Evidence of Disease Reduction Observed Among Patients Treated With Ovarian Cancer CAR-T PRGN-3005

Mary “Nora” Disis, MD

PRGN-3005, an investigational MUC16-directed chimeric antigen receptor T-cell (CAR-T) therapy intended for the treatment of patients with platinum-resistant ovarian cancer, is currently being assessed in a phase 1/1b clinical trial (NCT03907527). The CAR-T was designed with a feature expected to improve persistence with the intention of overcoming limitations that have held back the success of trials for other CAR-T therapies directed at ovarian cancer. Interim results from the study evaluating PRGN-3005 were presented at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois.

At the conference, CGTLive™’s sister publication OncLive™, spoke with Mary “Nora” Disis, MD, director of University of Washington Medicine’s Cancer Vaccine institute, who coauthored the study, about the key findings and their potential implications for the solid tumor treatment landscape. She discussed the efficacy seen so far with PRGN-3005, noting that in the cohort of patients in the trial who received PRGN-3005 intravenously with lymphodepletion, more than two-thirds of patients showed evidence of disease reduction.

OncLive: Can you provide the rationale behind your research being presented at ASCO?

Mary “Nora” Disis, MD: The study was composed of patients who had cisplatin-refractory ovarian cancer, which is very difficult to treat. There has been such success with CAR T-cell therapies in hematopoietic diseases, but that has not really translated to solid tumors for a lot of reasons—the tumors can't be penetrated by the T-cells—but most importantly, the T-cells don't persist long enough to really be able to do damage against the solid tumors. So, the rationale of this study was really a novel construct for CAR T-cells, targeting a very important antigen that's expressed on the tumor: MUC16. It's expressed on virtually all advanced-stage ovarian cancers. This CAR T-cell was engineered not only to express the antigen, but also to express a cytokine that would keep the T-cells alive for a long period of time. We think this overcomes 1 of the main reasons why CAR T-cells may not work in solid tumors.

What are the results from the study being presented at the conference?

The study being presented is the result of a phase 1 study looking at a few things. First of all, it’s the safety of the CAR T-cell therapy because many CAR T-cell therapies are associated with very severe cytokine release syndrome. We fortunately did not see that here; we saw cytokine release syndrome, but it was quite mild, so the safety of the infusions was really quite favorable. The second thing the study was looking at was whether the T-cells did persist—and they did. They persisted for weeks and weeks after infusion. We're still collecting the data, but the T-cells seem to persist for a very long time. The third thing that we looked at was how to deliver the CAR T-cells. Ovarian cancer is generally an intraabdominal tumor so we looked at intraperitoneal delivery, intravenous delivery, and then intravenous delivery with chemotherapy to lymphodeplete T-cells because we know that that lymphodepletion can make the CAR T-cells expand even more in the body. Then the final thing is we followed the patients for some type of response rate and in the arm that received the intravenous CART-cells with the lymphodepletion, over two-thirds of the patients showed some impact in disease reduction.

What are the next steps for this research?

The next step is definitely a phase 2 clinical trial, which is already underway. We've been able to establish a dose, we've been able to establish safety, we have some early, very encouraging clinical activity—so now this next larger trial will really be directed toward expanding the number of patients and really nailing the clinical activity of the approach.

Is there anything else you'd like to add about the research on PRGN-3005?

I think that this study represents a very novel method of the delivery of CAR T-cell therapy in the sense that we literally take the blood from the patients, we transfect the cells in the blood overnight, and the next day we infuse the CAR T-cells back into the patient. It's a very rapid way to generate the cells and infuse these cells—and with the cytokine added to the CAR T-cell construct I think that we will potentially overcome some of the major barriers that we have in getting this type of approach to work in patients with solid tumors.

What would you say is your main message for colleagues?

I think my main message is that these new generations of CAR T-cells—not only the ones we’re testing, but others, too—don't seem to have the very significant side effect we've seen in the first generation of CAR T-cells. I hope that strategies such as this will allow CAR T-cell delivery to occur in any hospital anywhere, as long as it shows efficacy.

Transcript edited for clarity. Click here for more coverage of ASCO 2023.

REFERENCE
1. Liao JB, Stanton SE, Chakiath M, et al. Phase 1/1b study of PRGN-3005 autologous UltraCAR-T cells manufactured overnight for infusion next day to advanced stage platinum resistant ovarian cancer patients. Presented at: the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois. Abstract #5590