COVID, that's what I mean by a T cell vaccine. And on that basis, this became the basis of the lymph syndrome trial. And it is now in colon cancer trials, and we're about to start, if you may want to talk a little bit about that and maybe David will speak to that.

I think the Lynch study is incredibly important to have these agents, which are so safe that we can give them to fit, healthy people, but we're living with a genetic time bomb. I mean, as Patrick has said, these are individuals who is an exceptionally high risk of developing colon cancer. It's a genetic time bomb and the possibility yet to be proven in the trial that we can intervene with these very safe agents which are targeted specifically on the genesis of those early stages of colorectal cancer is a remarkable step ahead. It really is.

And it just shows how safe the agents that best developed is make the real difference. One of the things that we've done because colorectal cancer is a difficult disease to treat with immunotherapy, it's traditionally a rather cold tumor. It tends not to be very well recognized by the immune system. And we've talked this morning and so far about what we can do to stimulate, to arm, to improve the activity of the body's own T cells, and key cells and so on. But the approach that we've taken is to see what we can do to make the tumor cell a more attractive target for the body, for immune recognition and disruption. And I guess one of the things that Patrick has done I think is to, I guess, assemble a toolkit. Those of us who are active in individual areas, he's had the vision and oversight to see how we bring these together in a combinatorial way. We'll see what we call synergy, 1 plus 1 equals 3. So we've used then what we call an epigenetic regulator. So we regulate the genes of the tumor cells themselves to turn a cold tumor hot. What do I mean by that? The flags or targets that the immune cell recognizes are called antigens, which are shown and presented at the cell surface of the tumor.

It's like look at that flag sitting on the surface of the tumor, which is part of the important recognition element for the body's own immune cells and the machinery of getting the antigen from inside the tumor cell to the surface is called the HLA system. And in many tumors, they close that machinery down as if the factory has been literally closed down. So even if the cells making antigens, there's no way that they can get to the surface and are, therefore, invisible to the cells of the immune system. So by using an epigenetic regulator, we can restore the activity of the factory. We can restore the machinery that then plants the flag on the cell surface that in a way the stimulated immune system that Patrick, that Beth and the team have worked on to activate can now fully engage with these attractive juicy hot cancer cells and do their best to destroy them. And if we then add ANKTIVA to the mixture with our epigenetic regulator, we're seeing 1 plus 1 plus 1 equals about 11, when we've looked at the mouse experiments that we sort of put together in this way. So we are incredibly excited to take the lessons learned here and to build in these with colorectal cancer, both teaching patients with advanced disease and in a setting of which we call the adjuvant system.

So if we reset the main tumor type, there may be tiny microscopic metastases, lumps of tumor left behind. So small, we kind of detect from using conventional CT, MRI scanning and in that disease setting in which is a high likelihood of the tumor relapsing, we think that, that would be an excellent clinical target with minimal residual disease that would allow us to target and to give the immune system, the best chance it's got of overcoming and eradicating any residual tiny microscopic deposits. And this can only come through this multidisciplinary approach that we've heard from Stephen from other colleagues, who are willing clinically to put novel innovative designs but to put trust in the sort of therapeutic values, the therapeutic agents that Patrick and the team have assembled, and we'll be able to bring in, I think, sensibly into clinical trial. So it's an exciting time.

Well, thank you, David. I'm so glad I brought scientists into the room because it allows -- I'm sure all of you understood that, not because he's Scottish, but maybe that the work that David has just exposed is so significant. And maybe I'll try and put that in English. And I'm glade here 1.1 is 11, but we'll -- but let me just explain what he just said, and I think it's certainly important. When you look at all the drugs in the market today, the checkpoint inhibitors, et cetera, going after colon cancer. Believe it or not, it's joining up to 20% of the colon cancers because they are only going after the colon cancers that they call heart, what they call MSI high in technical jargon. The other 80%, they can treat because there's colon cancer so think about it, our therapies today for 50 years, treats 20% of colon cancers. I don't think the public recognizes that. So what has happened is David and his team at Oxford have discovered why they are cold not hot because at the genetic level, these tumors hide, meaning they don't express the proteins on the surface to now even the T cells to recognize them in this core MHC1 to get more technical.

He has developed a molecule that, it's oral, that can be taken that tells those tumors stop hiding and expose yourself to become now not just 20%, 100% of colon cancers are exposed to the T cells. That molecule is called Zabadinostat, which will share with you in the next slide. But more importantly, what David and his team has done is there's yet another molecule, which we won't go into, is that they've been able to find the secret that the tumor is hiding and create a peptide that can actually find the T cell in the patient's own body, that is this elusive T cell that has already been educated. That's the future of T-cell therapy, and we'll get to that when we get to T cell therapy. So the revolution is happening, and this has been work now 10 years, 15 years.

20 years, and man. No, it's a really clever point, you're right with our other drug. What we can do is we can make hot tumors hotter. We've discovered a new source of antigen so we can mine the tumors on genome to make more antigens to be presented at the cell surface in that way.

And again, once we've known that mechanism, we can use that, we can put it into best adenoviruses, this is a rather love that we're building on even as we speak. But by building on those pathways, I thought of that make a hot tumor hotter. Clearly, we need to make it hottest. But maybe that's when we come back next year and talk to that.

Until you go on the red carpet. But now you begin to see the synergies. And this is why it's difficult for us to explain this to Wall Street and even to academia and our analysts because there's no one magic bullet. And we keep on finding this chess game. We're really playing chess and trying to understand what is this tumor doing? It's the smartest machine, as I said, and the fact that the tumor hides and this DNA that we call before junk DNA, it's technical non-lung coding DNA or RNA. They've been able to expose -- and by actually exposing that, we can now get deep into the heart of the tumor.

And by doing so, we can find peptides nobody has ever found before that the tumor itself is expressing that then that can put into adenoma and now teach the T cells or we can go fish it from the patient, grow them together with the NK cells. You begin to notice there is no chemotherapy here. This is all basic immunology at the most basic fundamental level. And folks think at the investor level that we're just spending money are crazy, we're not. What we're doing is trying to interrogate to a level we can cure a patient and give the highest quality of life. So having said that, we test all these theories not only amongst ourselves, but also with Jeffrey Schlom at the NCI and in very sophisticated models. And if we can show the next slide, where 1 plus 1 is 11. This is for you, David, this is your slide. Or is it -- no, this is Jeffrey's slide. Okay. So we collaborate so beautifully that we've been doing this for 6 to 8 years to get to Jeffery Schlom and his team. We really don't care who slide it is, whose work it is because it's all ours, together. So just to give you an idea, the CT26 is a colon cancer cell lining. And on the left-hand side is where you see the tumor volume, you go the tumors, and you could see on the left-hand side, the tumors grow in size.

And then the legend of PBSZ, N83, PD-1, Z plus N83, zabadinostat, N83 plus anti-PD-1. When you do all 3, so let me explain that to you. Z is zabadinostat. Look at the survival, the days post tumor implant, look at the top line, it's 100%. No, that's a mouse. Everybody can kill a mouse, I get that. But the other mice, look how they fall off. But then if you're adding ANKTIVA to that, look what happens to that and then an anti-PD-1, and that's why we needed Mark from BeiGene. And if you look on the right, 5 out of 8 of these cancers in this triplet, that's why David mean 1 plus 1 plus 1 is 11. But imagine, however, if you also put the animal virus into it. So this may sound ridiculous. But this did a clinic trial with colon cancer, Phase I and Phase II just with the adenovirus. And third line, remote treatment and prolong the survival to the extent that the FDA said, go ahead and do the trial of the single agent. Maybe you can talk about that.

Absolutely. So I think the data that Patrick just spoke to, and that is published, really demonstrates the power of even just one of these tools by itself. And in this study, we actually were working with Duke University and treating really late-stage failed all current therapies colon cancer patients. And by just administering subcutaneously this adenoviral vector expressing CEA or carcinoembryonic antigen which is your protein, your flag over expressed on colon cells as well as other -- many other cancers, we were able to actually really extend the lives of these patients. And I think that's a big difference between immunotherapies and chemotherapies that's very important is that really chemotherapies are administered until toxicity until you have to stop for the patient. And when you see the tumor come back, it re-grows at the same growth rate. Well, now with immunotherapies, by just applying that immune pressure on the tumor, you actually change the growth kinetics of the tumor, you actually slow down the tumor growth. And what you see with that is an actual extension of life. So it's different in chemotherapy, where you might see an immediate reduction, but then it comes roaring back with these immunotherapies even single agent, you're altering that tumor growth and allowing for these long tails of extension of life to be provided.

