Current & Future Role of Anktiva (N-803): Dr. Patrick Soon-Shiong

Introducing Anktiva and Dr. Patrick Soon-Shiong's Vision So today, this one discussion is going to be different because your job and my job is going to be at stake as an oncologist if the upcoming predictions in this conversation come true. And to be honest, we would all love that. Can we really cure cancer? Hello and welcome back to the Oncology Brothers Podcast. I'm Rahul Gosain, A practicing community medical oncologist here with my brother and Co host Rohit Gosain. As always with these discussions, our mission is to bridge the gap between academic research and community practice where majority of our cancer patients are getting treatment today. Speaker 2 That's right, Rahul. We have been talking about cancer treatment conversations around microbiome and immune modulation. Even going back that is before immune checkpoint inhibitor, we were using IL two treatment to excite immune system to recognize cancer cells. Today we're talking about immune respiration strategy, focus on Angtiva and Illinois 15 receptor super agonist To unpack what we have at hand. We're excited to welcome a true pioneer in the field of oncology doctor Patrick Soon Shuang, A transplant surgeon by training. Importantly, he helped change the field of cancer about 20 years ago. That is bringing NAP paclitaxel, which we still use in our clinic routinely for lung, pancreatic and breast cancers. Patrick, thanks so much for joining us. Speaker 3 Thank you for having me. Speaker 1 Patrick, welcome. As Rohit mentioned, your work led to the approval of NAP paclitaxel Abraxane back in 2005. And more than 20 years later, we're still using this heavily in our clinical practice. But now your work has been around Illinois 15 receptor Agnes with hope to cure cancer. This is currently approved in non muscle invasive bladder cancer here in the US And more recently this received an accelerated approval in Saudi Arabia for non small cell lung cancer with immunotherapy. Can you touch a little more on the mechanism of action for Angtiva? You know as medical oncologist, we feel very comfortable with PD1, PDL 1 and CTLA 4 blockade. But what's the biology around Illinois 15? Understanding Anktiva's IL-15 Mechanism for Immune Activation Well, thank you for having me. So look, I love the idea that I'm talking to community oncologists. That's where actually all the patients are. That's how we treat patients, where we can treat them as outpatients. And your patients are your patients for life. They trust you. They they're, they locally. And by the way, I heard your opening, this is not to replace the community oncology, in fact not in their handset. So let me give you a little bit of sad sort of scientific error, so to speak. You spoke about aisle 2 and you spoke about aisle 15. As you know, aisle 2 got accepted, approved way, way, way back for renal cell carcinoma. Sadly, the mistake, and this is where the mistake was in the scientific understanding. We've only learnt of this mistake now, aisle 2 and aisle 15, which is these two cytokines in your body. So they're natural products in your body, stimulate the same receptor on T cells and NK cells. So if you use Illinois 2, when it goes on to the T cells, guess what happens? It stimulates the suppressor cells. It actually went the wrong way and that's why it was not only toxic, it didn't work. On the other hand, when you stimulate Illinois 15 on your T cell, it proliferates the T cells and makes them a killer T cell. So in 2012, the NIHNCI wrote a paper that the most important cytokine or interleukin in the history of medicine that could cure cancer was Illinois 15. So why was it never approved or developed? Well, they tried. The NIH tried. NCI tried because when they injected it and lasts for a few minutes, it was gone. So we modified this Illinois 15 so that it has a long acting and subcutaneous injection. That's it, a subcutaneous outpatient injection to allow your body to be the factory. And this Illinois 15 lasts so that your T cells grow, your incase cells grow, your memory T cells grow, and now you have your killer cells around your tumor independent of the tumor type. That was a revelation that I said, wow, it's not what they call the cure of cancer. This is the foundation of how we can attack cancer and address it. What was really disturbing to me, and I trained under Don Morton in the Melanoma at UCLA and the Cancer Center. I did all the whipples and then I would follow the patients when the oncologist would treat them. As soon as you give chemotherapy, you should ask your colleagues. You all look at the CBC and you look at hemoglobin, you look for anemia and you give Epogen. You look at the ANC and you give Neupogen and you give Neupogen. So you can give more chemo, right? It turns out that the both chemo and radiation knocks out your NK cells and your T cells. Do you need your NK cells and T cells to kill