Published on April 30, 2019
Is CAR T-cell therapy the “next big wave” in immunotherapy for chronic lymphocytic leukemia (CLL)? Leading CLL expert Dr. David Maloney, from Seattle Cancer Care Alliance, shares findings from recent clinical trials and gives an encouraging, in-depth research update on CAR-T cell therapy for CLL. How are CLL patients responding? Watch now to find out.
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Transcript | CAR T-Cell Therapy for CLL: Where We Are Now and Where Research Is Headed
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Hello. I'm Andrew Schorr from Patient Power, and I want to connect you with an old friend who is one of the leading researchers in hematologic malignancies, Dr. David Maloney at the Fred Hutchinson Cancer Research Center in Seattle. He's at the University of Washington, and he runs a whole immunotherapy research center there, and he really gives us a window into what's going on with chimeric antigen receptor T-cell therapy, which has been helping right now in clinical trials, some of the sickest patients.
And, David, what is your other title related to immunotherapy there?
Well, I'm a Medical Director of the Bezos Family Immunotherapy Clinic here in Seattle, which is the first, really the first of its kind clinic dedicated to cellular immunotherapy of cancer.
All right. Well, we want to talk something that you've done a lot of work on, chimeric antigen receptor T-cell therapy. And you've had trials going on, and I know personally some people who have been in that trial for CLL, so CLL patients are wondering where are we now. An update for us, please, related to CAR-T for CLL. I still know, very experimental, but where are we, and where are we headed?
First of all, most patients with CLL are never going to need CAR-T cells, right? I think that's the—many patients with CLL don't even require treatment, and we have a lot of drugs that are quite active in patients with CLL. But there are patients where, in CLL, where our best drugs stop working, so such as ibrutinib (Imbruvica), the BTK inhibitors and then—and now we have venetoclax (Venclexta), but when people start failing ibrutinib and venetoclax then they can get into trouble, and CLL can obviously become a life-threatening disease at that point.
And we've had quite a bit of success targeting an antigen called CD19 with CAR-T cells in other diseases, lymphoma, and other leukemias, acute lymphoblastic leukemia in both pediatric and adult populations, and CLL cells have the same target. They brightly express CD19, and CAR-T cells are a very effective treatment that can be considered now in CLL patients.
We just actually presented at the American Society of Hematology meeting this year a second cohort of CAR T-cell patients who were treated with CAR-T cells and concurrent ibrutinib, and there was a—this turned out to be pretty active. And even in patients who had failed all of the standard therapies for CLL, about 85 percent of them actually had remission in their blood and bone marrow and a sizable number went into remission based on lymph nodes and other criteria. So we're very encouraged by this.
I mean, it's kind of a situation where most people with CLL do very well, but patients with very high-risk disease, 17p-deleted CLL, complex cytogenetics, bulky disease, our treatments don't work that well anymore once they stop working, and CAR-T cells will be an option. You have now—we have had two cohorts of about 20 patients each showing the proof of concept and showing the overall safety and kind of establishing the right dose.
And now those studies are being taken into multiple—multicenter trials across the United States with a product called JCAR017 which is from Juno Celgene, the company, and that trial is now in clinical trials where they're doing the Phase II portion of that and with the hope that that will eventually be able to be presented to the FDA and lead to maybe approval in that setting.
Wow. Okay. So you keep, as you're in trials you keep trying to improve the process. So where are we now? So for instance we've heard not just with CAR-T, but we've also heard about something called CAR NK cells, and so there are going to be other forms of this, less expensive delivery? Where might we go with this?
Well, that's really going to be the future, and the question is how is this all going to play out. Right now we have two CAR-T cells approved for the fuselage B-cell lymphoma or glasso lymphomas, and one approved—one of those is also approved for childhood pediatric care and adult leukemia.
The whole concept is right now a very patient-specific treatment. We have to take your T cells from the patient, modify them in the laboratory, grow them up and then get them back to you, and they're usually given after a round of what's called lympho-clean chemotherapy. Those T cells then engraft into the patient. They grow, and then they go after the tumor based on that CAR, the chimeric antigen receptor, and then they combine to hopefully kill those tumor cells and persist.
And this treatment turns out to be tremendously active, but it also can be very toxic, and so it's kind of a balancing act of these cells proliferating and killing the tumor then also causing the types of toxicity. And the chief toxicities we see are the cytokine release syndrome where the T cells or other cells in your body make a bunch of substances called cytokines which basically are what is responsible for you feeling absolutely lousy when you have the worst case of the flu in your life. And so that's what many patients may feel like when the CAR-T cells are killing their leukemia or lymphoma.
