The Evolution of Chimeric Antigen Receptor T Cell Therapy - Episode 9
David Maloney, MD, PhD: So I want to get a little controversial here, but we have a lot of other agents in ALL [acute lymphoblastic leukemia]. We have recent approval of blinatumomab. We have ADC [antibody-drug conjugate] targeted agents. Some of these are targeting the same thing that the CARs are targeting. So should we be treating these people with blinatumomab before they get CAR T cells?
Leo I. Gordon, MD, FACP: These are off-the-shelf products.
David Maloney, MD, PhD: Exactly.
Michael Pulsipher, MD: First I’d like to see a comparative trial to address this question, but I think that for blinatumomab the short answer to this is blinatumomab will only put about 40% of patients into remission if you have bulky disease. And that’s been shown in multiple adult and pediatric trials. But if you have minimal residual disease [MRD], blinatumomab can put 80%-plus of patients into an MRD-negative remission.
David Maloney, MD, PhD: But do they stay there?
Michael Pulsipher, MD: If they go to transplant. And again, in both adult and pediatric trials if your intent is to get a patient into MRD-negative remission—particularly transplant because you have a transplant eligible patient—that’s a reasonable approach. Now whether CAR T cell is as good or better, that would be a nice trial to do. But I don’t recommend blinatumomab in patients who have bulky disease. And the reason why is CAR T cells are so much better at getting them into a deep remission, and that’s the only way to cure in ALL, is a deep remission.
Leo I. Gordon, MD, FACP: Did you see ever CAR T, blinatumomab, in some sequence ever?
Michael Pulsipher, MD: Good question. I think if you have CAR T cells that work, I don’t know that you need blinatumomab. I think inotuzumab presents a different challenge. And inotuzumab has a higher chance of getting patients into deep remission in the 70% to 80% range. The one challenge with inotuzumab is increased risk of veno-occlusive disease, liver toxicity, and it must be followed by a transplant. And so you’ve got to make a choice. But there again is another good trial looking at inotuzumab versus a CAR T-cell—based approach.
David Maloney, MD, PhD: We have extensive data in the adult population with I think 40 to 50 patients treated with various CD19 CAR T cells. And our approach in the adult setting is that we should refer patients for transplant if they get into a complete MRD-negative remission, and they’re eligible for transplant, which usually means they haven’t already failed a transplant. So our data seem to support that being more of a bridge, which is a little different than what UPenn [University of Pennsylvania] data were suggesting. I think that this is a very controversial area and we’ll need to do longer term follow-up to do that.
Michael Pulsipher, MD: I agree. In adult populations we need to know whether you can have a long-term response with a 4-1BB vector like you do in children. There’s some suggestion that some patients can respond long term. But whether it’s as good as in children, we just don’t know yet.
David Maloney, MD, PhD: One of the worries in the post-allotransplant arena—and again, this is the 1 case where many of those patients had failed at prior allogeneic stem cell transplant in the original data—is whether this cytokine storm or the other toxicities are going to massively increase the risk of reactivating GVHD [graft-versus-host disease]. Has that been seen in the clinical trials?
Michael Pulsipher, MD: Just to give you a perspective, in the ELIANA trial, we had 1 patient who we worried had gut graft-versus-host disease. And it was biopsied and we carefully looked for the presence of CAR T cells, and we couldn’t find it. There are other patients who I’ve heard of anecdotally. We used to worry that it was going to be a big problem because, remember, 65% to 70% of the patients who get CAR T cells and go on these trials have already had an allotransplant, and so you are putting the CAR into their transplanted T cells from their donor. So we used to really feel that it was going to be a problem. If it is a problem, it’s pretty subtle because we don’t see it.
David Maloney, MD, PhD: Right. So what else do we know about mechanisms of resistance in general in these populations?
Nilanjan Ghosh, MD, PhD: I think the 2 mechanisms of resistance, which have been characterized to some extent, are CD19 loss on the tumor, making it escape from T cells, and the other one would be T-cell exhaustion. So T cell health. And if there’s something leading to more inhibitory molecules because it’s more PD-1 [programmed cell death protein 1] or PD-L1 [programmed death-ligand 1] expression, leading to another way of tumor escape. Or even the loss of CAR T cells over time where there’s an expansion, but then the CAR T cells are gone. So those would be the ones that come to mind.
David Maloney, MD, PhD: So how do we solve that?
Nilanjan Ghosh, MD, PhD: I think one way to look at it is to look at tumor biopsies in patients who are relapsing and stain for a CD19 to see if CD19 is lost on the tumor. If we have a better way to detect CAR T cells easily in the real world, as was just mentioned, maybe B-cell aplasia would be a surrogate marker, immunoglobulin levels could be a surrogate marker. But maybe there’s a much easier way to actually find out if someone’s really had a very good response to CAR T cells that then somehow escaped, and can you then retreat? If someone got a CR [complete response] with CAR T therapy, their tumor still expressed a CD19. And now the reason for relapse is that the CAR T cells, which were there initially, are lost. Then maybe we can use a second dose of CAR T-cell therapy. I would not advocate that for everybody because it’s expensive, it could have adverse effects, but it could work in a targeted population.
So I think this whole group of patients who have relapsed post-CAR T, and that was also presented at ASH [the American Society of Hematology meeting] this year  in the real-world setting, is probably the next unmet need. And trying to understand the mechanism of relapse and trying to target the right treatments for that population is the key. Right now in the trials that are ongoing, some of them are adding PD-L1 inhibitors, immunomodulating molecules, post-CAR T. We have the platform study, which is looking at that after liso-cel [lisocabtagene maraleucel], and other studies that are in that space. But I think individualizing that a little bit mechanistically would make more sense.
Michael Pulsipher, MD: So there are 2 things to mention that are happening at ASH now as well. In order to overcome the problem of CD19-negative relapse, we absolutely have to target more than 1 antigen. ALL is the best model to really look at antigen selection because you can do flow cytometry and see beautifully what antigens are there and you can really have a great way of targeting.
There is a whole series now of the next wave. And the next wave really is multiantigen targeting. A number of studies have been presented that show CD19/CD22 combinations, and they’re done differently. Some have them on the same construct, some have them on different constructs in the same cell, and some have pools where you’ve got CD19, CD22, and then CD19/CD22 together. And these very interesting and intriguing studies so far have shown high rates of remission, but we don’t know how long they’re going to last. And we have to be careful with that because if you put a whole bunch of multiple antigens in our CAR, you may exhaust it and you may not get those long-term responses that we’re seeing in some of the 4-1BB vectors like tisagenlecleucel. So with this next wave, I really think in order to be successful, you’ve got to figure out how to have long-term expression in ALL of 2 antigens—take your pick, CD19, CD22; CD19, CD123, whatever it is—in order to succeed.
Leo I. Gordon, MD, FACP: And understand that if you think about multiagent chemotherapy, this is multitargeted CARs, the concern I have might be, would you wind up with a CD19- and CD22-negative recurrence?
Michael Pulsipher, MD: Absolutely.
Leo I. Gordon, MD, FACP: Yes, that’s right.
Michael Pulsipher, MD: We didn’t start curing ALL until we used 3 agents, and then we had to take care of the CNS [central nervous system] problem too. But it’s 3 agents that did it.
Transcript Edited for Clarity