Educational content on VJHemOnc is intended for healthcare professionals only. By visiting this website and accessing this information you confirm that you are a healthcare professional.

Share this video  

ASH 2021 | First-in-human: BCMA CAR-T plus gamma secretase inhibitor in R/R myeloma

Andrew Cowan, MD, University of Washington, Seattle, WA, shares the latest findings from a Phase I first-in-human trial (NCT03502577) of BCMA-directed CAR T-cell therapy in combination with JSMD194, a gamma secretase inhibitor (GSI), for patients with relapsed/refractory (R/R) multiple myeloma. To date, 18 patients have been treated with JSMD194 monotherapy run-in, followed by BCMA CAR-T therapy. The combination was shown to be safe and well tolerated, with one patient experiencing a dose limiting toxicity. JSMD194 administration was shown to increase BCMA expression on plasma cells and gave rise to rapid and durable responses to CAR-T therapy. These results suggest that combining BCMA-targeted CAR-T therapy with a GSI may augment anti-tumor activity. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.

Transcript (edited for clarity)

We have the honor of presenting our data this year on our study of fully human BCMA CAR T-cells with a gamma secretase inhibitor and relapsed/refractory multiple myeloma. And we are presenting on the total accrual of 18 patients to this study that we’ve accrued and treated with a median follow up of 20 months. So just a little bit of background about this study. So BCMA is a common target for immunotherapy in multiple myeloma bispecific antibodies, CAR T-cells, antibody drug conjugates are all utilizing BCMA...

We have the honor of presenting our data this year on our study of fully human BCMA CAR T-cells with a gamma secretase inhibitor and relapsed/refractory multiple myeloma. And we are presenting on the total accrual of 18 patients to this study that we’ve accrued and treated with a median follow up of 20 months. So just a little bit of background about this study. So BCMA is a common target for immunotherapy in multiple myeloma bispecific antibodies, CAR T-cells, antibody drug conjugates are all utilizing BCMA. In our research, we have some preclinical translational work from Fred Hutch, from the lab of Dr Damian Green, showing that we can increase BCMA surface density on plasma cells through inhibition of gamma secretase, which is a cell membrane protein that cleaves BCMA off the surface. We showed in some translational models that using a GSI, we could not only increase BCMA density, but we could also potentially augment anti-tumor efficacy of BCMA CAR T-cells. So that was what led to the development of this first in human trial.

So in our study, we use a fully human BCMA scFv and we combine it with a GSI, which is JSMD194. And the dose that it was given with in the study was 25 milligrams three times a week for a total of three weeks after the receipt of BCMA CAR T-cells. As I mentioned, we’ve treated 18 patients so far. The patients were heavily pretreated; a median of 10 prior regimens. About 40 to 50% had prior treatment with BCMA targeted therapy, both BCMA ADCs, BCMA bispecific antibodies, and BCMA CAR T-cell therapy. So that was something that I think that was unique about our study.

And we had an overall response rate of 94% in the trial. And even we saw this type of response at very low dose levels. The first dose level was 50 million CAR T-cells and we saw responses at all of the dose levels, even the lowest one. As an example, the first patient we treated on study has had an excellent response now in a stringent CR and has maintained that for almost over three years. So the median progression-free survival of patients treated on this study was 11.8 months. But when we looked to see if there was an impact with respect to receipt of prior BCMA therapy, we did see that the PFS was much better for patients who had not received BCMA targeted therapy. The median PFS has not been reached while for people who had had BCMA targeted therapy, it was only two months. We saw similar trends with overall survival.

As part of the study, we also did a run in with the GSI before we treated people with CAR T-cells to look at discrete effects of the GSI on plasma cell surface BCMA density. We showed that when we gave the GSI for three doses, 25 milligrams, and repeated the bone marrow and blood, we could increase BCMA density up to 157-fold routinely. So one aspect of the research that we were able to confirm from the translational work was that in humans, we can also increase BCMA density pretty dramatically and pretty routinely.

With respect to toxicities, I would say it’s fairly expected for what we would see with CAR T-product. About 94% of patients had cytokine release syndrome. Most of those were grade 1 or 2. Neurologic changes were common. Our study predated the use of the ICANS and ICE scoring system for neurologic toxicity. So any neurologic change was considered and 66% of patients did have a neurologic change. And there was only one DLT on the study in a patient with grade 4 CRS and disseminated aspergillosis.

So in summary, we’ve shown that BCMA CAR T-cells in combination with a GSI, we can routinely increase BCMA surface density on plasma cells. The depth and duration of responses amongst many patients is highly encouraging. And I think that this approach of combining a GSI with BCMA targeted therapy is certainly one that warrants further study.

Read more...