Immunotherapy Use in Advanced Lymphoid Malignancies - Episode 11

Where Does CAR-T Fit in the Context of Transplant?

Transcript:Andre Goy, MD, MS: What do you think? How do they [CAR-T cell therapies] fit in the context of allotransplant? They serve as a bridge to an allotransplant. Are they going to replace transplants?

Frederick L. Locke, MD: Well, I think there’s hope that this could replace allogeneic transplant for ALL. It’s in its early days. What we know from different trials conducted at the NCI, also Memorial Sloan Kettering, is that patients who had an allogeneic transplant as therapy for ALL can safely have cells collected and CD19-directed CARs manufactured. It can be used after allogeneic transplant. Whether an ALL patient who’s getting CAR-T cell therapy goes into a complete remission, whether you should sit on that patient and wait and see how well they do, or whether they should get a subsequent allogeneic transplant, that question remains to be answered. Although, allogeneic transplant is a proven therapy with thousands of patients treated with ALL. So, we think we have to use caution to say, this early on, that it will replace allogeneic transplant for relapsed/refractory ALL patients.

Andre Goy, MD, MS: We have experience at our center with the NCI using CAR donor lymphocyte infusion (DLI). The problem when you use DLI post allotransplant to try to have a stronger anti-lymphoma effect is you very often get graft versus host (GvH), right? And so, here in a patient who had failed DLI, we actually got them CAR DLI, and from the donor. It was very interesting because we had zero GvH, and we had some patients that converted back into CR who had refractory large-cell lymphoma. We presented this at ASH, and it was published in JCO recently. And I think this is something that I agree with you on. I would not abandon the allotransplant right away because, for some of these patients, it’s more like a bridge for patients who have been resistant to chemotherapy.

Krishna V. Komanduri, MD: Let me throw something out because there’s often a common misconception. The vast majority of allogeneic transplants that we do are for myeloid diseases. And, often, people think, “Well, we’re succeeding in ALL, and we’re going to be doing this for myeloid diseases.” Let me just remind everybody—and it’s a simple concept, but it’s amazing how often people forget this—that the antigens that are likely to be the targets of CARs, and certainly there are myeloid CARs under development, are also present on normal hematopoietic stem cells. So, it’s very likely we can live without B cells, but we can’t live without myeloid stem cells. Even if we have a myeloid CAR that’s very successful at ablating that malignant clone, and maybe perhaps better than the combinations of anthracyclines and ara-C (arabinofuranosyl cytidine), we’re going to actually have to do hematopoietic stem cell rescue or transplant to fix that. For sure, allogeneic transplant for myeloid diseases isn’t going away any time soon.

Andre Goy, MD, MS: There is an ongoing trial of an anti-CD123. There are some off-the-shelf CAR-T cells, and those are interesting because they basically remove the MHC (major histocompatibility complex) and remove the T-cell receptor. And so, therefore, they are allogeneic, off-the-shelf. They persist for a few months. There are preliminary data on this young girl that was treated in London with a refractory leukemia and who has been in remission for now quite a while.

Ian W. Flinn, MD: There’s also one other major group that’s developing CAR-T cells—the University of Pennsylvania and the Novartis group—and they also had very impressive results. Dr. Shuster has presented, on multiple occasions, their experience in large cell lymphoma. They used the 4-1BB construct, I believe. In that experience, Dr. Shuster is using various different chemotherapies in order to keep people in remission after acquiring the cells and prior to, as a condition of the regimen, the infusion of the CAR-T cells. And they’ve had amazingly durable responses in patients with refractory large cell lymphoma. You’ve seen that data, Andre.

Andre Goy, MD, MS: You’re right. I actually presented it a few months ago, again, at ASH, and I talked to him the other day. Once a patient has reached a CR in their series—and obviously, they are all refractory patients and poor-risk patients who would do very poorly otherwise—they have had very durable response in over a year. This is in patients who have refractory large-cell lymphoma with no further therapy. So, I think this is really exciting. Also, in the first clinical data from UPenn, three patients with CLL, and it was in heavily pretreated patients, they responded pretty well.

Transcript Edited for Clarity