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Arie Belldegrun on the immunotherapy revolution

Octavian Report: Could you lay out in basic terms for an intelligent layperson how immunotherapy works on cancer, and why it’s different from previous treatments.

Arie Belldegrun: First, I have three decades of immunotherapy experience. It’s not something new. Now, everyone wants to position their product as an immunotherapy product — because that’s the buzz. But for years, it was not so. It was hard work, just working at the bench, creating data and providing what today is modern immunotherapy.

Essentially, over the last five decades, the approach to cancer was to hit the cancer cells wherever they are, in a non-specific way. Which means chemotherapy. It kills the good cells and the bad cells. You treat 100 percent of the patients for a 15 to 20 percent response.

A lot of people are getting all the side effects, very few are benefiting. But you couldn’t personalize who should be getting what. So the field moved to what’s called targeted cancer therapy, meaning: learn the basic mechanisms and pathways by which the cancer cell operates, and try to block these roads, either by blocking their blood supply or blocking their way of proliferating and growing.

Immunotherapy is something completely different. You do not attack the cancer. You manipulate the immune system. The immune system works in a simple way, asking: “Are you mine or you are not mine? Do you belong to my body or you do not? If you do not belong to my DNA, my body, I will reject you.” And who is rejecting it? Killer cells called T-cells. And these are kind of at the center of everything that’s happening today: they recognize “mine” and “not mine.”

Now, cancer is quite smart. After a while, it learns to shield itself from the immune system by building kind of a fence around itself. Then the body cannot recognize the cancer as foreign, as not part of the system. And therefore, for years, immunotherapy did not get attention. But recently, with new genetic engineering technologies, you can take those very same T-cells and engineer them to do whatever you want them to do, rather than what the cancer wants them to do. Suddenly, everything has changed.

And that’s also part of what Kite is doing. Engineering your own T-cells. We take your T-cells out of the body. We engineer them very specifically. And we give you, the patient, your own T-cells but now super-charged — and with a sort of GPS designed to take the engineered T-cell, the killer cell, directly to its target. They have an antenna that tells them, “This is a cell that needs to be killed.” And it is killed. So you are not using chemicals to kill the cancer. You are using your natural immunity in a more activated way to kill the cancer. That’s what’s special about it. Potentially, immunotherapy can be combined with everything. It can combine with surgery, combine with any other treatment existent up to now. One stream of the new immunotherapy, checkpoint inhibitors, is becoming an industry of $20 to $50 billion. And we have the technology, today.

OR: Do you think this will work with every kind of cancer?

Belldegrun: I cannot say every, but many types of cancer, because this is not specific to a single type. Let me back up and say that, for years, the notion was two types of cancers are most sensitive to immunotherapy. One was melanoma. You saw a rush to develop a melanoma treatment. The second one was kidney cancer. And while the immunotherapy was developed first for them, suddenly we realized that it actually works for lung cancer. It works for prostate cancer. It is now moving to many other tumor types — even bladder cancer, where we never thought that it would work. It’s using the immune system to reject your own cancer. And the immune system doesn’t care if the cancer originates from a melanoma cell or from the brain. It’s like a professional killer.

OR: So is it a matter of identifying the right target on the cancer cell? Is that what’s at the heart of what’s making this therapy work?

Belldegrun: That’s the key. And that’s where all the IP is running to. The whole world is looking to find targets for cancer immunotherapy. That is the bottleneck of the industry. We signed a huge deal with Amgen, a multi-year, multi-product deal, through which they are providing us just those targets. We provide the technology; together we will use it to develop the next generation of drugs. We needed them because they own now both deCODE and Micromed’s genetics, among others, which they bought for $1.6 billion precisely to acquire these targets. Each target is a specific target.

These targets allow the engineered T-cells, the killer T-cells, to make sure they are acting only on cells of cancerous origin, and not on normal cells. If, for example, somewhere in your body, in the biliary tract or in the brain, there is an antigen similar to the cancer, the new T-cell will destroy it immediately as it destroys the cancer. We need to make sure that the T-cells attack tumor-specific antigens that do not exist in any normal tissue in the body. One such antigen was found in an area in the bowel, and what happened? The T-cells melted the cancer but also created a hole in the bowel. This also occurred during the treatment of a brain cancer — a hole in the brain. So you have to go very slowly, very carefully. And that’s the reason why the FDA so far has not yet approved any drug.