cancer? And the answer that is yes. I mean, we all of us never been taught to look at ALC, not ANC, but ALC. And the reason for that is it's never been a treatment ever in the history of medicine to stimulate your NK cells with a single injection and increase your ALC. We have now found that if your ALC is below 1000, you're in real trouble. If we get your ALC above 1000 to 1200, we triple the median overall survival of lung cancer. We've done a randomized clinical trial to show that in lung cancer against check, check when inhibitors, check when plus Angtiva the ALC goes up, check when goes down. If you get chemo radiation, you should look at your patients at your center radiation. Look at the ALC 2 weeks, 3 weeks after it. I would guarantee you 90% ALC will be dropped below 1000. So this is what happens where for the first time we have in our armentarium ability to give a patient an outpatient injection and stimulate the ALC. And once you do that, all of a sudden patients that were in progression turn around. So we are now seeing complete responses in glioblastoma, recurrent glioblastoma. We're seeing patients with triple negative breast cancer, a lung cancer, prostate cancer. And the answer is why? Because it's universal. So this is one of the first universal truths is that we have in our body the power within us to stimulate the very cells that kill cancer with a simple subcutaneous injection that's already approved but a tiny subset of bladder cancer. Promising Clinical Data and Future Cell Therapy Potential Well, thank you so much Patrick. To cover that important mechanism of action that is trying to expand and activate the natural killer cells or NK cells to restore anti tumor immunity. Well, as you've mentioned, multiple studies around Inktiva have shown that what we are trying to do is improve that lymphocyte count. From US standpoint, we have this approved in bladder space. Speaker 3 So if you go to ncclintrials.gov and type in the word QUILTI made-up that word, it means quantitative integrative lifelong trial. We've done that in triple negative breast cancer, pancreatic cancer, headed neck cancer, Hodgkin's lymphoma published and it's you're seeing this universal increase survival. So let's talk about even lung cancer. We did a randomized clinical trial in first line lung cancer showed specifically statistically significant increase ALC when we compared the checkpoint inhibitor alone versus checkpoint inhibitor plus Entyva. We then did a single arm trial in patients with failed chemo radiation progressing on checkpoint second line lung cancer where the current standard in your practice will be docetaxel median survival 7 to 9 months. Every trial that's been done. The pragmatic trial showed that no matter what we do, it's 7 to 9 months. When we take these patients, we raise the ALC to 1.2 and about 78% patients, we're now seeing median survival of 25 months in these same patients. So yes, it's applicable. And then we did it the same trial called quote 3O5510, different tumor types, exactly the same thing with the hazard ratios of .3 to .4, highly significant, highly statistically significant. And we submitted this now for publication in one of the peer reviews. It gets more exciting than that because if we can use your body as the factory to make NK cells, imagine then if we give you a injection of Angtiva and then three to four days later we do what we call an apheresis. We've now invented the way of taking that leukophoresis, deconstructing that into NK cells, INKT cells and T cells and grow them in the billions, freeze them down and give them as a product, as an outpatient hang to any patient. These NK cells are allogenic. They're in clinical trials right now. We call them MSNC, which is memory cytokine enhanced in K cells. And my goal is when you combine these two, you literally will have the World Bank of Natural Killer Cells for all community oncologist to hang as outpatients in their clinic. Speaker 1 You know we keep talking about community oncology and this being outpatient because that is the big need. Our patients want to stay closer to home. And coming back to the result from QUILT trial, these results are exciting and we should not sit on something that is active and not get this to our patients right away. But we also have to be cautious in ensuring we're not providing false hope and that is where a large phase three trials come in place today. Where do we stand for Antiva in terms of clinical trials and how close are we of this becoming a reality for patients again? Navigating FDA Approval and Expanding Global Access What data do we have in today for larger studies and the. Speaker 3 Answer is, is yes, and we're doing them. So what's happened if you recall during checkpoint inhibitor days when it was a big sort of excitement and Merck got about 30 indications, all single arm trials, all under the process of accelerated approval so patients could benefit