Ashish Kamat:

Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center. And it's a distinct privilege today to welcome Dr. Patrick Soon-Shiong, who really needs no introduction. I mean he's a giant in the field, in so many different fields. But today it's a pleasure to have him here as Executive Chairman of ImmunityBio to talk to us about the mechanism of action of N-803. There's been a lot of activity with N-803 in the BCG unresponsive patient population presentations at landmark conferences. And of course we're really excited about the clinical data.

But, Patrick, today thank you for taking the time out of your busy schedule and spending with us discussing the mechanism of action and some future steps that you envision for the molecule, the drug, and the field in general. So with that, the stage is yours.

Patrick Soon-Shiong:

Oh, Ashish, thank you so much for giving me the platform to talk about the mechanism of action. It's really something I love talking about. The results, I'm excited to say, will be soon coming out in some peer reviewed journal. But this opportunity to really describe the mechanism of action is such a great privilege and opportunity.

So, let me speak very quickly, just to summarize the next slide. And as many of you may know, this has already been published, the phase 1 work, which is very encouraging, independent of the dose of 100, 200 and 400 micrograms in both papillary and CIS disease in the naive setting. Nine out of nine patients had a response or disease free after. And the what was very exciting was the duration in 24 months.

The next slide. The results that we are talking about today in the BCG unresponsive setting, this is the CIS disease. And as Ashish just mentioned, this has been presented at multiple conferences already, including AUA and ASCO. But a 71% complete response with a 26.6 months duration of response and a cystectomy avoidance of over 90%. And the disease specific survival of 100% speaks to the question of what is happening here when you combined BCG plus IL-15. And I thank you for the opportunity to literally take the time over the next maybe four or five slides, the next slide, to try and address and speak to why we think this immunological mechanism is happening.

Unfortunately, to really understand this I need to take us through multiple steps of thought. The first step is what is the Natural Killer Cell and how does it work? The next step is what is BCG and how does it work and why does it cause relapse and why does it become unresponsive? And the next step is what is N-803 this IL-15 superagonist and how does that work? And then finally, when you combine these two, what happens to give you this immune memory and this complex crosstalk and the role of Gamma interferon?

So unfortunately, it's not a simple answer in terms of trying to understand the mechanism. And I'm going to try and be methodical and take us through first the NK Cell, BCG, N-803, BCG plus N-803, and pause after each one of those and then really put them all together in this complex crosstalk to really explain why are we getting this duration of over 26 months.

So let's start first about Natural Killer Cells. So this Natural Killer Cell story remarkably was only discovered in 1974. So it's within our lifetimes that this cell was discovered. In 1990, I published the paper while I was assistant professor at UCLA working on both pancreas transplant and pancreatic cancer and published the fact that there's this Natural Killer Cell that results in direct killing by cell to cell contact of pancreatic cancer. In 1992, Dr. Hans Klingemann discovered a natural killer, NK-92, that's why 1992, cell line. And that's what we are engineering to give off the shelf. But I think it's now been fully understood that the Natural Killer Cell, unlike a T and B cell, recognizes the tumor on the right, as you could see from this video, and with its activating receptors kills the tumor quite literally through these granzymes.

And what it does, it finds in this tumor cells that have loss MHC-1 and it can no longer be recognized by T cells called the missing self. I bring that up only because this missing self or loss of recognition by MHC-1 is unfortunately an effect of BCG itself. So to capture the understanding what a Natural Killer Cell is, it's basically a cell, immune cell, that's floating around in your body, it's been around for 500 million years, that when it recognizes either an infected cell or cancer cell goes for it directly and kills it by inserting these granzymes, as you could see from this video. These five publications at the bottom of the slide speak to the characterization of this Natural Killer Cell.

The next slide is how does BCG work? Well, it turns out that from 2001, Brandau in this paper, showed that NK Cells were essential for effective BCG immunotherapy. And BCG, in 2014, was discovered to generate what we call trained immunity in macrophage cells in Natural Killer Cells. And that's the reference you could see I refer to in the slide. But what was really exciting in 2020 as recently as Van Puffelen showed that this concept of trained immunity with BCG is one of its mechanism of action that allows this BCG to activate Natural Killer Cells and T cells and then kill the bladder cancer. And so therefore BCG is an active immunological agent. Unfortunately, what happens, and I'm going to draw a little bit here, is that after it kills the cancer cell with the Natural Killer Cell and T cell, what happens is BCG also down-regulates the tumor so it no longer can be recognized by T cells with MHC-1 loss and it's a form of tumor evasion. And now we have the super selected resistant cells to T cells and we end up with BCG unresponsive bladder cancer.

So this mechanism of action of BCG is really newly understood from 2001 all the way to 2022 of it activates, induces, trains, and then activates NK and T cells, very responsive in terms of activating the tumor but then relapses.