This is a new type of cancer therapy that we are moving very rapidly, but at the same time, very cautiously into approval. Our plan at Kite is to start the first ever multi-center trial of this tech this year and submit the data to the FDA in 2016. If all goes well, the product will be on the market in 2017. And our competitor, Novartis, has a similar timeline.

What we are doing is giving one single infusion to the patient. And that’s the difference. We are not giving a treatment for life. These cells are long-lived. They live as long as you do. They have memory and they don’t lose their specificity. So if the cancer starts growing, they immediately come after the cells and kill them even six months later.

OR: It sounds as though there really shouldn’t be side effects to this treatment.

Belldegrun: Yes and no. These cells are not attacking normal cells. They are not going to create hair loss. But they are melting tumors within weeks. Where is all the debris going? Into the blood. And it can take time till it is cleared from the body. So you have what’s called cytokine release syndrome. Therefore, in the first two weeks, you have side effects. But after two weeks, all of that disappears. Patients don’t need anything else. The longest we have now alive is over five years. And these are patients that, barring our treatment, could not have lived more than six months.

OR: Why does it work on some people and not others?

Belldegrun: Very good question. We need more patients to understand why. So far – see January’s issue of the Journal of Clinical Oncology — we have reported 92 percent success with this type of treatment in a variety of blood cancers: lymphoma, leukemia, very aggressive types of cancers that everything else failed to treat. Why the others did not respond, we don’t know yet. Eventually, we will learn why. But for now, there’s not enough experience to answer that question.

OR: Can you explain CAR (chimeric antigen receptor) treatment for blood cancers versus TCR (T-cell receptor) treatment.

Belldegrun: Yes. The investor world somehow decided that CAR’s are for treating blood cancers and TCR’s are for solid cancers, but that is not the case. This is just the beginning. With CAR, we went after a target, the most low-hanging fruit in the body. Every B-cell – not T-cell – every B-cell in the body has an antigen called CD19. And therefore, when you develop leukemia or lymphoma, there’s a proliferation of these B-cells. And there is more of the CD19. So we said, “If we make our target for destruction CD19, we will tell the body, engineer it. You engineer the T-cells to kill every CD19, you will eliminate all the blood disorders.” Eventually, CAR will work for solid and for hematologic or for blood disorders, and TCR’s which are now believed to work more in the first steps in solid oncology will work also vice versa. We were the first company in the world to do this five years ago. Today, you have Juno, you have Novartis, you have Celgene. You have all the big pharmas getting into it. It’s a relatively young field, and CAR and TCR’s are two-platform technologies which are very powerful. One is the engineered CAR and the other one is the engineered TCR.

The difference between the two is that CAR is attacking targets that are sitting outside the cell, on the surface of the cell. The immune system can see these targets. The problem is that from all the targets that are known, only five to 10 percent are sitting on the cells. All the rest of the targets are inside the cells, and the immune system cannot see the targets inside the cancer cell. So you needed a technique by which you bring outside the targets from inside the cell.

That’s TCR in very simple words. TCR is a technology which brings the target that is buried inside the cancer cell and exposes it outside the cell, so that the immune system can destroy that cancer cell. Kite Pharma is the only company that is currently treating patients with both platforms.

OR: Some of the more recent trials are using combination therapy.

Belldegrun: Not yet. In immunotherapy, yes, but not in engineered immunotherapy.

OR: If it’s truly engineered, do you think you’ll even need combination therapy?

Belldegrun: A very good point. I don’t know, but I believe that in the beginning, everybody goes with a single agent. But since you would not get a 100 percent success rate, the question comes: should we combine it with another type of immunotherapy? I believe that you will see also combination therapies as well, number one. Number two: what are the checkpoint inhibitors doing? The checkpoint inhibitors, which are currently on the market, are anti-PD-1 or anti-CTLA-4. What they are doing is removing the foot from the brake of the immune system. That’s all it’s doing. It’s not pushing on the gas. We, to continue the metaphor, are pushing on the gas.

But the immune system is not meant to be supercharged. So immediately, the body develops a mechanism of down-regulating, downplaying this pushing on the gas, and it’s pushing on its own brake. So the other medication, i.e. the checkpoint inhibitors, are removing the foot from the brake. Not letting the body push on the brake.

If you want to win the race, you both push on the gas and remove your foot from the brake. It’s very simplistically put, but that’s what the logic is. You cannot push very hard on one area without the body saying, “Hey, let’s stop and re-evaluate.” When we are supercharging it, there will be some mechanism that the body will inhibit it. The Yin and the Yang.