And the other toxicity which we don't understand as much is this neurologic toxicity. People can become confused, and this can become quite frightening.
The good news is that in almost all those cases people do recover, but it rarely can be very toxic or even fatal in rare cases, and that's why everyone is trying to figure out what's the right dose of the T cells, do the actual type of T cells matter? So there are—these products are all different.
And I think the most important lesson for everybody is you can't just say, oh, CAR-T cells and assume that they're the same thing. There are CAR-T cells from Kite or Novartis or Juno, they're all different. Every single one of them is different. There are different constructs. There are different molecular constructs, and they're associated with different rates of toxicity. And so these require treatment right now in centers of excellence, and they have to be done in centers that really know what they're doing and can manage these symptoms.
But there's a lot of room for improvement. We could make a different CAR. We can put different molecules in the CAR, and, as you said, we could maybe even change the cells. Maybe we could go to something called an NK cell, and there's some data coming out of some centers including MD Anderson that that might be an interesting approach.
So I think that the challenge here is you how did you get another one of these approved when you have three or four or five already going through approval process. And, as you a said, right now they're really expensive. Currently the cost of some of these CAR-T cells is in the $370- to $475,000, and that's just for the T cells. That's not for the cost of care. And so these a challenges. The costs need to come down.
We need to—you know, there may be even in some patients we can't collect their cells. They've had too much prior therapy. One of the biggest problems is fludarabine (Fludara), actually. Fludarabine knocks out your T-cells for many years, and at least in the old days that was the standard of treatment for people with CLL, not so much anymore. So we have challenges getting T cells from some patients.
Could you use somebody else's T cells? Could you use third-party T cells, and many companies are trying actively to figure out how to do that. Now, I personally think that's still going to be a challenge because it's difficult to—you can't give a third party cell usually without getting rejection or getting those cells quickly rejected, and that's a problem with the NK cells as well. But there's some tricks, and I'm excited about it. It's a great field to be in. It's like my third career, so I'm excited about it.
Well, that's what I wanted to ask you about. You were on the ground floor of monoclonal antibodies for hematologic malignancies, and that made a big difference for so many of us. So with this whole immunotherapy approach, is that the next wave?
Well, I think it's absolutely the next wave. The antibodies were a tremendous advance. Rituximab (Rituxan), which I was lucky enough to work with, you know, that really changed the survival of many patients with CLL and with almost all of the B-cell lymphomas, and so that's a tremendous advantage. There are some new antibodies that are coming along that might be replacing that in some circumstances, but still, antibodies are a mainstay of treatment.
So CAR-T cells are basically using an antibody to direct the T cell to killing, so it's really a—it's kind of a marriage of some of the principles we learned in transplant where if people have a bone marrow transplant or stem cell transplant for another donor the main reason those transplants work is that the immune system of the donor actually rejects the CLL or rejects the tumor.
Now, unfortunately, that can also cause a lot of problems like graft-versus-host disease, which can lead to a lot of problems, and patients can die from these complications, so we don't often do those kinds of transplants, for example for CLL, but we still do in some cases. But a CAR-T cell kind of marries the best of an antibody causing the specificity with the transplant immune system even if you're using your own cells, and now those T cells can attack your own tumor. So it's kind of a full circle for me, tell you the truth. I'm now using cells to be redirected by antibodies, which was kind of what I first started my career in.
So, lastly then, you're our window into where we are now and where research is headed. So do you feel we're going to get there, Dr. Maloney, that we can really be curing people and that these technologies, the drugs used together maybe where then people can stop, they can say they're cured immunotherapy when they need it, that this can really get us to a place we're never been before?
I absolutely believe that. I think already we know we can cure CLL by an allogeneic stem cell transplant in some patients. I don't know what that percentage is, maybe 40 percent or something, so that proves that immunotherapy can potentially eradicate the disease. And I think that now as we get better drugs that are much more active and much more directed towards the CLL cell rather than killing the bone marrow and killing all the other collateral damage, that this will just get better.
The CAR-T cells are representing another modality that I'm certainly right now hopeful will be a big wave in the future. But it's early years, and we've got a lot to learn. But it's also exploded. You can tell just by the number of inquiries we get, the number. It's a hot topic right now in cancer therapy.
Dr. David Maloney from the Fred Hutchinson Research Center, Seattle Cancer Care Alliance, University of Washington, lots of titles. Thank you so much for being with us.
Thank you, Andrew. It's always a pleasure.
I'm Andrew Schorr. Remember, knowledge can be the best medicine of all.