Updates in Targeted Therapies for B-Cell Malignancies - Episode 14

Potential for CAR T-Cell Therapy in B-Cell Lymphomas


Stephen J. Schuster, MD: Yesterday we presented the 49-month median follow-up for our patients who were treated with CAR [chimeric antigen receptor] T cells for refractory diffuse large B-cell lymphoma and follicular lymphoma. I can say with confidence that the responses we saw early on and previously reported at 2 years are durable. After the first year of remission, relapses are very rare. The good news is that I will extrapolate from the studies we did at the University of Pennsylvania to the large registrational trials by Novartis International AG, Kite Pharma, Inc—Gilead Sciences, Inc, and Juno Therapeutics, Inc–Celgene Corp. Their results, which are now approaching 2 years, are likely to be similar to ours at 4 years because they’re reporting similar responses as we are at 2 years.

Looking at the best response rates in 24 patients with diffuse large B-cell lymphoma, we had a 46% complete response. And at 4 years, about two-thirds of those patients were still responding. Only 1 patient who had a complete response had progression of disease after a year. They were durable responses.

In follicular lymphoma, we had a cohort of only 14, but the response rates were even higher. We had 71% complete response rates and hadn’t reached the median response duration at 4 years. However, we did have several relapses in follicular lymphoma after a year, as opposed to large cell, where we had only 1 relapse. The higher initial complete response rate leads to the figures that I just mentioned.

The good news is that these are durable remissions that can be achieved with a single treatment using the genetically modified T cells. They offer a line of therapy for situations where we previously had nothing to offer. As you know, last year and in 2017, the CAR T-cells were first approved in the US. And then last year the Novartis product, which we developed at Penn, was approved for lymphoma. That is really gratifying.

I think there’s room for improvement. There is always room for improvement. We’re not at 100% with large-cell lymphoma. That’s where I see a lot of potential space for us to improve outcomes by incorporating some of the new technologies that are being presented here at this American Society of Clinical Oncology Annual meeting

There’s a lot of exciting stuff going on. There are very impressive results that have been presented for the bispecific antibodies, which are essentially a form of cellular therapy like CAR T cell, except that instead of genetically modifying the T cells, you give an antibody derivative, which can engage the patient’s T cells with the tumor cells. The response rates are really impressive. We don’t have the durations yet, but I could see partnering these agents with CAR T cells so that we can target more than 1 antigen. The CAR T cells we use target just 1 antigen on the tumor, which is CD19. The bispecifics can offer additional antigens without even doing genetic modifications. I could see that being 1 application.

The number of targeted therapies that have been presented at this meeting, like BTK inhibitors—as you know, in CLL [chronic lymphocytic leukemia], ibrutinib has essentially changed the paradigm. There are data now showing a survival benefit for patients to get ibrutinib as part of first therapy. I think it’s replacing the chemotherapy approach to that disease.

It turns out that ibrutinib has off-target effects that enhance T-cell function. We actually did a trial in chronic lymphocytic leukemia at the University of Pennsylvania in which we treated patients with ibrutinib for 6 months, and for those patients who had less than partial response, we went ahead and did CAR T-cell therapy, continuing ibrutinib throughout. We had excellent results. We did MRD [minimal residual disease] testing, and 10 of 11 patients were negative. This was a study that was led by Saar Gill, MD, PhD, at our institution. As you know, MRD negativity in CLL bodes for a very good long-term outcome. It’s a good biomarker, which we don’t have for all the diseases.

Mantle cell lymphoma is another area in which I see the near future as very promising, in terms of advances in therapy. There were data presented here using a similar CAR to what we used at the University of Pennsylvania. That is 4-1BB costimulatory CAR. It was sponsored by Juno-Celgene in mantle cell lymphoma.

The follow-up is very short, but the responses were really promising. There was a very high response rate, and thinking along the lines of what was presented with BTK inhibitors and mantle cell lymphoma, there is another opportunity to combine, as we had in CLL. Looking at all these different modalities, including small-molecule inhibitors of intracellular signaling and new immunologic techniques, and seeing potential to overlap or integrate these approaches, makes me think that we presented some nice data. Maybe 4 years from now, I’ll have even better data to present, because we plan to do a lot of combination studies to improve outcomes.

Transcript Edited for Clarity