OR: You’re saying you’re going to need both of them.

Belldegrun: I’m not. No. Right now, we all have outstanding data with single agent treatments, but I think eventually, it might be that for some type of tumors, it will be even better to use a combination. But we don’t know. Nobody has done yet a combination immunotherapy with these two types of treatment.

OR: You’re two years away from being on the market. That’s pretty fast, isn’t it, for an oncology product?

Belldegrun: Correct.

OR: Are you being fast-tracked?

Belldegrun: The FDA is working with us to expedite these treatments and bring them to the market, because they see how effective they are. These studies are relatively small studies. Fifty to a hundred patients, all patients who are on their way to die. The FDA says, “The minute we are convinced that your treatment is safe, the product will go on the market.”

OR: Will doctors be able to prescribe it for patients at an earlier stage?

Belldegrun: Eventually, I hope so. At my prior company, Cougar Biotechnology, I developed a drug for prostate cancer, Zytiga, which is sold today by Johnson & Johnson. It brings in two to three billion dollars a year. We started with patients with advanced metastatic prostate cancer. Patients who had less than six months to live. That’s what the FDA approved, eventually. Then, when we sold the company to J & J, they took it earlier in the disease, took it to the earlier stages, and then to patients who were merely diagnosed.

They moved it, but this is a process: you have to get approved again by the FDA. But we are starting with patients with a short time to live, and therefore, the study is not going to be a three-year study. Either it works or it doesn’t work. We know what happens if it doesn’t work. So that’s why you will see that that will generate, if successful, relatively quickly multiple products.

OR: There’s always been a lot of talk about cancer becoming a chronic disease. Do you see that happening over the next decade?

Belldegrun: A very good question. When the NIH talked about that, they had in mind a picture of what I started in the beginning of my discussion telling you about targeted cancer therapy. Targeted cancer therapies don’t cure anybody. They extend life. However, our drugs are for the first time, you can say, going for the cure. And in some patients, they are completely cured: a patient who had three months to live is now playing golf and jogging five years later. That’s a cure. We are going for the cure. Everything before went to convert a deadly disease to a chronic disease.

OR: Kite has an amazing patent portfolio. Will it be doing commercial manufacturing for the product when it goes on the market?

Belldegrun: We have not announced it yet, but we are working very diligently on manufacturing. We should be ready in 2016.

OR: How big a market do you see for this? It sounds like it could be enormous.

Belldegrun: It is enormous. It’s a lot of billions.

OR: And this is all happening in the last few years?

Belldegrun: Yes. The revolution is happening in front of our eyes, and everybody is joining the party. All the big pharmas want to be there. They don’t know yet how to do it, but they are looking for the best way to join it.

OR: So they’ll have to buy Kite.

Belldegrun: They don’t have enough money. We have too much fun here.

OR: This is the third company you’ve founded, correct?

Belldegrun: That’s correct.

OR: What’s the secret to your entrepreneurial success?

Belldegrun: You need to have a nose for what’s coming. But other than that, be passionate about what you do, and be committed. I have been treating patients with cancer for 30 years and I see the limitation of what our knives can do and what our chemotherapy can do. It’s the challenge to do something beyond that.

OR: You recently gave up seeing patients?

Belldegrun: I gave up being in the operating room. I am seeing patients, but half a day a week, because I don’t want to give it up completely. I don’t want to detach myself from the cancer patients. I see only patients with cancer.

OR: The drugs that Kite has coming on the market: which cancers are those targeting?

Belldegrun: The first one will target a blood cancer which is called DLBCL: Diffuse large B-cell lymphoma. That’s the most common malignancy and a very challenging one — once you fail chemo, nothing works. Novartis is targeting a leukemia type that’s called ALL, acute lymphocytic leukemia, but that’s a smaller market. We’re all going to start for the first time with blood disorders, blood cancers, and then move to other types of cancers.

OR: Was there a moment when there was a significant breakthrough? Who’s going to get the Nobel Prize for this?

Belldegrun: The Nobel will be given for this work. That’s for sure. I cannot tell you if it’s this year or next year, but this is Nobel-deserving. If you ask me who are the two most likely candidates to get it, I see the leaders as Jim Allison from MD Anderson, who invented the whole concept of checkpoint inhibitors, and Steve Rosenberg — Steve is the father of all modern immunotherapyfrom the National Cancer Institute at NIH. And Steve is part of the Kite collaboration.