from it, which they should, and then did confirmatory randomized trials thereafter. We've done multiple single arm trials, one randomized lung cancer trial and then now we're doing randomized confirmatory first line, second line randomized trials in lung cancer, in bladder cancer. Let me talk to that and I think that's mainly managed by the urologist, but I think I need to talk to that. So we went into what we call BCG unresponsive, non muscle invasive, which means these patients have no other alternative than a total radical cystectomy. There's no ethical comparator. So the FDA allowed single arm trials. We did that trial for what we call CIS plus or minus papillary and not only we've completed that trial, the patients now free of their cancer, some of them 10 years now. We then come if they gave us approval for CIS plus or minus papyri. We then did another single arm trial for papyri alone and we arguing with the FDA you re approved CIS plus or minus papyri And by the way we believe it's the same disease if you get peppery alone without CIS. Just because somebody didn't see the CIS or doesn't exist I'm not allowed to give it. Now that to me as a physician doesn't make sense because this patient now is in danger of what could progression from non muscle invasive into the muscle with metastasis and death. Or go get a total radical cystectomy with a huge mortality and sepsis when this drug is already approved of CIS plus or minus papyri, but you happen to come into the clinic and says, oh, I only got papyri, forget it. So these are the kinds of, I wouldn't say arguments. This is the kinds of science that I need to sort of discuss and have a very open scientific discussion is where is the safety issue, why we're preventing Americans from benefiting it. So out of desperation, I've gone to Saudi Arabia. It's not approved in Saudi Arabia and it's going to be approved in. I just was on the phone last night with the head of the Saudi Arabia FDA who says we want to now expose this to all tumor types. And I'm moving flying out in a few months to Saudi Arabia and bring my team. But this is really bothersome to me because I want to now bring it to all the community oncologists and we will find some ways where we can Chrome and I can, I want to open this up train everybody have access to it both for the cell therapy and the Antiva. Anktiva's Low Toxicity and Broad Therapeutic Applications Well, thanks. Speaker 2 For covering all that, Patrick, we'll see how this all plays out in long term and especially regulatory approval process here in US. But if this was to get approved widely outside of bladder cancer for oncologists, Patrick, what are the common side effects that we should have on our radar with regards to Antiva? Speaker 3 So we've had already 8000 doses in 800 patients given as subcutaneous. The major side effect, be it or not, is a flare at the site of injection, a little red flare. Guess what that is, It's your NK cells growing in your skin. And then the other side effect is you get a little bit of a fever, which we want because we're activating your immune system is as if you got a cold that day. That's it. That's the majority of the side effects. And that goes away within two to three days. What is is, is really reactivating what is in nature. So we're not giving you a drug, a small molecule and invented. We're literally giving you a cytokine that your body actually manufacturers and we're activating what your body actually does in times of infection, in times of cancer. And believe it or not, even for senescence, immune senescence, for longevity. So we treating patients with now lung COVID as part of the trial. We treating patients with HIV. So we want to clear the virus. We're treating patients with HPV cancer. We've cleared their virus. Not only cleared the virus, we've got incomplete responses in head and neck cancer. So this is a universal truth. What we've done, we've unveiled what's in your body as opposed to giving you a chemo. Poison doesn't mean we don't use chemotherapy. I use Abraxane at such a low dose to actually splash out the tumor, expose the receptors, and then the T cells are around to go do the job of killing the cancer from the outside in. That's the vision here, killing the cancer from the outside in with this natural killer cell and T cell. Speaker 1 And when we say that something's well tolerated, you brought up side effects, We really have to be careful. But this indeed seems to have minimal side effects. And a lot of our medications are actually moving that subcutaneous side of things to begin with. Anktiva's Role in Immunotherapy 2.0 and Lymphopenia Patrick, before we close, stepping back to look at the bigger picture, many of us are excited about this, but we're also cautious. Theoretically, this all makes sense. Restore lymphocytes, activate NK and CDT cells, and now you're turning that cold tumor to hot. And now pair this with your checkpoint