Developing CAR T-Cell Trials

Transcript:

David Miklos, MD:There’s another possibility here that we haven’t discussed with our viewers. That is, that using a CAR [chimeric antigen receptor], which is foreign, is also potentially a good thing, because while we’ve often thought we want to have the CARs persist and provide antitumor responses, especially as ALL (acute lymphocytic leukemia) patients, the investigators have frequently advocated. On the other hand, if you hit them hard, and you wipe out the lymphoma, perhaps the best thing that happens is that the recipient’s immune system does reconstitute, eliminates that CAR T cell, and allows normal B-cell recovery, T-cell recovery, and CD4 cells. I’m going to point again to Michael Jain and Fred Locke’s work published in Haematologica now, where they show the CD4 counts being less than 200 in half the patients beyond a year. Many people wonder if that’s the thymus in the older adults, the high-dose fludarabine, or perhaps B-cell aplasia contributing to a damaged germinal center. We don’t know. It’s an exciting experiment.

Stephen J. Schuster, MD:It is. I’d love to do the experiment. I had the chance to read the Haematologica paper, as well. And that’s unique to that product. We have different data with tisa-cel [tisagenlecleucel]. For some reason, the immune system seems to regenerate much more readily. You see earlier B-cell recovery, immunoglobulin recovery, and cellular recovery. I don’t know a hypothesis that would make me think it was the CD28 costimulation, although I guess some kind of cytokine-mediated thing. God knows, a lot of hand waving in immunology.

David Miklos, MD: The Allogene [Therapeutics] experience is an experience of 2 things. It’s the experience of lymphodepletion. We went back to reconsidering lymphodepletion and all aspects of it. Increasing the dosing of the Cytoxan, increasing the dosing of the monoclonal antibody that’s against CD52, staggering the lymphodepletion, putting the lymphodepletion at the same times. Studying the absolute lymphocyte count has turned into the most interesting experiment that I’ve done in a long time, which is not very elegant, Steve, but incredibly important, as they’ve shown in some of their data slides that they presented at the meeting today. The expansion of the CAR and the clinical response rates correlated with the extent of the lymphodepletion that was achieved.

Stephen J. Schuster, MD:Yes, that makes sense, because there has to be room for expansion. I don’t necessarily think chemotherapy is the smartest way to do it. I don’t know at what stage of lymphocyte development CD52 becomes expressed. I’m sure somebody does. And I’ll wager that there are precursors that are present if you use CD52 alone to deplete cells, that you’ll have faster lymphocyte recovery than if you use a chemotherapeutic approach that is more likely to hit primitive, or more primitive, lymphoid precursors. But I don’t know the answer.

David Miklos, MD: That’s part of the experiment, you can use this targeted therapy against the cells of the recipient’s lymphocytes that is leaving the stealth CAR-T cells immune. And likewise, Steve, you can go back at day 14 or day 30 and pump the cycle again and give another dose of anti-CD52, knock down the recipient’s T cells again, and allow expansion of the CAR, if you think you need it, without redosing and without having allosensitization, which is potentially exciting.

Stephen J. Schuster, MD: And we’re planning, if we can ever get out of COVID-19 mode and now riots in the street, to actually begin to work with Allogene at Penn, as well. In our discussion, there may be differences in terms of the importance of persistence, because you don’t have the persistence with Allogene that you would with an allogeneic product like this, that you have with an autologous product. But there may be differences between diseases in terms of the importance of your system. Anybody want to comment on that? It seems as though resistance is less important in lymphoma than in ALL, based on what we’ve seen in the clinical studies. And that may be right.

Loretta Nastoupil, MD: …In lymphoma, these are mature cells. You just need to wipe them out 1 time. You don’t necessarily need CARs to persist if they’re effective at eradicating the tumor cell, whereas in acute leukemia, that might be a little bit different.

Stephen J. Schuster, MD: The cells are more stemlike, they’re repopulating, or just those young people can get up again and again and again. You keep knocking them down, and they keep getting up.

Transcript Edited for Clarity