And that's what you saw in several of the other slides earlier. So if you imagine the power of the T cells alone and now you come in with these other agents, such as [indiscernible], which cranks up that expression, like the PD-1, like Patrick said, if you hold back to PD-1 or the regulatory T cells of PD-1, but you don't have the activated T cells, there's nothing to actually affect the cancer. Well, that's what the beauty of marrying these agents together that you're now conducting that symphony within the human body to bring on the effectors, hold back the suppressors and the timeliness of that, you're now able to hold that beautiful concept for the host and allow their own system to overcome the disease.

And that's what we talk about. I think it is an orchestration of a concept. It really is a concept. And there's a concept happening dynamically in real time. And when Beth showed me that data just a single agent adeno-CEA giving this strong patient of life, it really reaffirms that this concept that we need to do, which means that at the end of the day, we want to reactivate the T cell, and that's why a checkpoint inhibitor, and Mark may want to speak to that because we tried with every other Merck, Bristol-Myers, et cetera, said, will you share with us your checkpoint? And there's lots of reticence whatever that may be for whatever reason. But when we went to B1, they won, and John Oyler, the CEO that was not only open arms, but to me, I believe is one of the best checkpoints. So I'm not -- I don't have any financial relationship with B1 whatsoever. Scientifically, I think it's one of the best checkpoints. And maybe I'll have Mark if you could speak to that if you don't mind.

Yes. Thank you very much for that. And as I've been reflecting on your comments today about the importance of the lymphocyte compartment just to say a few things about tislelizumab and how it's different.

So everyone in the audience will be familiar with PD-1s and how they work that basically, they find an inhibitory receptor and inhibitory protein on the service of lymphocytes, which in turn then leads to T cell activation. Now what might be less familiar is that there are other white blood cells in the tumor microenvironment called monocytes or macrophages. And when they find these lymphocytes that are decorated with antibodies, it's their job to actually destroy those lymphocytes, to kill the monocytes because they shouldn't have the antibodies on them. They're second subway because they're infected by a virus or something like that. So the body didn't evolve in this context of receiving therapeutic monoclonal antibodies. It turns out that the monocytes and macrophages recognize those antibodies through what's called the Fc gamma receptor. And tislelizumab was uniquely designed to not have binding the Fc gamma receptors. Or to put it more simply that tislelizumab was uniquely designed to avoid evasion and ultimately preserve the lymphocytes that have been activated to fight that cancer. So we think that this is a very exciting combination, Patrick, to the point you were just thinking about synergies or rational combinations to take a lymphocyte, a molecule that expands and activates lympocycline apartment combined with a PD-1 that was designed to be lymphocyte protecting, we think makes all the sense of the world.

And I would just say that for tislelizumab, for those of you who aren't familiar with it, this is not just theoretical. They were approved for 3 indications here in the United States. We are approved for at least 1 indication for -- in 40 countries worldwide with more submissions underway. So we're very excited about the opportunity and when I reflect upon the amazing Kaplan-Meier plot that you showed earlier today, of course, the data in the patients with a high lymphocyte count is so striking -- but even in the patients with a lower lymphocyte count, they substantially overperformed the historical control of docetaxel, as you mentioned. So we're hopeful that this combination can bring patients with PD-1 progressed non-small cell lung cancer, a lot of benefit, particularly in light of the unmet need for those patients.

Thank you, Mark. I think it's not a fair fight when you think about it. Here you have a checkpoint inhibitor that actually protects lymphocytes and then you have ANKTIVA that actually stimulates and proliferates lymphocytes versus docetaxel that kills the lymphocytes and steroids that kills lymphocytes and you're asking to compare the 2. To be honest, I think it's a ridiculous trial that we should even do. But we are going to go to the FDA with the data that we really have, where we've done ANKTIVA plus nivo and the data I showed you ANKTIVA plus nivo [ pembro ] that got us 21 months. But you follow regulations and the regulation says do a confirmatory trial so we are doing and this trial is in motion. As I said, it's -- we know what the data is going to show for docetaxel, it's going to be 7 to 10 months. There's just not -- nothing is going to change. You know what docetaxel is going to do to the patient. And interestingly enough, one of the difficulties we're going to have is be able to recruit patients in the United States because now American patients are smart enough to say, we don't want docetaxel. So we are bringing this sadly to a global trial.

That's why the help of B1 is going to be so helpful because they are all around the world. It's very frustrating to us to have to even do this trial because you ask yourself, if you're the patient that's actually allocated in the docetaxel. Is that even ethical? So I just leave it out. I'm already in enough trouble. So I'll just leave. But Mark, maybe I'll ask you and David to react to that. I mean, what do you think about a trial like this in terms of we can almost predict the outcome.

So it is a challenge. We have -- and to be clear, tislelizumab is not approved in second-line non-small cell lung cancer. So I don't want to convey the wrong message. We have present studies in second-line non-small cell lung cancer. It is operationally difficult to enroll patients to docetaxel monotherapy. It is -- should we say formally a regulatory standard of care, but it's not commonly administered molecule. And then the other problem is that we really rely upon randomization, have scientific integrity in the study, but you can't effectively blind this type of study.

The side effect profiles of the drugs are so different. The patients will know what they perceive and that in and of itself presents its own set of challenges to the integrity of the study, keeping patients in the study, keeping them motivated and engaged. So yes, there are real challenges with delivering this type of design that yet. As you say, the regulations are there and certainly, we aspire to beat the expectations of regulatory authorities in terms of the data package.

David, do you want to comment?

No, no, well said. I mean I agree with Mark. I mean we're here in Hollywood and little boy watches The Mandalorian who says this is the way. And for those of you who have similarly aged children. And we're just sort of caught up aren't we, in this sort of group think in the sort of very traditional way that we have of doing things.

Now there may be an opportunity, you're knocking at the door. I know that you and Richard knocking at the door and doing your best to see what you can do to sort of bring some of the pillars down. But I think for the time being, the trial as is will give the answer that all of us predict and it will meet the needs of the regulatory authorities and so on in a bit, but I agree with you that there will be casualties along the way, and those will be with patients not with us.

Well, I can tell you from an outset, David, it is not possible for me to know of any patient that's in third-line lung cancer that has a 20% opportunity to have a 5-year survival rate with docetaxel alone.

I agree.

And we've shown that with a hazard ratio of 0.3, which then says, why? So you're right, I am knocking on the door. I maybe try and kick the door. I'm not sure what I'll do to the door. But the opportunity to have common sense now with hopefully the new FDA to ask this question, why do you want to do this to patients? What box do we want to check and why? Especially since ANKTIVA is approved, tisle is approved and Doxi is approved. But if I showed you the pictures of the horrific side effects which we have, which I want to spare you, which was presented at ASCO 2024 of the horrific pictures of the side effects of docetaxel. You will ask yourself, how dare we put patients at risk by giving them this trial, yet we're forced to. So -- and that's what I'm going to try and knock on the door, kick the door, scream. But I'm hopeful that common sense will prevail with this new administration at the FDA. Any other questions for -- before we close this session. Any questions from anybody. And then we'll talk a little bit about another checkpoint when we get to the cell therapy, but we'll talk about that.

Okay. The next one is going to be a treat, Dr. Jennifer Buell and Dr. Lennie Sender. And I'll ask them both to introduce themselves, but maybe, Phil, if you put the next slide up in terms of where we are in this BioShield. So now we move towards the cell side and somebody asked this morning, could you actually take your cells from your body and grow them? And the answer is absolutely.

And you'll see some interesting things today where we're going to show you something at the end of the session. I think Jennifer is going to see for the first time as well. So thank you, Jennifer, for coming. Dr. Buell, she is one of the most amazing scientists whenever we speak. When you talk about oncology, that's not immunology, and you talk about virology, that's virology, not immunology and you talk about radiotherapy. And so therefore, these disciplines don't really talk to each other, except when I speak to Jennifer, she talks all these languages in an amazing way. And then Dr. Sender, you will hear his introductions with us on cell therapy from UC Irvine Center. Jennifer, maybe you want to introduce yourself, and thank you for coming.

Well, thank you so much for those kind words. It's an honor and privilege to be here. And I have to first say, congratulations to you and your team for the progress that you have all made. I mean your pathbreaking and changing a paradigm in the treatment of oncology that is not only so necessary, but the potential is limitless.