The next slide is to talk about how does N-803 work? If I can go to the next slide. And what is this N-803 or Anktiva? Well, this is the heart of the molecule. The heart of the molecule is the IL-15 and IL-15 receptor alpha. And what that molecule does, it binds to the receptor of the T cells and it binds to the receptor of the NK cells. And its job is to activate and proliferate these two cells. So these are the killing cells. It does a fascinating job because it is also not just an IL-15, it's a mutated IL-15 that binds to the receptor of the T cell that specifically activates killer T cells and not T Reg cells.

The other advantage of this, it has this FC fragment that gives it a long half life and it can therefore be given either subcutaneous or intravesically as we do for BCG. So in essence, it brings these trained macrophages, it's been trained now by BCG, it brings in Natural Killer Cells in bringing activated T cells. And by so doing it actually draws in memory T cells.

So here are these papers in 2009, 2014, 2016. Again, I refer to these papers in this publication that has been published over time with the basic fundamental analysis and knowledge of how N-803 works by bringing the killing cells to the local tumor micro-environment, taking advantage of the train immunity through the IgG opportunity and the train immunity of the macrophages of BCG prior, activating NK and T cells. And interestingly, by activating the NK cell, all of a sudden the NK cell can go after exactly what BCG has wrought, i.e. the cell with MHC-1 loss. So now this NK cell which is trained to find cells that have lost their ability to be recognized by T cells and kills those cells. So you now have the combination effect of the IL-15 in this way.

So what you see here, and obviously this is way too deep for us to go into for this talk, but this is the basis of what we call the NANT cancer vaccine. And we have now published this work for pancreatic cancer where the heart of the matter is the Natural Killer Cell. The heart of the matter is overcoming not giving T Reg cells by having IL-15 activating not only the Natural Killer Cell but the tumor cell, the T cell, I beg your pardon. And by activating the T cell and the dendritic cell, you drive memory. All this crosstalk is now culminated in the BCG plus N-803, which I'll try to take you through the next slide.

So here we go with all that fundamental dissertation behind us that, what does BCG do? Well BCG, it comes and it induces these things called PAMPs or DAMPs. It causes this bladder tumor cell to think it's basically infected. And in so doing, it up-regulates your innate and adaptive immune system and this innate system of the NK Cell is there to actually recognize an infected cell. But it also has an added new advantage of this trained immunity. So BCG now starts training, giving memory, to these macrophages. So this explains why BCG is so highly effective initially. But then what happens is that the BCG itself induces MHC-1 loss an evasion from the T cell. So now, no longer can the T cells recognize it. And we have a super selection of these resistant bladder cancer cells. So you go from relapse to refractory to unresponsive.

And this is the kind of patient now that we enroll into our 3032 trial in which a patient has a T-cell resistance, MHC-1 loss, and a trained macrophage. And what happens next? Well, what happens next, the combination then of a BCG prime which induces these DAMPs and continues to do so, and continues to stimulate the fact that there's NK Cells and T cells. But now you have a boost of IL-15 that induces NK cells, T-cells, and memory cells. And what happens there when you do that, you see then this concoction of local immune systems of NK cells, CD-4 cells, CD-8 cells, T cells, Memory T cells, and really gamma interferon, which changes then the profile of this tumor cell where no longer is MHC-1 loss, it now up-regulates to MHC-1. And the consequence of this [inaudible 00:13:06] happening results in a complete response. So the mechanism of action then is a pure immune effect of an orchestration of the NK Cell, the CD-4 cell, the CD-8 T cell, the memory cell and orchestration of gamma interferon.

Next slide, which takes us to the durable response. My belief is that what's going on now, we're really generating sufficient memory and in closing then we've gone from the concept of trained immunity, and this is a new concept now, coming up in the cancer space, the infectious disease space, immunological space of the concept of trained immunity to immune memory. And that's the mechanism of action I believe is going on here. And I'm so pleased to say that this is a first clinical validation of this concept that if you orchestrate the immune system, that your body has the power to really overcome tumors without high dose chemotherapy. So, thank you, Ashish. I hope that that helps speak to at least the mechanism of action.

Ashish Kamat:

It certainly does, Patrick, and thank you so much for taking the time. I mean you really distilled a lot of information, a lot of science, into a very short time for our audience, which is great. And I must confess, I didn't realize that you'd been working on this since the 1990s. I mean you have a long history with this for sure.

A couple of questions, and obviously we talked about the mechanism of action today, but our audience and people listening in have the clinical study in mind and they're excited about the activity that, as you said, has been presented at different conferences and should be out in publication relatively soon. So let me ask you questions related to the mechanism and also the clinical efficacy. You dose the N-803 along with the BCG and there is a school of thought that postulates that there can be exhaustion of NK Cells if you give IL-15 at a higher dose level or more frequent than it can. Each patient is different, but you can exhaust the NK Cells. Do you have any hypothesis or any postulate as to how long do you think patients can be retreated or will need to be treated with this combination to have a durable response?

