Panelists: Krishna V. Komanduri, MD, Sylvester Comprehensive Cancer Center; David Maloney, MD, PhD, Fred Hutchinson Cancer Research Center; Sattva S. Neelapu, MD, University of Texas MD Anderson Cancer Center; Michael Pulsipher, MD, Children
Krishna V. Komanduri, MD: David, we have the ZUMA-1 study which, again, there will be further reports about at this meeting and a publication soon. What is the indication that led to approval of axicabtagene ciloleucel, or axi-cel, in October?
David Maloney, MD, PhD: We’re tremendously excited to have an approved CAR T-cell for lymphoma. And axi-cel, or axicabtagene ciloleucel, was the first one. The results for the study were basically treating 101 patients with a CAR and they had to have relapsed/refractory diffuse large B-cell lymphoma or diffuse large B-cell lymphoma transformed from follicular lymphoma. Those are predominantly the 2 main groups. In the clinical trial actually, they had to have even higher risk disease, relapsing within 12 months of an autotransplant in other populations. The actual label is 2 prior therapies in relapsed/refractory disease, and that’s the way the label now indicates.
The bottom line is about 50+% of those patients had complete remissions, and they appear to be fairly durable. The data we have in the PI label was through 8.7 months or 8.9 months of follow-up. And we’re anticipating data at this meeting looking at about a year to 15 months or so of follow-up. Everyone is quite excited because it appears that these remissions are quite durable. But that’s still a question about the field. The early work from James Kochenderfer, and Steve’s earlier work, suggest that patients who have a complete remission can have durable remissions. And I think some patients are out 5+ years in those studies. And so, this is tremendously exciting.
I think you have to remember these people are not even eligible for an autotransplant or they had already failed. So, you can’t say “rescue them with a transplant” because they couldn’t either get it or they already had failed it. This is a population that has a significant unmet need and just tremendously exciting results. The treatment was pretty well tolerated, but we talked about the toxicities. Cytokine release syndrome and neurotoxicity were significant. Almost half of the people required some type of intervention with either IL-6, or a receptor antibody blocker, or with steroids. So, I think we have to temper our enthusiasm by that, but the results speak for themselves. There is nothing else that would give this kind of a remission in this population. Tremendously exciting. It’s being opened in about 11 or 12 centers initially and that will greatly expand probably to 100 centers over the next years. So this should be thought of as a treatment option earlier on in the case of these patients’ disease.
I don’t think you have to wait until the fifth, sixth, seventh phase I study. This should be moving up and it’s an approved setting; second relapsed disease should be treated. Obviously, as we talked about, the question is, can we threaten autotransplant? Will CAR T cells do away with autotransplants? It’s possible. The studies that are going forward will be taking people at first relapse, randomizing them to CAR T cells or transplant and some iteration of that. So, it’s very possible that if these results pan out and hold out in an earlier setting, that may be better than what we can do, even in the chemosensitive population where the results are about 50% best case scenario with an autotransplant.
Krishna V. Komanduri, MD: I have to add my own enthusiasm. I have to say that we were one of the higher accruing sites to the ZUMA-1 study. I did see patients who were absolutely refractory who would certainly not have been eligible for transplant, we were even considering hospice, who had pretty remarkable responses. But I think that with the aggregate data, I think you justify that enthusiasm. Again, I think for those of us who are in the transplant community or in cellular immunotherapy, the trials have to be done, we have to obviously confirm the persistence of responses and look at that.
But the data are looking very encouraging. These curves on the success of iterations do appear to be flattening out as they did in prior studies from the NCI. I share that enthusiasm, and I think that this is really a good time for all of us who are interested in these diseases, lymphoma and immunotherapy in particular. I want to talk a little bit about the nuts and bolts of this. Again, for those who are not familiar with this, we do an apheresis, we prepare the cells, and then we bring the patient in during the manufacturing process or when the cells arrive back at our site and give them really some chemotherapy, right? So we give what we call lymphodepleting chemotherapy, and that typically consists of fludarabine and cyclophosphamide (Cytoxan). Do you want to talk about the reason for that?
David Maloney, MD, PhD: Yes. It’s a key point a lot of people don’t quite understand. What the heck are you giving Cytoxan and fludarabine for? Because these people are already chemotherapy-refractory, and often we would not anticipate that that amount of Cytoxan and fludarabine is going to cause any kind of major response, and in fact, that’s true. The reason that lymphodepleting chemotherapy is given is to actually reduce the number of endogenous T cells, and when that happens, the body makes signals and cytokines to actually stimulate T-cell production. And that’s when we want to introduce the CAR T cells to then allow them to engraft better and expand.
Dr. Kochenderfer, also at this meeting, has studies, as do we, showing that if you give this lymphodepleting chemotherapy, you actually will increase those levels of serum cytokines, such as IL-15, and then that correlates with the expansion of the CAR T cells.
We have done experiments sequentially using just Cytoxan, or then adding fludarabine, and by adding fludarabine, we got much greater T-cell depletion, much better cytokine production, and much better T-cell expansion. So, we think it’s really critical to do this, and it’s a theme that is seen generally across the CAR T-cell trials, although I think Steve used slightly different regimens in his trials. You may want to comment.
Krishna V. Komanduri, MD: I think from a biological standpoint it was actually shown in HIV-infected patients and patients post-allotransplant that when you have that lymphopenia, you have high levels of both IL-7 and IL-15. That drives actually NK cells, which are not relevant here, but also T cells, and I think that that’s exactly right. So, the fludarabine and cyclophosphamide reduced the endogenous number of lymphocytes. They drive up those cytokines that help to drive now the expansion, which is also antigen driven. They reach their target, they expand, and these cytokines help to drive that.
David Maloney, MD, PhD: Exactly.
Krishna V. Komanduri, MD: So, I think this is exciting. I think we talked about the fact that in the trials versus the label indication, the label indication just says really 2 prior therapies. Would you agree that that’s a little bit broader than what was done in the ZUMA-1 study? Steve, as a lymphoma person, do you think that’s where you would refer somebody?
Stephen J. Schuster, MD: I think that the label is broader than the types of patients who were treated in the study, and I think that we have to remember they are incredibly exciting results. We’re saving lives that we couldn’t have saved just a few years ago, and I have a tremendous amount of enthusiasm for this. However, this is gene therapy. We have 5 years of follow-up. We don’t have 15 years of follow-up. So, I would just caution people. If we have therapies that are successful for patients who have been around for a long time, we should continue to use those. At this point in time, if somebody is a transplant candidate, I think that that’s the standard of care. So, I wouldn’t say because somebody had a relapse after R-CHOP and got some Rituxan and didn’t respond, they had 2 prior therapies now, and I would move on to this. I don’t think we’re there yet for this.
Krishna V. Komanduri, MD: Let me add to that. I think that one of the things we like to say in the transplant community is when you look at the number of patients with high-risk AML, we would argue that no academic hematologist would disagree about whether a leukemia doctor or a transplant doctor saw them, that many of those patients actually just never get to the center. We know that there’s a dramatic underutilization. So, the one thing I would say is the community doctor doesn’t necessarily have to make a decision about whether it’s appropriate to treat that patient. In fact, that’s a very subtle and complex discussion, but what they should do is at least refer for consideration. Don’t you agree with that point?
Stephen J. Schuster, MD: Yes, absolutely. I agree with that.
Krishna V. Komanduri, MD: And they can look at clinical trial opportunity and look at the commercially available products.