And I'm just really humbled to be a part of it. Jennifer Buell, I'm the President and CEO of MiNK Therapeutics. And for those who don't know MiNK Therapeutics, we have been focused on the development and scalability and delivery of an invariant natural killer T cell. So up on the slide you just saw, the iNKT Dr. Soon-Shiong mentioned earlier, this is a very unique and powerful -- one of the most highly conserved cells in immunity. We've known about it really for the longest period of time, but what has challenged the industry is the isolation and scalability of the cell type.

We've been able to tackle that through a specific proprietary technology that allows us to not only take the cells from a donor but then to isolate, purify and scale these cells to levels that allow us to distribute them and make cell therapy really quite accessible both in oncology as well as in other diseases of the immune system. And what's so spectacular about these cells and the discussions that we've been having together is, we have seen firsthand the power of what IL-15 can do with some of the most important cells that were in the immune system.

Not only can they enable the cells to naturally proliferate in vivo but also the durability and persistence that you see in vivo actually in a human, actually allows us to see persistence beyond what any available or conventional T cell therapy or NK cell therapy or other therapy can do when you add in the potential of IL-15. We've taken technology to actually leverage this very important cytokine and engineer it to armor our CAR iNKT cell therapy. So it sets ImmunityBio up with this portfolio to actually do some pathbreaking things beyond what you're seeing already. And to take a cell, armor it and have not only the tumor killing potential, but then also the natural within human proliferation and persistence beyond 6 months is something that we have not yet seen before in this space. So it's such a pleasure really to be here. Thank you for the opportunity.

Thanks, Jennifer. And thank you all. Thank you, Patrick. So I joined Patrick 9 years ago, sort of found my soulmate. I'm from South Africa originally. I did the first transplant as an intern in Johannesburg, South Africa, so I fell in love with cell therapy. And as a transplanter, we were using horrendous doses of radiation and chemotherapy. And I always wanted to get down to less therapy and understood it was the cell. So when we talk of immunotherapy, we talk about cells. And what can we do?

And with Patrick and what ImmunityBio is doing, we've learned that we can manipulate all the cells that are necessary for that immunotherapy approach. We can make cars, we can make CARS, we can make memory-like NK cells. We can make some of the newer cells, maybe Patrick will talk about. But we've been able to do this, and we did it at scale. When I joined Patrick, he said to me, that's a project in someone's lab, making 1 patient dose per week. He says, you've got to be able to make it to scale because there are thousands and tens of thousands of patients and how do we do it? While the magic glue was ANKTIVA. And we have something really magical. When you add ANKTIVA to cell therapy, we do something that no one else can do with any other type of therapy.

Thank you so much, Lennie. So let's break this down for those -- if you look at the cell therapy board here on the left-hand side, this is how we started off with this NK cell line. So it's like having a HeLa cell line, think about that. In 1992, there was a patient with the cancer of NK cells, which we then pulled out and it grew like weeks, and we figured out would the FDA ever allow us to put that into the patient because we could engineer that and grow that, radiate it so it doesn't become cancerous and inject it.

And that's what we've done with PD-L1 t-haNK and CD19 t-haNK, both in clinical trials. The PD-L1 t-haNK is really important. When it's PD-L1, it's basically going after a myeloid-derived suppressor cell. So for the first time, not only activating on the left-hand side, the killer cells, we have to suppress the suppressor cells. So that was the purpose of that combination, and that was what we put in pancreatic cancer. So when you see a pancreatic cancer patient, you asked -- somebody asked early on about the neutrophil lymphocyte ratio, where the neutrophils are high because they're actually suppresses. And we need to go after them with the PD-L1 t-haNK and kill them.

And then the lymphocytes are low, and that's why we have to give the ANKTIVA. That combination got a complete response in center to read. And we just published now in oncology, 5-year complete free of disease in patients with metastatic pancreatic cancer, and she's still around. So I want you to understand that this biology works on the left-hand side. But it doesn't persist as Jennifer mentioned. And there's this unique cell that has been around for millions of years. I say sometimes 500 million years, 100 million years.

And if cell been around for that long, is doing something really important, and that's iNKT cells. And that iNKT cell is a combination of a T cell and an NK cell. And that's what you call invariant NK T-cell can give it to anybody. So the opportunity to actually grow that and -- but it requires IL-15 to stimulate that, here we go again. And then finally, you'll see up here a memory NK cell. At the end of the day, the fight of cancer is actually between 2 cytokines.

If you look at the 2 major antagonist and protagonist, on the one hand is interferon-gamma, and the other one is TGF-Beta. Now I'm getting a real technical. But if you reduce everything down to TGF-beta and gamma interferon. And if you can outweigh TGF-beta, which is a suppressor by upregulating gamma interferon, which is a killer, you win. And that's what these NK cells do. They stimulate gamma interferon and actually upregulate the exposure in the tumor cell and kill.

So next slide. When I met -- when we started this program, the opportunity to create through a single apheresis. This is a very technical slide. I don't expect you to get it. But you can pull out this amazing cell in your body called the gamma delta T cell. That is superman of T cells. You can pull out this amazing NK cell called iNK T cell. That's a superman of NK cells. And then you can manipulate that NK cell to create a memory NK cell. We are doing all 3 at the ImmunityBio, the opportunity to work with our collaborators into all 3 through a single apheresis. However, I said to Lennie, this is a process, not a product. And I said we need to convert this into a product, meaning when I say a product, a vial that you can cryopreserve and keep forever, and hang for 30 minutes as an outpatient. And some of you who visit the clinic says, we've done hundreds of patients like that.

The next slide. And this is a real picture of where we're doing and how we did it. And now you'll sort of see the improvement of the process.

Next slide. Before you get to the video, which we will hold off. This is all-hand manufactured. Next slide. And as you can see, these are your NK cells that are produced from the apheresis, next slide, and then they hung as a blood transfusion. So the opportunity for us to create what I call the American Red Cross of cancer, quite literally, cryopreserve thousands of those in the T cells or NK cells. Jennifer was a little more modest about her work. I'm going to ask her to speak to a little bit about what they've done with kids with colon cancer and how they've seen some amazing responses when they combine it with their checkpoint -- maybe you can speak to a little bit to that.

Thank you very much. So certainly, as you've heard, colon cancer is a growing disease. We're seeing a substantial increase in incidents, particularly in younger individuals, and we personally seen very young individuals under 18, 8, 11, 15 coming in through the young onset clinic and requiring intervention. And for the majority of these colon cancer tumors, the majority are something called microsatellite stable, the most difficult to treat. And you see that not only are these so difficult, they also are really pervasive. They're highly metastatic and they typically go to areas that are immune privileged with metastasizing in the liver.

What we have established is a combination therapy that's been really quite active. And that is taking the invariant natural killer T cells and you can administer them as just a single administration. And what we observed biologically, immunologically, through immunohistochemistry, you could see that sort of an immune cold tumor, an immune desert tumor on the slides becomes substantially infiltrated. And you can see that the iNKT cells will help to chaperone CD8 T cells across the stroma, and then they can start to help eliminate the tumor. We combine this with checkpoint modulating antibodies.

And there are 2 antibodies that we're working with most often and that's a standard PD-1 called balstilimab as well as an Fc-engineered CTLA-4 called, Botensilimab. And the combination of these agents allow you not only to modulate the tumor microenvironment, when you administer the iNKT cells, you see the proliferation, you see the trafficking of CD8 T cells into the tumor. And then you see the activation and improvement of T cell clones, especially the diversity of your immune repertoire.

So by increasing that immune infiltration and changing the dynamics of the immune system, you armor essentially your fighter cells to eliminate the disease, and we're seeing a substantial amount just by way of numbers, currently available chemotherapy will give a tumor shrinkage in 2% of patients -- 2% to 5% of patients and disease elimination in 0% of patients. It's a uniformly fatal disease, MSS colorectal cancer. What we're observing in that more than 25% of the patients actually see their tumor shrink. And we now have more than half of the patients alive at 18 months, over 65% of the patients alive at 18 months.

We're going to continue to push. Dr. Soon-Shiong made some very provocative statements that I very much agree with that our regulators really do need to be more open in order to drive innovation in this country. And I think with the continued push and the inexhaustible push that the immunity team is doing, I have a sense that we're going to start to see movement in [indiscernible] an openness to getting some of these nontoxic chemotherapies -- immune therapies to patients as opposed to the chemotherapies that they're getting now.

The tolerability profile that the team mentioned earlier is very similar to what we're observing. Patients maintain their quality of life. There are very limited tox associated, no grade 3 tox associated with the iNKT cells. We do see some colitis associated with the Fc-engineered CTLA-4. It's reversible and preventable with TNF alpha predosing. So there's an enormous opportunity here and the concept of then addressing lymphopenia in this population will expand the number of responders dramatically, I believe.

