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Andrew Schorr on location in Atlanta at the American Society of Hematology meeting, and one of the areas that electricity lesson plans middle school’s talked about a lot now is chimeric antigen receptor T-cell therapy. We’ve been talking about it for a while, and now there actually are approved medicines for us. One of the leaders in the field is Dr. David Maloney from the Fred Hutchinson Cancer Research Center and the University of Washington Seattle Cancer Care Alliance. Thanks so much for being with us.

Thank you so much, Andrew. You know, so much has changed since the last time we talked several years ago. Since then, we actually established the Bezos Family Immunotherapy Clinic at the Seattle Cancer Care Alliance, which is a clinic dedicated to the delivery of cellular immunotherapy. So we were really convinced there was going to be big time at that time. Thanks to the commitment of several families and generosity of the SCCA, and that’s borne out already. We have two products FDA approved.

One, tisagenlecleucel (Kymriah), which is a mouthful, but that’s approved for adults and pediatrics—adults up to the age of 25 with ALL. And we now just have our first commercial approval of axicabtagene ciloleucel (Yescarta), which is now approved for adults n game with refractory large cell lymphoma. So tremendously exciting. We’re getting those incorporated into the clinic, and it’s—I couldn’t have even imagined that we would be here within such a short period of time.

We’re actually making a living drug. And so the idea is we take your T cells out of your body, reprogram them with a virus to express a receptor, and that’s call the CAR, chimeric antigen receptor. It’s based on an antibody recognition unit with the internal parts of a T-cell receptor. And the bottom line is that when we modify the T cells that way and give them back to you those T cells can latch onto the tumor cell via the CAR, by the antibody, and then they can kill that gas monkey cast cell, and that will also give them a signal to expand and proliferate and then go off and kill more tumor cells. So it’s kind of an explosion of proliferation to actually deal with the cancer.

Well, that’s a good question, and not all CARs are the same, right? So I think that’s really the major issue. But at this meeting we’ve seen extraordinary results, and so kind of the late?breaking data as of today that was just published in The New England Journal [of Medicine], again effective today shows long-term results now out about a year and a half, 15 months, 16 months with the Yescarta, the axicabtagene ciloleucel, and that shows that about 40 percent, 41 percent of patients are long-term survivors of this treatment, and they’re in remission.

This is extraordinary, because these patients would not even have been impact of electricity in the 1920s eligible for a transplant or they’d already failed a transplant. This is revolutionary therapy, and we’re only applying it to the hematologic malignancies right now, at least with major success, but we’re now looking at having three products available in large?cell lymphoma. When we get around—when the FDA gets caught up with the clinical trials we’ll have a Novartis product and we’ll have—likely have the Juno product all competing in the same space with different CARs and different toxicities and probably different activities as well.

Yeah, that’s what I’m just saying, with this publication in The New England Journal of Medicine we’re seeing our first look at year and a half data, and those plateau curves look really, really good tgas advisors. Meaning that, you know, when you look at the event curves there’s only really been one event at one year in one patient, and so that leads us to hope anyway that this could be long-term durable remissions.

But you’re absolutely right. There are toxicities, and those toxicities can be formidable, in fact, they can be life-threatening and there have been patient deaths, you know, on these trials. But you have to remember their chance of dying from their disease is 100 percent, and so the risk/benefit I would say strongly would support the use of CAR-T cells.

But the two main toxicities we see are the cytokine release syndrome. And so that’s where, as the T cells encounter a tumor they proliferate, divide, expand, and they secrete cytokines, and this makes people feel like they have the worst case of flu of their life. They can have high fevers, low blood pressure, and can be very, very ill, and that’s called cytokine release syndrome or cytokine storm.

The second toxicity, which we don’t understand as well, is neurotoxicity 935 gas block where people become confused and they can even go into a—even a coma, and this can be quite frightening for family members especially. And we don’t understand exactly the cause of that. We have some ideas about the pathophysiology, but fortunately it’s almost always reversible, and so most patients 100 percent recover from that.

The cytokine release syndrome, that’s where people get really high fevers and low blood pressure and things like that, we can treat almost instantaneously with a drug called tocilizumab that blocks the receptor for IL-6 gas bubble in back. And it’s a miraculous drug in terms of cytokine release syndrome. People often get better within hours of that drug, and it can certainly take care of those kinds of symptoms. But we’re still learning about the neurotoxicity.

Now, could it be different in the future? I think it could be, and I think we’re beginning to see that not all the products are the same. We’re working with the Juno product that was devolved through our studies at the Hutch, and by actually fixing the mixture of CD4 and CD8 cells we seem to be getting much less toxicity and a better dose response and dose toxicity relationship, and so the incidence of cytokine release syndrome was about a third of some of the other products. And so we still have a long a ways to go, but tortugas ninjas this is really, really encouraging.

So the approved products are for pediatric and young adult ALL up to age 25 with at least two prior relapses. The second approval for large-cell lymphoma is for aggressive lymphomas, and patients have to have failed two prior rounds of therapy. So often that’s a transplant, sometimes not if you couldn’t even get to a transplant. So that’s really the only places they’re currently approved.

But that’s just the hemo malignancies, and so what everyone wants to know is what about solid cancers? What about breast cancer, lung cancer, things like that? And we’re actually starting clinical trials in that. I think it will be a much, a much tougher bar to be able to get these kind of really good remissions in these patients, and we probably will need combinations, but we’re really excited about it and seeing some interesting early effects.

He’s been devoting his life really to these sorts of leading-edge approaches, and CAR T-cell therapy is an area that as he says has not just great promise but starting to save electricity use lives. And so if this applies in some of the conditions he talked about, inquire about it for you, and watch this space carefully. Dr. David Maloney, Seattle Cancer Care Alliance, and Fred Hutchinson and the University of Washington, thanks so much for being with us.