Patrick Soon-Shiong:

Yes. So we've shown actually normal healthy volunteers where we've given subcutaneous N-803 and look at the peak effect of NK and T cells and then as it wanes and the second peak effect. And it turns out every three weeks is the ideal. If you go too close to each other, you then truly get into exhaustion. So every two weeks is too soon. Every three is ideal. We've done doses at basically the same time, the six plus two that you've done. So the number of doses we give in about a year is about 12 doses. And then we give maintenance about four doses per year over. So over a three timeframe in which we've gotten, it's about 20 doses of N-803.

Ashish Kamat:

Okay. Great. And the other question that often comes up, and I know I had this question when I saw the initial results because the side effect profile is really almost in many ways too good to be true, right? We have these patients that have been previously treated, they have severe side effects with BCG. And when they get the combination of BCG with N-803, their local symptoms are much better than one would expect. Now do you think that this is because of, and again please correct me if I'm wrong, but there is a Yin and Yang and in some patients it's believed that IL-15 might actually have an anti-inflammatory response, for example, Crohn's disease. Is that what you think is going on behind the better than expected tolerability, or is there some other mechanism?

Patrick Soon-Shiong:

If I could pull out that slide full on that NK slide, the slide that shows the NK. And this again now is a hypothesis, Ashish, because we haven't really studied how and why. The beautiful thing about an NK Cell, it has about 30,000 receptors on it. This is really still an untested cell. It's an amazing cell that has on the one side activating receptors, and in other side of it inhibitor receptors. So it is the cell in your body that actually gives you balance, the Yin and the Yang of the agent is really real because the inhibitor receptors is on the anti-inflammatory side of it. And the activating receptors are the activating side of it. When we do this NK-92, interestingly enough, it has no inhibitor receptors and that's why it's such an amazing killing machine. We can engineer this NK-92.

When we up-regulate the NK cell in your body with IL-15, this is what we up-regulate. So this is where I am hypothesizing. Now I cannot tell you why or how, we're just seeing what we're seeing, i.e. the effect. But it appears that NK Cells or IL-15 appears to damp down any super-inflammatory response or cytokine syndrome. We've not seen that in our solid tumors, any cytokine. In fact, quite the opposite, even when you give checkpoint inhibitors. Again, anecdotally again, you see some abrogation of the immune side effects of a checkpoint. We appear to see a high IL-10, some IL-10. And where the IL-10 is a cytokine it damps down because it has two kinds of effects.

So I can't give you a scientific answer of why I'm hypothesizing that when we give the N-803, and by the way, there's no systemic absorption. When we give it in the bladder, there's nothing that comes into the systemic circulation. So it's a local effect. So if BCG is having its effect locally with regard to inflammation, is there some dampening effect by the inhibitor receptor of the NK Cell? That's my hypothesis at this point, but I can't explain why with great scientific rigor. But I'm hypothesizing this is what's going on.

Ashish Kamat:

Okay. Well, thank you very much. That makes a lot of sense. Patrick, I could sit and chat with you on this topic for an hour. But let me sort of hand the stage to you and any closing thoughts, whether it's in relation to the timeline of the drug or other disease states or anything you want to share with our audience about this combination for our bladder cancer patients and N-803 in general?

Patrick Soon-Shiong:

I think it's been made public that we filed the BLA and the results are sitting with the FDA for the review. We've also completed the papillary BCG and the non-invasive papillary study right now. And we've made that data public as you know, and we've met that primary endpoint. And we get over 50% disease free survival at 12 months for papillary disease. So it looks like there is, and similarly with regard to the safety in both papillary and cysts. So it looks very exciting that within these two BCG unresponsive categories, the results are similar. I can only obviously have to wait for the FDA's decision of where that goes. I'm also pleased to say it's a little premature to announce until it's fully, but it's been at least editorially accepted, the cyst data at the peer reviewed journal. And that'll be coming out soon. And then finally, we are moving towards recruiting our BCG naive study.

And then thirdly, we have to think about is there a way of having a study in which we can actually replace BCG with our, and we can contemplating taking gemcitabine plus N-803, for example, versus BCG and N-803. And would the gemcitabine have the same damp effect as BCG does? And what we've seen, at least in our solid tumor studies, when we give low dose chemotherapy as a damp effect, it works in pancreatic cancer. For example, we've doubled the survival in third line pancreatic cancer, metastatic pancreatic cancer patients.

So I think this is the first, as I said, it's such an honor that within the world of, I'm a surgeon, so I did pancreas transplant in the world of surgery of urology, that we can bring this truly immunological treatment without chemotherapy intravesically at a local level to the market, I hope, with the FDA approval. But at least the signs have shown that we've made a difference in terms of really cystectomy avoidance in over 90% of patients will respond.

Ashish Kamat:

Right. Excellent closing points. And once again, thank you for taking the time, Patrick, and spending with us. Great to see you.

Patrick Soon-Shiong:

Well thank you, Ashish. Thank you so much for the time. I appreciate that.