Thank you, Jennifer. Before we end the session, I'm now going to surprise you with the video. One of the challenges that I really think we can't afford. We can't afford $1 million CAR T cell therapy. There is no way that patients who could benefit from it, go bankrupt from $1 million CAR T cell therapy. So what we have done has become a very quiet process of roboticizing this technology, which has never been done. And together with Dr. Lennie Sender and myself, we initiated and began this process. When you look at Starlink, the little things that you put on top of your roof is now about $200, $300 versus a couple of thousand because 100% of that manufactured is through robots. The opportunity to take this very time, difficult, manual process of cell therapy, but you could actually software train robots. So let me now show you a video.

[Presentation]

So the opportunity for us to democratize now cell therapy and CAR T cell therapy and NK cell therapy and bring it down the cost, some affordable cost that can actually be actually distributed to the rest of the world is very, very, very real. And as I said, the opportunity for our country to become as a foreign policy to bring health to the rest of the world is a real opportunity. And I'm really proud that you're all part of that. Thank you. Okay. Thank you.

So the next, I think as Carlos is going to be on another call. Okay. So next is a little change in direction. Tim, where we're going to talk about something that -- if you don't mind, Tim, I' afraid just you and I know. There's no Carlos, so...

No, no I'm here [indiscernible].

There we go. Fantastic color. It's a talk about Long COVID. And this has been percolating unfortunately with us at ImmunityBio since the onset of COVID. So let me give you a little bit of perspective and history. What's happening? Okay, whatever. The history is that when COVID occurred, it was around November of 2019, and I recognize it by understanding this virus. And as I said, it was a very painful moment because it was exactly around the time that Kobe Bryant passed away. And we had a funeral session where thousands of people were together. I was standing next to -- sitting next to Gavin Newsom.

And I said, I'm worried about this virus because it's different. It's not a respiratory virus. It's a systemic virus. It's a virus that actually has at the tip of its spear the ability to go into every blood vessel. It has at the tip of its spear to go into your brain or the blood vessels of the brain. And Carlos and I looked at each other and said, we have to write a paper and we did. We published a paper together. Dr. Cordon which I'll have him introduce himself soon and Dr. Tim Henrich soon, that COVID is cancer and cancer is COVID. What does that mean?

That if we make ourself aware to understand COVID that it will penetrate every blood vessel and it's a systemic disease. We need to think of it differently. Most vaccines are given in vaccinology as an antibody-based vaccine. But the antibodies block it, but doesn't clear it. And the key to everything was clearing the virus from your human body because the hallmarks of a bad virus is its persistence. And we'll talk about that with Dr. Henrich. And if it persists and does other things, which is scary by acting like HPV or hepatitis. There are only 7 viruses that cause cancer.

And the way they do that is you and I, we all have in our body, a think called p53. And if it knocks out p53, it knocks out your protection for cancer. There's a thing called RB, does the same. It's a thing called MHC1. If it knocks out these 3 things, it's a hallmark. So this is not a downer call because we've [ hovered ] this for [ 45 ] years, quietly between myself and ImmunityBio, Amy Proal and Tim and the team because unless there's a therapy -- potential therapy to overcome that, we would create such an alarm that they'd be panic. And as I said, when we went to Henry Jackson Foundation and the thought leaders of the country said I should publish it. We still haven't published it, we will soon. But I wanted to use this opportunity to expose this from science that we haven't done. It's somebody else's science, and that's what this session is going to be.

So Tim, if you may want to introduce yourself, and thank you for coming.

Sure. Thank you so much for the invitation to come and have us talk about our work. And I should mention I'm a Professor of Medicine at University of California, San Francisco, just up north. I -- just as an aside, I'm also a physician scientist that I take care of people with cancer who develop severe infections in the setting of chemotherapies, radiation therapy, et cetera. So profound cytopenias, including lymphopenias can lead to very, very pervasive systemic infections, viral infections, fungal infections. And my team is not the team that a cancer patient wants to see when you're in the hospital. This means that there is a problem because of the treatment for cancer. So that's just an aside of that.

But in my day job, I'm a virologist and a viral immunologist, and I have been studying how for about 20 years now, how chronic viral infections impact immune health, impact human health and how we can harness the immune system to really clear out and resolve chronic viral infections. But there's as [ Dr. Soon-Shiong ] was saying, there's a tight axis between chronic infection, tumor risk and cancers. And a lot of cancers are actually viral related, and that's something that we're very interested in looking at going forward.

So I met him when I was introduced to Dr. Amy Proal, and she runs PolyBio, non-for-profit institute that we support to really ask this question. And I got into the first Zoom call with everybody and amazing scientists that you support across the country. And my heart sank, when I started hearing, you all talked about 2 years ago, which now just got published. And I want to ask Tim maybe to present some of those slides today and the implications of those that's not been published. And then the implications of even what you've then found and your colleagues also found what happens with the NK cells in that circumstance.

So Tim, could you take it away with the first slide. But before we do that, let me introduce Dr. Carlos Cordon, who is somewhere, there you go.

I'm here, I'm here. I'm just calling [indiscernible] almost all other times [indiscernible].

So Dr. Cordon -- Carlos, could you just maybe introduce yourself what you do and where you are in your foremost pathologist at Mount Sinai.

I'm Carlos Cordon-Cardo and I'm the Chairman of the Department of pathology for the system of Mount Sinai Health, which is one of the largest in the East Coast. Before that, I was the Vice Chair and Associate Director at Comprehensive Cancer Center at Columbia University. In Columbia spent over 20 years between [indiscernible] and Memorial Sloan-Kettering. We essentially were one of the groups that founded what we call Molecular Pathology. At Sinai you can call it we were very much at the epicenter of the disease, and we were able to very rapidly produce detection methods as well as stratifying the disease. And we have been very worried about what we have been finding, and how we are following up with our patients, and we will probably talk more about that with these slides.

Thank you, Carlos. So we'll get to -- we'll ask both Tim and Carlos to present the data, and then we'll have a discussion about what happens next. So Tim, off you go.

Sure. So just the background, we were studying mostly chronic HIV infection and how people living with HIV have immune dysfunction and chronically. And what we were noticing in people that were recovering from Long COVID, and we actually started this cohort back in March of 2020. When we saw the initial cases from outside the United States with this infection, so COVID-19 or SARS-CoV-2 is not your standard RNA virus respiratory infection. That was profound lymphopenia, profound immune dis-regulation and obviously, quite a bit of morbidity and mortality in folks that have immunocompromised or immuno-senescence in advanced age.

And so we thought that there was definitely going to be something about this virus, it was not just going to resolve quickly, that there had to be some type of long-term implications of having SARS-CoV-2. And so what we noticed is actually back in April, May of 2020, we had participants that we had rolled right after acute infections, so 2 to 3 weeks later, but they weren't getting better. So 3, 4 months later, even up to 5 months later, we had people that were division 1 collegiate athletes that could hardly walk up a flight of stairs without getting winded or just profound fatigue. We have people with neuro-cognitive issues, with GI issues, with cardiopulmonary symptoms, with orthostatic hypotension and you name it. There's a lot of different types of symptoms.

And we started to say, what's going on at the immune system here in people with Long COVID and so we took a deep dive and we started to identify that people that have these symptoms had elevations of chronic inflammation, things like IL-6 or other of other cytokines that really suggest that there's some kind of chronic persistent trigger of that immune system over time. But not only were people revved up and inflamed, but they also had a dis-regulated immune system. So the T-cells, for example, the cytotoxic T-cells were exhausted. It was dysregulated with antibody production and the helper CD4 T-cells. They just weren't working together in concert. And that told us, okay, the T-cells don't seem to be normal. And this was even 6, 7, 8 months later, in people who had mild to modest infections, did not require hospitalization over time.

And so we said, what about the NK cells as well, because we know that NK cells are really this, as you're saying this first-line defense or shield, this immunoshield for the person. And we noticed that certain types of NK cells. So this is the phenotype or type of NK cell that is cytotoxic that it's able to go and to kill these cancer cells, to kill viral infected cells were actually significantly lower in people that have Long COVID versus those that had full recovery and even lower than what we saw before the pandemic as well. And that actually seemed to be worse, they even had lower levels, the more symptoms and the more symptomatic a person was at that time. So that gave us a lot of concern that if you have an infection that now leads to chronic immune dysregulation, T-cell exhaustion and low cytotoxic NK cell function, what's going on and what could be the implications for human health?