blockade, you've coined this term of this being immunotherapy, 2 point O, but clinical practice and approvals are all driven by these survival curves. Is NTIVA ready today for that prime time? And we've seen this over and over. Majority of phase one, phase two trials don't meet our expectations in phase three studies. As your final thought, Patrick, what should I tell that next patient about ENTIVA that I'm going to see next? Well. Speaker 3 Not only we'll show you the survival curves if you have now we in fact at this conference I did and that's the basis of what if the Saudi FDA approved the hazard ratios are .3 the survival curves go to. There's no, to my knowledge second line has failed chemo, radiation checkpoint progressing on checkpoint lung cancer that's given you now 25 months median survival in which we have patients now some patients 36 months. There's another treatment left for these patients. So the good news is that you're right, it has to be steep not only in science, but in data. And for example, the bladder cancer is published in new in journal Medicine. The fundamentals of this work is published in Nature. The clinical data right now with metastatic pancreatic cancer has already been published where we have patients now seven years metastatic pancreatic cancer. So I think, and these aren't anecdotes because they're like one off anecdotes, this is very much like Epogen, Neupogen. When you give Epogen, you don't ask what cancer because you need to restore the anemia. When you give Neupogen, you don't ask what cancer because you have to restore the neutrophils. Well, when you actually measure the ALC, do you not need to restore the NK cells and T cells? And this is what's crazy, by the way, There's an ICD 10 code for lymphopenia. Speaker 1 Absolutely so. Speaker 3 Why would the government put out a code to diagnose lymphopenia and yet not allow you to fix it? Even the efficacy vis a vis cancer? I don't think anybody disputes that you want a normal NKNT cells. No matter what happens to you, whether you young, old age, infected COVID cancer, you want a normal NKNT cells. So if your lymphocytes down below 1000 and I will ask your oncology friends do a pub Med search and type in lymphopenia. You will then be amazed by the numbers of papers since the 1990s. All tumor types that if you have lymphopenia, the hazard ratio. The Kaplan Meyer curbs showed a highly statistically significant higher mortality rate. If you have lymphopenia. So it is that kind of logic that I'm trying to put out there and that division within the FDA is called a non malignant hematological support division. And that's what this is. This is hematological support of your immune system that is measurable by simple CBC. Recap: Anktiva's Potential to Reshape Cancer Treatment We've covered quite a bit here starting out with understanding the mechanism, fashion data at hand and future direction with Antiva. This has been a fantastic discussion. And Doctor Patrick Sunshine, thank you so much for sharing your vision and for decades of your work that has already reshaped the field of oncology. Starting out with nap paclitaxel to this new chapter of Illinois 15 Super Agnes. Many of us are hoping to look back on this broader immune restoration strategy as another inflection point in how we treat. Cancer or perhaps cure cancer. Thanks so much for joining us. For our listeners, let us go. We're a quick recap from today's discussion. Speaker 1 Today with Doctor Patrick Sunshine, the one who got nap patlotaxel approved more than 20 years ago, we had a chance to discuss Antiva N803 and Illinois 15 receptor super agonist designed to expand and activate NK cells and CDA T cells. Right this minute Antiva is approved for a small subset of non muscle invasive bladder cancer and this recently got approved for non small cell lung cancer with immunotherapy in Saudi Arabia with what are you walking away with today's discussion. Speaker 2 Well, Rahul, I must say this is exciting, especially when you tie in that this can be used for entire tumor field itself. Theoretically, what we're talking about is immune therapy, 2 point O where we are turning cold tumors into hot and having our immune system recognize these tumors and rather fight it, which sounds very enticing. Though we still need randomized data at hand where we are looking at survival at long term and even patient centered outcomes. Though what we're seeing here is better tolerability, the side effect profile seems very favorable. Speaker 1 I completely agree, that whole idea of modulating the immune system hopefully will get us to a point where we turn cancer into more of a chronic disease. But we still need more positive studies and larger data here for Angtiva, which we are eagerly looking forward to. Thank you for tuning in. Make sure to check out our other conversations around FDA approvals, conference highlights and treatment algorithms. We are the oncology brothers.