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Ashish Kamat: Hello everyone and welcome to UroToday's Bladder Cancer Center of Excellence. Today it's my pleasure to introduce to you, to all, a special guest who has been on UroToday before, but today Dr. Patrick Soon-Shiong, who's Chairman of ImmunityBio, a surgeon scientist, a deep thinker, someone who's truly involved in wanting to do and has now actually gotten approval for a drug that will do great things for our bladder cancer patients here with us in the studio. Patrick, welcome.

Patrick Soon-Shiong: Thank you so much, Ashish.

Ashish Kamat: Patrick, very exciting news, and we're going to break this down in a few easy-to-digest snippets for the community that's listening, the educational value, and the urologists at large. First off, if you could share with us your journey. What made you think of bladder cancer, IL-15? What got you involved in this field and how did it evolve?

Patrick Soon-Shiong: What got me really involved is I was doing cancer surgery at UCLA for pancreatic cancer, and also doing pancreatic transplants at UCLA. I trained under Dr. Donald Morton who was using BCG for the treatment of melanoma. By 1990 I wrote the first paper on natural killer cells, and it became very apparent to me that the parent cell that either kills the transplant when you do transplant rejection or has an opportunity to kill the cancer is this natural killer cell, which is 500 million years old. That began the quest while I was at UCLA and it says we have to find a way to activate your immune system to fight the cancer.

Ashish Kamat: It's amazing. Your background as a transplant surgeon and a transplant immunologist is what led to this stimulus. Take us through the journey of how you moved from there with the mechanism and the IL-15 into bladder cancer. Just briefly, because everyone's interested in this.

Patrick Soon-Shiong: Everybody uses chemotherapy and even everybody uses BCG, and now as it evolved, everybody uses checkpoint inhibitors for all tumor types. It became very apparent to me that we were winning the battle. We see a response rate. We were winning the battle even more when you talk about progression-free survival, but we weren't winning the war. The war is a cancer-free overall survival with the duration of response. The complexity of this immune system, the more I studied it, the deeper I got. It was like getting into an astrophysics room looking for God's particle and it just got more and more and more complex and became really clear that there were cell-to-cell discussions between T-cells and K-cells, IL-15 discussions about proliferation.

I needed to not only sort it out but actually derive a product that clinicians like myself and like yourself could use in everyday life that is safe and active and would synergize BCG, which is an amazingly good stimulant, to activate your immune system. That's how I started this journey, 2010, it's now '24, across first developing Abraxane, now Anktiva, and it's soon the next generation of another molecule. But I think this is a slow walk towards changing and transforming bladder sparing in the community of urologists.

Ashish Kamat: We'll clearly talk about the drug and its approval and indications in a segment shortly, but if you could take a little bit of a deeper dive into the mechanism for those in the audience that are truly interested in the whole hot/cold tumor, the NK cells, how the B-cells, T-cells interact, the whole memory effect, that would really be enlightening.

Patrick Soon-Shiong: I will share with you and maybe we'll give you a slide that you could put on that I drew in 2016 when I shared this with the White House to say we want to launch this cancer moonshot and this is how I think the body's cancer cells work. It's a crazy drawing that I presented in Toronto.

But to boil that down to the essence, it turns out that all the therapies that we use—chemotherapy, radiation, BCG, checkpoints—cause what we call a Darwinian progression to a clonal selection of a cell that hides from the T-cell. I call that an MHC-1 negative T-cell, a cold tumor. We all recognize the cold tumor.

We all recognize the T-cells, like checkpoint inhibitors and CAR-T can treat all tumor types as shown by Merck and Bristol-Myers. But all of them get to a point where the tumor has selected the cell regardless of cancer and bladder cancer, prostate cancer, or kidney cancer, that is cold. If it's cold, the T-cell can't recognize it. And guess what God has given us? God has given us where if any cell is MHC negative, you and I have in our body a natural killer cell that looks for that cell and kills it. That was the key to actually activate this natural killer cell to kill this clonal selected cell and not only kill it, but then stimulate a thing called gamma interferon. You may know about interferon way back in the urology space. What gamma interferon does is it reactivates the receptor to the T-cells. Now you rescue the T-cells. Now, when you have a combination of the natural killer cell and the killer T-cell, you now kill the tumor and you get the complete response. But that's not enough because it is the duration of this complete response that really matters.

In order to get the duration, you need to stimulate the memory T-cell. Once you have these two cells working, the memory T-cells come on with the gamma interferon and the natural killer cell, and that's the mechanism. I call that the triangle offense of the natural killer cell, the memory T-cell, and the killer T-cell. With one molecule, we can actually activate that and that's the Anktiva molecule. It's taken me eight years to get it through the system, develop it, demonstrate it, and now get it approved.

I see that as the next generation immunotherapy for bladder cancer, soon hopefully for kidney and prostate cancer, lung cancer, but that's how it works. Converting a cold tumor to a hot tumor with an Anktiva cycle in which we use BCG within the same workflow as BCG and synergize with BCG.

Ashish Kamat: It's a perfect segue into the whole study and the approval and so on and so forth that we'll come to in the next segment. Thank you for taking the time to explain the mechanism to our audience. There are some that clearly just want to know if the drug works and there are many that actually want to do this deep dive. Hopefully, we'll be able to get that slide, put it up, and have it for everybody to look at on this UroToday podcast.

Patrick Soon-Shiong: Thank you for having me, and you're right, we'll talk about the what, which is, what does it do? This is about the why or the how. As you know, I love talking about the why and the how, but soon we'll talk about the what. I appreciate the time. Thank you so much, Ashish.