And I can also say that there are certain signatures that we see in viral-related cancers, which include chronic inflammation and immune dysregulation that can actually allow cancers to persist into metastasize and to grow. And unfortunately, we are starting to see a bit of the signature in our immune system that we would see in some of these viral-related cancers as well. So again, I don't want to be a cause of alarm, but I think this is something that we need to be aware of, and we need to study, and that's exactly what we're doing, a deep dive.

If you look at the hallmarks of these oncogenic virus persistence is one of them?

That's right.

Replication persistence, loss of RV, loss of the TP53, loss of HLA-1. Let's talk about your findings in persistence.

Sure. So one thing that we also noticed over time was that people were not able to clear the virus from their immune system. And so when we started looking the 4, 5, 6 months, up to 2 years after initial infection. This is in a cohort before we saw a lot of reinfection, which we're now seeing as well. So this is for people infected early on and then say, 2 years later, we're actually seeing in, for example, the gut immune cells. So myeloid immune cells in the gut, dendritic cells or macrophages, we're seeing actual viral persistence, not just virus itself, but we're seeing some of the RNAs that are made during replications. These double-stranded RNAs of the virus itself. And it wasn't everybody, but certainly was in some people up to 2 years after their initial infection, we're seeing persistence as well.

Are there any of these slides [ hold ] that you can speak to maybe?

Yes. And so what we're seeing here is that if you look, for example, different types of T-cells set. So this is a lot of science up here on this slide, so it's difficult to distill down. But I think what we're seeing normally is that cell types that are lower include different types of T cells that are either trafficking to tissues, for example, where they needed to have antiviral effect, or the express immune checkpoint. So these are exhausted T-cells. And why did T-cells become exhausted in the setting of infection?

Well, you need to have chronic antigen persistence that drives those cells to try to proliferate over time. And over time, they just get exhausted. They become dysfunctional. And that, to us, is the clue that there is also ongoing viral presentation in some of these participants as well. So that's a lot of detail for that one summary right there.

And then the final slide, I think we have here. So I think what you're basically saying then is that not only persistence, you actually can image them. You've actually biopsied them, you biopsied -- not tumors you biopsied the colon. And you've seen it replicate and it's not on the surface of the colon. It's what we call the lamina propria deep inside the colon?

Deep inside, yes.

So I think -- and the good news from the perspective of where we go next, it's clearly important to go clear those cells to move those cells from your body that are infected, and they can be recognized by NK cells, if the NK cells were actually active rather than dysfunctional. That's fair statement?

Yes. What we've been finding in our -- for example, I've got tissue studies is that where virus persists, there's actually exclusion of these cytotoxic cells, whether they're NK cells, cytotoxic T-cells or these are the indication that they are. And we're seeing genes being transcribed from the host immune response that actually allows virus to potentially escape some of this cytotoxic killing. And what this does is creates [ a leap ] for hypothesis is a downward spiral. You have an infection that causes chronic inflammation, but at the same time, it's also evading immune clearance by these cytotoxic cells, the NK cells and these cytotoxic T-cells. And so ANKTIVA was a natural next extension was why don't we rev up those cells or reactivate the cells that we need to finally clear out chronic viral persistence within these deeper tissues throughout the body. So that is just starting now.

What you just described as a virologist, sounds like a cancer doctor, actually. When you say that's what we mean by COVID's cancer cancers COVID, because cancers behave the exact same way. You have the cancerous cells that has found amazing ways to immunosuppress the surrounding cells even though they exist, your NK and T cells, which means there's a lot of TGF-beta around myeloid-derived suppressor cells, which, by the way, is the hallmark of well-established signs, that's what the COVID virus does. The COVID virus has found a way to stimulate immunosuppression. You agree with that?

I would agree with that. 100%.

Okay. So now we have an agreement between a cancer doctor and an immunologist and a virologist. But let me ask you what would the pathologists find? So if I can then turn to this -- if it walks like a duck and quacks like a duck, is it a duck? The question is, if it persists, it immunosuppress and replicates, then the next question, if I go to the next slide, is, does it block or inhibit the production of your P-53, which is your protective gene from cancer?

I read somewhere, I don't know if it's true, but I think it is that elephants don't get cancer because they have 8 P-53s in them. Imagine if you have zero P-53s in a virus that immunosuppress and protect and persists. And this is where Dr. Cordon and I have been working quietly not only in patients with Long COVID, but also in the autopsies, what you call warm autopsies, ways trying to find and extract out the COVID virus across ultimate tissues, but more importantly, now discovering COVID virus in cancer tissues. So I wanted Dr. Cordon, we've not published this. We are in the process of putting together the paper. But I think it was so important that we have this opportunity for Dr. Cordon to now present this.

Yes. Thank you, Patrick, and thank you all for allowing me to be here today. The reality is that as Patrick was mentioning, COVID has a lot of the landmarks of cancer. When we think about -- and we talk about metastasis, we think about tumor cells. But as we teach medical students, the term metastasis means colonizing that distance. And that's what some bacteria and viruses do, they may enter into your nose, into your lives, but then they go into your lungs and in the case of SARS-CoV-2 [indiscernible] through the blood vessels can colonize the blood vessels and go into different organs and systemic disease.

So in that context, together we publically publish a paper in cancer cell, doing the staging and talking about the similarities between COVID and cancer. May I have the next slide?

And over the study of many autopsies, we were one of the first groups that published the largest series of autopsies during COVID with a 100 autopsies. We learned a lot. We were the first to identify the virus, both by electromicroscopy and special technologies in different tissues, including the endothelial cells of many organs, including the endothelial cells of the brain, which can explain for the brain fog that patients have and that unfortunately, some of the long hauls also complain. And interestingly enough, in some of the autopsies of COVID and post-acute syndrome of patients, we are seeing by both RNA sequencing on tissues from these rapid autopsies as Patrick was revealing the presence of viral RNA across many different organs.

And not only that the sequences are present but in some of the instances, the amount of high viral RNA that maps into some of these organs reminds us of some of what we have seen in the very acute response of some of the patients, when we were able to do -- when quantitative assays such as quantitative PCR from national [indiscernible] that we were taking. This is a small summary of many different autopsies. And as you can see, viral sequences have been obtained from many of these patients. And in specific cases as the diagram on the right side, you can see that multiple organs. It's in the lung, it's in the lymph nodes, it's in the intestines, it's in the spinal fluid and it can be also in the brain. So this put us at a different momentum, since then we have done many more autos and producing more data.

And what we are observing is that some of the positive syndrome, some of the long haulers or the patients, the autopsies autos that we see these days are extremely complex. These patients, many of them relatively young, come with a great deal of organ failures affecting many of the tissues that in the past, we didn't see as affected. May I have the next slide?

And one of the things that we have been able to also discover as identified in this slide is the fact that when the virus gets into cells, it promotes the down regulation of critical tumor suppression genes. As you can see in the slide, after just 24 hours of infection, the main antigen presenting system, the HLA-1 antigens disappear as you cannot see up there in this slide -- on the screen. That makes the cell to escape immune surveillance, making the cell almost like a phantom. It's not recognized by the immune system. And almost at the same time, after 24 hours later, both P-53 and later on RV are also down regulated. P-53 allows the cell to escape mechanisms of cell death. So now you don't have just a phantom, you have a cell that can become almost like immortal.

And by the way, individuals that are born with a deficient P-53, 100% of them develop cancer and many of them during their youth. When we also realized that RV was also deleted, which is a critical molecule that controls cell division and cell proliferation, allows the cell to keep growing and to produce this kind of work, inflammation and disease. So based on these concepts, may I have the next slide, we also observed that critical pathways of chronic inflammation were very much upregulated on the contrary in some of these organs, the blood vessel development, the cell activation, the cytokines.

So, next slide, when you put all of that together, has allowed us to postulate that SARS-CoV-2 infection may promote in the long term, cell transformation and tumorigenesis by 2 possible and not necessarily mutually exclusive mechanisms. First, the persistence of this viral infection or at least the expression of some viral proteins in specific tissues may allow some of these oncoproteins or part of these proteins to sequester some of the tumor -- some of the suppressor regimes such as the human papillomavirus or some other virus that will produce that inhibition of HLA, P-53 and RB, allowing the cell again to be a phantom to escape mechanisms of cell death and to keep growing.

At the same time, since this proteins and these damages persistent in many tissues produces a chronic inflammation that also promotes cell proliferation, which has been shown to lead to cell transformation. This mechanism is also well known, for example, in human hepatitis where after major repetition of infection or the persistence of these foreign proteins and these viral attacks, we produce a response that is also the very beginning of a transformation of cells and the development of the tumorigenic malignant phenotype.

