Video

CAR T-Cell Therapy Response Rates

Andre Goy, MD: I alluded to the limits and practical issues to get access to the CAR [chimeric antigen-receptor T] T-cell therapy. But what do we do to try to make it better? With this ASCO [American Society of Clinical Oncology] 2020 Annual Meeting data, there was a small experience on re-treatment. Can you re-treat those patients with CAR T? And the reasoning behind this is that there is some evidence that these T cells will not stick around long enough. There was some discussion that on the need or not to have precise CAR T-cells. We had about one-third of the long responders in the ZUMA-1 trial who did not have resistant, long-term precision CAR T cell.

With the recovery of the B cells and even immunoglobulin, after a year we can see the CAR T cells disappear. But there’s also the idea that we can re-treat those patients who relapse. This was a small number of patients who were from the axi-cel setting, and over half the patients achieved a response: 4 CR [complete response], 3 PR [partial response]. What was interesting is that some of these responses can be durable: close to 3 months, up to 225 days for the longest. There was a rate of CRS [cytokine release syndrome] at re-treatment, but it seems there was less neurotoxicity and maybe also less CAR T expansion. We don’t know exactly how to read this, but it’s feasible.

There is an interesting question being explored at some other trials: Can we do repeat infusion of CAR T? That’s 1 strategy. The other 1 is that can we improve by bringing the CAR T earlier. That’s the question about the timing of the CAR T if we do it earlier in the second line. There’s the ZUMA-7 trial that has completed, but the results are pending. This other study is with liso-cel and tisa-cel also at a second line with a crossover, so in second-line therapy, randomizing against salvation transplant.

There was an interesting study looking at liso-cel in patients who are not transplant eligible. It is an interesting study because liso-cel potentially has an initial toxicity profile, so it might be easier to do. It’s a slightly different product when the CD4 and CD8 subtype of T cells are prepared separately and infused separately. They get the same for the patient. What was impressive in that study was not a huge number of patients but that the overall response rate was 89% and the CR rate was 56% with very low toxicity, and 12 of 29 patients we have done as an outpatient. This is really important because that offer is potentially an option for these nontransplant-eligible patients. It’s for durability, but this is something to take into account.

As for the results and data on the dual CAR T anti-CD19 and -CD22 in combination with pembrolizumab, there’s a very interesting study called the ALEXANDER study. The rationale for this is there is a subset of patients in large cell lymphoma that become resistant to CAR T because they lose CD19 expression. It’s something we see more frequently in ALL [acute lymphoblastic leukemia] as a mechanism of resistance than in large cell lymphoma, but it still happens. And so we try the dual CAR T CD19,-CD22 with PEMBRO [pembrolizumab] to try to see if we can improve. Knowing that a checkpoint blockade is also 1 of the mechanisms of resistance, can we improve the responses seen? This is dose escalation, not a large number of patients. But the response rate was very high: 10 of the 11 CRs. A small number are ongoing. There was no grade 3 CRS and 1 grade 3 neurotoxicity. The recommended phase 2 is 150 to 450 million, and we did want PEMBRO [pembrolizumab] selected.

The last study at ASCO that is worth mentioning was the ALLO CAR T-cell off the shelf. That is a product called ALLO-501, a gene-editing-based technology to remove the T-cell receptor and CD52. This is also used as a dose escalation, presented by Dr Sattva Neelapu. It shows a response rate of 63% with half these patients in complete remission, and 75% of the patients who responded were still in response at the time of cutoff.

That’s also interesting because there was no GvHD [graft-vs-host disease], and there was allogeneic healthy T cell. There was no dose-limiting toxicity, 1 grade 3 CRS, and no neurotoxicity. That’s very appealing because it would be off-the-shelf, ready-to-go T-cells. Potentially that’s very important because 1 of the factors of failure of CAR T is the T-cell fitness. Patients who are heavily pretreated have a lot of immunosuppressive adverse effects with the active disease of ongoing lymphoma. These patients don’t have the best activity. If we have normal allogeneic normal T cells, that might address the problem.

The last aspect that is also important was from ASH [American Society of Hematology Annual Meeting], and this is the BiTE [bispecific T-cell engager] antibody because we know that patients still can fail quite a bit of CAR T cells, and it was an anti-CD20 bispecific antibody, a BiTE antibody, presented in a plenary session at ASH. It was very impressive because this was a response rate of 39%, 22% CR. But there were some responses, durable and a CR durable in continued remission, even in patients who had stopped therapy after 16 months of treatment. This is also being explored in the frontline setting in combination with chemotherapy, CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]–POLA [polatuzumab] versus R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. A number of initiatives are trying to address the new unmet need that we have in CAR T cells. Now we know how to manage more toxicity. Can we improve on efficacy and look at easier ways to use those CAR T cells?

Transcript Edited for Clarity

Related Videos
Tracy George, MD
Elias Jabbour, MD
Eunice S. Wang, MD
Dasom (Caroline) Lee, MD
Nosha Farhadfar, MD, and Chandler Park, MD, FACP
Eunice Wang, MD, and Chandler Park, MD, FACP
Muhamed Baljevic, MD, FACP and Jorge Cortes, MD, discuss upcoming studies and emerging data being presented at the 2024 ASH Annual Meeting.
Minoo Battiwalla, MD, MS
Farrukh Awan, MD, discusses treatment considerations with the use of pirtobrutinib in previously treated patients with hematologic malignancies.
Francine Foss, MD