So based on all of these things, we postulate that the possible role of SARS-CoV-2 in facilitating tumor genesis and definitely producing a very persistent and difficult chronic disease in the so-called COVID [ Long colors ]. Implications that would be important for our community at large. And as we were saying, we don't want to produce an alarm. And there is a difference between alarming and alerting and sharing some data based on real time and knowledge that allows us to take the next steps.

Thank you, Carlos. Maybe I would like to sort of just explain a little bit, if you go back to that slide. Because I think I saw this work about 2 years ago, Carlos, and I think we looked at this together. And it truly scared the pants of me. I really mean that. And what he's saying is completely right. We don't want to alarm but we do need to alert. And the opportunity for us to get prepared now. We really -- you talk about national preparedness. When you talk about a pandemic, this is the potential of a pandemic to happen. And I don't know how many people have gotten COVID in the country or the world, but billions maybe.

So if you look on the left, on the right-hand side, when you see on the corner, you see P-53, you see that blank. You see RB, you see that blank, see MHC-1, you see that blank. That blank occurred on the left when you took a cell and you infected it with COVID. So this is real fundamental biological data. We are now testing these in people. And that's why I say this correlation of this biological work where we absolutely know of the immunosuppressive activity of a COVID virus, combined with persistence and if you look at that thing called HPV above there, that's the alert. Is this an HPV cause -- like an HPV virus, is it oncogenic?

Just like you have GARDASIL that actually prevent you from getting HPV. It doesn't prevent you from actually curing cancer when you have HPV. And we have a trial now with adenovirus targeting HPV T-cells or you can get a T-cell to kill the HPV infected cell and clear that. And then, Tim, you want to speak a little bit about -- I think we can talk about the clinical trial we are about to start. You'll have an inundate request. We give you a home number, it will be all good?

Yes, yes.

But I think what's important about us starting with Tim was he has this ongoing temporal follow-up or people didn't have COVID now have -- resisted COVID and then can we clear the virus? So if you want to speak about that?

Sure. Yes. And to put this in perspective, about a conservative estimate from the New England Journal just a few months ago or half a year or so ago, it was about 3% of U.S. population has experienced Long COVID symptoms sometime after SARS-CoV-2 infection. And that may not seem like a lot, but we're talking 3 out of 100 people, millions and millions of people just in the U.S. alone. And what's interesting is not only are we seeing viral persistence in people that have symptoms, but we also see some viral persistence and up to about 8% of people without symptoms after COVID. And so that suggests that even without Long COVID symptoms, people could potentially be harboring chronic virus over time. And then obviously, again, I don't want to be alarmist, but this is something that we need to think about or even is there some sort of silent Long COVID or some type of long-term health impact to quite a significant part of the population over time.

Again, not to be alarmist, but I think it's something that we need to think about and to do this. And so we've been running what we call the LIINC study at UCSF. We now follow about 1,400 people longitudinally every 4 months. We check in. We do symptomatic questionnaires. We do blood testing, we look at gene expression levels. We look at proteomics. We look at inflammation, biopsies, guts not all 1,400 people, but we do gut biopsies, we do bone marrow biopsies, now as well because from PET imaging we've seen this regulated T-cell activation in bone marrow, and that always is cause for concern. We've actually just performed our 22nd bone marrow biopsy in people with and without Long COVID. We do lymph-node biopsies as well, and we do a whole noninvasive PET imaging center.

But what this does is this allows us to do these pathogenesis focused clinical trials where we can take a drug like ANKTIVA, we can give it to people that we know have essentially life-limiting Long-COVID, not only can we follow symptomology over time, but we can do a really deep pathophysiological dive. What's happening? Can we improve our inflammation profile? Can we reduce viral persistence? and we -- hopefully, we'll see a reduction in some of these escape mechanisms that the virus has enabled to cell from escaping immune pressures as well. So these are things that we're very keen on doing.

We've already ran about 3 or 4 other clinical trials of antiviral, monoclonal antibody and some other modes. But this is the one that we're super excited about because this is what we see in the data so far. We see reduced cytotoxic NK cell reaction, we see dis-regulated T-cells, and this is what we need to fix in order to clear out virus and to prevent some of these downstream changes potentially from occurring.

Well, I can't tell you how -- first of all, thank you for that insight. You bothered me even further. This is the first time I heard about bone marrow T cell dysfunction, which drives me up the wall now. But having said that, the sad news and I'll just say it again, in an e-mail in March, June 2020, I announced this to the NCI and NIH that we have lymphopenia and could we try ANKTIVA in combination or separate from remdesivir because antivirals doesn't actually stop this problem, antivirals may reduce the load, it doesn't clear the virus. And I've been seeing this tune about we need to clear the virus since 2020.

For whatever reason, we won't go into that now, we were denied. And I think this is when I think where we -- I needed -- I think there's a moral obligation for us as a company, frankly, to even just speak out even though that's at risk that we need to actually prepare for the human race actually for the country to actually have the solution. It needn't be our solution. It needs to be anything that can clear this virus from your body, whoever has it still in their bodies. And we don't know, as Tim said, how many people have it. But we do know 16 million, that's about roughly the number have Long COVID.

So with that uplifting presentation. But there is hope. I really mean that, and that's why we were willing to come out now, even though we've known of this data for 2.5 years, 3 years, to speak to a fact there is hope, and we need the country to come together, the agencies to come together, whether it be NIH, NCI, CDC, the FDA.

So with that, I'll open it to questions. And I hope or maybe there are some questions or maybe Tim and Carlos, you maybe have a last comment before you take some questions?

Yes, I just want to mention that -- but again, it has taken us over 2 years. We kept repeating these experiment with different cell lines, we have different tissues from different patients. We have not published because we wanted to begin to make sure that we were not going to alarm, but we're going to alert. But this is a very robust data. And again, together with the complexity that we are seeing in some patients, the complexity even in the autopsies that we are doing and in some of patient populations have an increase in the presentation of cancers meaning the young people makes us feel that this is time to, again, be alert and make sure that we can use the tools that we have for every detection as well as for the treatments that will allow us to really clear the virus, rather than just waiting to see other developments.

Yes. I would just say that this is a big unknown. We don't know what's happening, and this is the time where we need to study. We need to investigate, and we need to try a novel ways of purging chronic virus and hopefully, that will restore human health over time. And what we've seen already just from our imaging studies is that we've entered a new immune set point post-COVID. So if we look at scans that we did before COVID for other reasons, control groups versus those after, they're different. The T-cell activation states are different. And we've reached a new population set point, and we don't know what that means in terms of human health. And it's really urgent that we look at that and we understand how dysregulated T-cell even NK cell function is will impact us over long periods of time.

Well, I think you sort of hit the nail in the head about the new immune setpoint. I mean I don't know people really realizing what you just said is so profound. If we, as a nation have hit a new immune setpoint, all I can say, I hope this administration understands of all the programs that they should actually support people like Tim and Carlos. It's really doing, I think, amazing work with regard to understanding this Long COVID. We really need to not only prepare but really figure out how we can actually change that set point to the immune systems because NK cells and T-cells do matter as i said. So with that, I'll take questions.

So I think we say thank you, Patrick, for bringing this to our attention through compelling presentation. A question for Tim and for Carlos. Tim do you know if there is any correlation between your clinical prescriptive phenotypes, the immunological changes you hope and the physio-biological and the rapid changes that Carlos has described [indiscernible].

They're certainly interrelated. I think it's difficult to pick out specific, for example, clinical symptoms or phenotypes that correlate with specific immunologic phenotypes that correlate with specific gene response phenotypes and cellular host [ file ] responses. And so we do know there's a very close connection there.

I think understanding what that is, is very difficult, partly because it's such a heterogeneous disease. There's heterogeneous presentations clinically. It's difficult when we're working with patient surveys and interviews of there's a lot of variation in that setting. But I think the overall finding is that regardless of the systems that people have, and we have seen, for example, people with neurocognitive symptoms or cardio-pulmonary symptoms do tend to have, for example, more EBV reactivation, different types of inflammatory markers, but there's a lot of crossover. There's a lot of the venn diagrams are very overlapping, I guess, you could say, in that setting.

But we do know they're related. And I think we really need to parse out what those are. But again, the common themes are immune dysregulation, and the failure of the immune system to really purge viral infected cells that may be there.

And I think a question for Carlos was, have you seen any morphological changes in epithelial cells that you've seen the molecular biological changes there or they are changes in differentiation. So we looked under microscope [indiscernible] very typical pathologist [indiscernible].

This is what we are doing right now. I mean, we are moving from the profiling of autopsies to start also looking at biopsy tissues. And as it has been discussed, I mean there is a lot of overlapping. But at the end of the day, with numbers and in depth analysis and with the new technologies that we have at hand, I think that we can really start unveiling some of these mysteries and I think that it would be very important for the good orchestration of clinical trials in this patient population which is going to grow with time for sure.

But I think question is Carlos, do you start seeing dysplasia and aplasia and adenomatous changes?

Or in some of these tissues mainly, we have seen that. But it's now important because with the autopsy we essentially are capturing just a moment in time and it's at the end of a life and a journey that has been also very much happening by any other developments. I think that -- what we are seeing now is -- and that the right studies is to do it more on a time frame and start looking at biopsies and we need the resources to do that well.

Yes. We have -- I mean, anecdotally, we have seen, for example, B-cell clonal proliferation in bone marrow in people with Long COVID. Whether that's a normal finding that we can see in the population of background or not, I think we need to wait to see. So I don't have any definitive statements on that. But we are now going forward actually with poly-bio support. We're finding all kind of new incident cancer cases, especially younger folk and enrolling them in our LIINC study to try to do a really deep pathophysiologic dive to see -- to understand if there is a viral persistence and if there are immune response similarities between Long COVID and what we're seeing in some of these tumor folks as well.

Well, I know what I'm going to put in my paper, the cells look funny.

I want to thank the eloquent presentation. More of a comment than a question. I think for me, as a cancer physician, what is truly striking is hope. The hope that answering these key questions especially with COVID as a model system will finally unlock some of the key questions we have about HPV, about its treatment for head and neck cancer, for cervical cancer, being able to use this potentially to target nasopharyngeal cancer and EBV. These are the things that have bothered -- Patrick talks about the things that keep me up at night, right? These are the things that we know that people get cancers because of oncolytic virus. And maybe for the first time, we can bite back. So thank you again for your work.

Well, thank you for that question because that sets up perfectly for the next session because it's virus against men. And whether you get infected or whether it causes cancer and if we're going to bring up Dr. Sender. And I think we have -- let me see if he's available, good. Dr. Tewari, Krish. And you're going to talk today about ovarian cancer, and then we'll also talk about a little bit about the HBV, viral induced cancer. And as you know, ovarian cancer, sadly is a very devastating disease because it's really picked up late from a symptom perspective. And again, we will share with you some data that is very exciting if we can pick it up early.

But maybe Krish, if you could introduce yourself, and thank you for attending. I know you had patient today, so you couldn't be here, but thank you for coming on Zoom.

Yes. I'm really happy to be here and see everyone virtually. My name is Krish Tewari, I'm a professor at UC Irvine Medical Center. And I'm a Gynecologic Oncologist. I take care of patients with advanced ovarian cancer, newly diagnosed and recurrent metastatic cervical cancer and endometrial cancer. Those are the 3 main types of patients or main types of cancers that I take care of and I run clinical trials in all 3 of these diseases. And so I'm really honored to be part of this discussion today.

So let me put up the first slide on really where we're going. And just to tell you about the opportunity if we think of this as a BioShield where, for example, you could use the adenovirus to teach a cell that can go after HPV. You can use ANKTIVA to activate your bodies NK and T cells and you could even use a PD-L1 t-haNK to actually kill the suppressors and maybe an [ sank ]. That's a not crazy combination, but this is really just basically an in-vivo and ex-vivo lymphocyte rescue, that you can see at the bottom.

If I may, we had the privilege of looking after a patient that we were made aware of that was about to get surgery for ovarian cancer. And I think with CA-125, you can put up that slide. And the patient came to us in October 2024. And you could see her levels was 477 or 502. And she is a kaiser patient.

And so I picked up the phone and we called the Kaiser doctor and said, "Look, we know what your standard of care is. It's going to be carboplatin and Taxol. That's the standard of care. And then you go do surgery. Now Taxol require steroids, it will wipe out the lymphocytes, Carboplatin will creates ANCs or neutrophils. That's fine. I think you're going to need to do that. We'll -- but would you then allow us to bring the patient into our clinic and Dr. Sender is here. And we wrote to the FDA what we call a single-purpose IND. And then she came in on 5th of November, getting Tiva and then you see -- and then by 26th of November and by 10th of December and just by Christmas, completely undetectable.

So you see by 23rd of December. And then interestingly enough, she not only had CT scans, but physical exam and they couldn't palpate this tumor, which they could easily palpate before. And then by the time she had the surgery in February 7, there's a 98% drop in her CA2 levels down to undetectable levels. She had the surgery. She had circulating-free DNA tumor cells present in the blood and then now they're not detectable. So I want to share with you this possibility, just as I shared with you in the prostate cancer patient. We get them early in the neoadjuvant setting. There's a real opportunity to change the paradigm of cancer care. And this is all done as an outpatient, all as an outpatient.

So with that, next slide, we want to start a protocol, and this is the protocol I'd like Dr. Krish and Lennie to discuss where we will be addressing this in ovarian cancer. So Krish, maybe you can take it away and your thoughts on ovarian cancer. And he's a little modest, he is the foremost thought leader in the country on ovarian cancer. So I think you're hearing truly the foremost thought leader in ovarian cancer.

Well, thank you for that. I wish my mom was alive to hear that. So that patient that was discussed, Dr. Lennie had contacted me in the fall of last year about this patient, and I was thrilled to hear that she was able to get this novel treatment and did so well. The reality is most patients are going to respond to neoadjuvant chemotherapy prior to surgery for ovarian cancer, but the response is not as dramatic as what you saw on the CA-125 biochemical profile in the previous slide. That was remarkable. And further to have the circulating cell-free tumor DNA go to 0. It's just not -- it's unheard of. And so again, it's an N of 1, and that's why the study right here, which seeks to enroll up to 40 patients is going to be important because it needs to be -- it can't be emphasized enough that the majority of women with advanced ovarian cancer die of this disease and the percentage of patients with advanced ovarian cancer amongst all ovarian cancer patients is about 90% because as you've heard, there are no early symptoms for this disease, and there are no validated screening tools.

So the vast majority of patients have advanced disease. They respond initially to chemo. They undergo surgery, but invariably, the disease returns. So studies like this, this treatment schema here, it's like a Phase II design in a sense, up to 40 patients. They get a neoadjuvant treatment period where they're getting standard of care with nanoparticle albumin paclitaxel and carboplatin along with study drug and then undergo cytoreductive surgery.

Now these patients at the time of interval cytooreduction undergo intraperitoneal therapy, which is not really standard these days because we've just not studied the right drugs to give intraperitoneally. All our studies have come out negative. But again, here, we're doing something unique and novel and intraperitoneal therapy, whether it's heated intraperitoneal chemotherapy or just straight IP therapy that's not heated to 41 degrees, scientifically and mechanistically should work, but we just haven't had the right drugs. And I think this study has an opportunity to study the right medicines to be able to deliver on the promise of IP therapy. So there's a lot of stuff going on.

And then following that, the adjuvant period cycles 4 through 6, you can see the schedule, the sequencing of the medicines. And then after that, there would be a maintenance phase, maintenance therapy. It's not on the schema, but the maintenance phase is dictated or predicated on the genetic profile of the tumor. And so patients with BRCA1, BRCA2, germline and somatic mutations, they can be placed on maintenance PARP. If you have non-BRCA germline and somatic mutated tumors, but they do show evidence of homologous recombination deficiency by virtue of loss of heterozygosity, large-scale state transitions or telomeric allelic imbalances, they can go on to receive maintenance therapy with PARP inhibitor plus bevacizumab, which is our anti-angiogenesis drug.

So this is a unique opportunity. It's not being done anywhere else. This is a novel drug. It's using standard of care treatment. And also doing -- it reflects what's being done in the community. Most patients do get neoadjuvant chemotherapy. But the idea with the IP therapy portion at the debulking surgery is also really takes us to the next level, and it's a very promising trial.

Thank you very much. Let me -- if I may, show you why this is not only novel -- but not crazy. Remember when I said, one of the things we needed to do was to expose the tumor and ABRAXANE, which we develop in carboplatin, given at a low dose, stresses the tumor to start to expose its surface. Once it exposes its surface, the ANKTIVA with the NK cell and T-cell can recognize the tumor and kill it but the tumor then does something against that. It sends out the suppressor cells to suppress these NK and T-cells and this PD-L1 t-haNK kills suppressor cells. And this sotevtamab which is now in Phase II, suppresses the endpoint of TGF-beta of the suppressor cells.

So there's a real biological rationale on this protocol. It's not -- let's go to something at the wall and see what happens. This is the same protocol that we use for pancreatic cancer, glioblastoma, other drugs -- other tumors. Because whatever you use, whether you use SBRT, ultrasound, whatever we use a low-dose chemo to expose the tumor, activate your killer cells, suppress the suppressors is really what you need to do. So I want to call that a sort of a full circle of why this is not some combination that is not rational, which is another challenge, which of these cells don't you want? An NK cell, a T cell.

Which of the cells don't you want to suppress? The myelo-derived suppressor cells. And which tumor don't you want to expose? And that's what I need now to bring to the FDA, and I'm so grateful because the RMAT that we got approval of for, actually allows the concept of these combinations. So with that, at least, Krish, I want to thank you for taking your time to come and see us. And Dr. Sender has been working on this PD-L1 t-haNK that we spoke about at the last session. So I think are there any questions to Dr. Sender and to Dr. Krish before we sort of wrap this session of fireside chat.

I don't know if you want to mention Krish, about the HPV because it's in the cervical cancer?

Okay. Krish, maybe we're going to talk about that then on -- is the cervical cancer that you're starting that trial now? Have you started trial?

So number one is we have this trial just about ready to go, Krish. So you'll be getting the final draft of this protocol. But also in the HPV, we've done the Phase I of adenovirus HPV and the data looks really good. The safety data looks excellent. Clearly, and since you're one of the leading experts on cervical cancer, this about 500,000, 600,000 women get cervical cancer from HPV. We also know the head and neck cancers with HPV and anal cancers from HPV but you and I have been talking about the next study and follow-up on the Lynch syndrome, where the addition of [indiscernible] ANKTIVA plus our adenoviral vaccines is so powerful in the BioShield. And then we thought that this would be perfect for the cervical cancer. I don't know if you want to just comment on cervical cancer and sort of the paucity of opportunities for women these days once it's recurred.

Yes. So cervical cancer is a very important disease. HPV is still creates the disease of epidemic proportions, 600,000 new cases globally, over 360,000 of these women die, and this is a disease that really affects young women when they have small children at home, women that may be in the beginning of their professional careers. So it's a very, very tough disease. We've made some progress. Anti-angiogenesis therapy and checkpoint inhibitors have improved median survival in patients with recurrent and metastatic disease to about 24, 25 months. But still 2 years is really not enough time for these relatively young women.

And so the advances we've made in first-line recurrent metastatic therapy have created a new population of patients that comprise a high unmet clinical need, and those are patients in need of second-line therapy. Right now, we have an antibody drug conjugate tisotumab vedotin that's FDA approved. This is a medicine that the objective response rate is about 17% in the second-line setting, not great, but it's been approved because we really don't have much else. Most patients will have been PD-1 checkpoint exposed at least in this country. And so rechallenging them with checkpoint is not going to be feasible unless we add something to the mix.

And so the protocol we've proposed is to use a therapeutic HPV16 vaccine, combining it with checkpoint inhibitor. It could be nivolumab. It could be another anti-PD-1 antibody and testing them in patients that have progressed on chemotherapy plus pembro, i.e., those patients that are in need of second-line therapy. And so this adenovirus HPV vector is really a therapeutic vaccine, which is likely to not just cause tumor shrinkage like, for example, the antibody drug conjugate tisotumab does, but maybe even move the needle forward and maybe even improve survival because at the second-line setting, there's very few options. The other options that may be available if they're HER2 positive by immunohistochemistry 3+, they could get in HER2. Response rates are good with that antibody drug conjugate kit.

But again, the responses are short-lived. And so patients who respond to first-line therapy but relapse and need second-line therapy, invariably, they're going to die. So I think this is an opportunity to study the therapeutic vaccine together with a checkpoint inhibitor in these patients in need of second-line treatment. And again, these are young women. It's an unmet -- high unmet clinical need and an opportunity to do some good.

Thank you very much. I think the -- really, you keep on hearing this word of short-lived. And when you think of antibody drug conjugates, which has become another sort of hot potato or hot toy whatever you want to talk about, it's just another chemotherapy. It's really a chemotherapy that's attached to the antibody. And if a chemotherapy gives you the short lived, which then takes us all the way back to the beginning of the talk. We've got these assumptions as embreading with us for 50 years, that we have to go chemotherapy radiation checkpoints. And when you do that, you actually almost with certainty, push yourself into short-lived responses. And so if you think about that, which is exciting now through this activation of all this -- and thank you, Krish, for calling it a therapeutic vaccine. We now have to call it a BioShield.

We have this opportunity to really to go from long-lived to long complete responses, whatever you may call that, and that may even be the cure if we get younger people early on. So thank you so much for attending Krish, I appreciate that very much which I think closes this fireside session. Thank you, Lennie.

It takes us to the closing. Now if I can then summarize and ask first of all, Rich, to give you his little report, and then -- if you can come up here Rich, we can talk full about the BioShield if we can put that up, the first slide. Go ahead, Rich.

Yes. So first thing I want to do is just thank everybody for being here. I know it's been a long day, but I think you probably saw there's a lot going on.

Any time you stop and think about this, the first thing I was going to do is I always want to thank the patients and families, whether it's on the commercial side or whether it's on our trial side, and it's never just the patients, the patients and their families. And I heard the word hope at least a half a dozen times used today. It's not just hope, it's the realization. I also want to take time to thank all of our investors and analysts for being here. I know that there's a lot of you that came in, in person. We had over 1,000 that were online throughout the day. That takes a lot of real effort, and I appreciate you to actually show up and do those.

But I want to talk specifically to the employees now. Working at ImmunityBio is not a job. It's not a career. It is a true calling because I know there are a lot easier places to work because we literally work 7 days a week, and we are working for one reason, and it's this man's mission and vision right here. But I really want to thank Patrick. Patrick, you're the reason everybody is here, but you're the reason for that hope. Patrick and I have now worked together for a number of years, and I've told him this many times, I said, I don't know anybody who works as hard as you and no one's ever called me an easy pleasy guy through these. Literally, he could be sitting on a beach somewhere doing nothing, but yet he's devoted his life to saying, I want to bring a cure to cancer and let people throw stones at me for saying that in my lifetime. And we're literally on the brink of this right now.

As we close on this piece right now, I always tell everybody, think about ImmunityBio in 2 sides of this house. One, what are we doing in urology, and we're not a urology-only company, we're not an ANKTIVA-only company. And it's really important, and we love that space, but also think about what we're doing in all of oncology, infectious diseases and everywhere. On the urology side of the house, Matt, who I'm looking at right now, wakes up every morning with an e-mail from me or a text message saying, okay, we need to do more than we did yesterday. Literally every day, he gets that same message from me and every day he replies back. I understand, I get it, and I assure you we are. When you saw the chart on there, it's coming true.

Now what's really important this year was that submission that we just announced of the papillary BLA. We will be the -- while others have tried to hold us back, we're the only company that we're aware of that has submitted for that. And having a true regulatory approval is very different than just guidelines. It also allows you to then submit that globally.

We have already submitted and again, to our knowledge, we're the first and only who've submitted for EMA and MHRA approval in this space. And while the trials in naive are very important to us, the things that make me just absolutely blown away is the lymphopenia, the pancreatic cancer, the non-small cell lung cancer, what you saw with prostate, ovarian, all of that is going to change the face of what it is that we're going to do. And so for all of the employees that are here dedicated and I know sacrificing and I appreciate it, we are making a difference. And with that, I'll turn it over to Patrick.

Thank you. Phil if you can get that cancer BioShield slide up . I don't think it's up. So I think I'm going to close now and will be 2-minute close so that you all can be relieved of this long day. And thank you for being here, just as Richard said. And as we started with this discussion, when I say lymphocytes matter, it's not just 2 words. As you heard throughout the day, NK and T-cells duration matter, survival matters, most importantly quality of life matters. No point of us actually treating a cancer patient and giving them the last few days of their life pain and suffering for both them and the families.

So the opportunity for us to actually do that, next slide. And the idea that we have had this missing link for all these years. And it's not a fault of doctors that don't look at ALC because there was nothing else there, next slide. And the opportunity now to change that course is really a simple yet profound change which I believe will be a paradigm change in cancer. And so this is how that we said this is an inflection point for us in April 2024, which really allowed me to come out now and express this missing link. And that triangle offense, and I thank Luka Doncic and we are in good shape with the Lakers, that triangle offense is really what's going to change, I think the paradigm of cancer care for the -- hopefully, for the next 50 years. So thank you for all of that. And if there are any questions, I'm happy to take them and we can take them after the fact, I know it's been a long day. And again, thank you for your attention today.