Intravenous PRGN-3005 Plus Lymphodepletion Shows Early Promise in Ovarian Cancer

Mary “Nora” L. Disis, MD

PRGN-3005 autologous UltraCAR T cells given with or without lymphodepletion was well tolerated and reduced overall tumor burden in heavily pretreated patients with ovarian cancer, according to data from a phase 1/1b study (NCT03907527). The intravenous delivery and the mechanism of this approach may allow for more successful use of CAR T-cell therapy in this disease and beyond, according to Mary “Nora” L. Disis, MD.

Results presented at the 2023 ASCO Annual Meeting showed that intravenous administration of the product resulted in dose-dependent T-cell expansion regardless of subsequent lymphodepletion. However, the addition of lymphodepletion stabilized or decreased CA125 levels in 89% of patients (n = 9).

Notably, patients who received the single intravenous infusion of PRGN-3005 after lymphodepletion experienced a 67% reduction in tumor burden, and administration of 2 infusions in a patient led to a 28% reduction in tumor burden. PRGN-3005 was well tolerated and did not produce any dose-limiting toxicities, neurotoxicity, or ophthalmologic adverse effects (AEs).

“With the cytokine added to the CAR T-cell construct, we will potentially overcome some of the major barriers that [exist with] getting this type of approach to work in patients with solid tumors,” Disis said in an interview with OncLive®.

In the interview, Disis expanded on key findings from the phase 1/1b study of PRGN-3005, discussed next steps for the trial, and explained how this research aids efforts to effectively utilize CAR T-cell therapy in ovarian cancer and other solid tumors.

Disis is director of the University of Washington (UW) Institute of Translational Health Science at the Center for Translational Medicine in Women's Health, the associate dean of UW School of Medicine and Translational Science, and dean of Research and Graduate Education. She is also a Helen B. Slonaker Endowed Professor for Cancer Research, professor of medicine and oncology, and adjunct professor of Obstetrics & Gynecology and Pathology at UW School of Medicine in Seattle, Washington.

OncLive: What was the rationale for evaluating PRGN-3005 autologous UltraCAR T cells in patients with advanced stage platinum-resistant ovarian cancer?

Disis: 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 [hematological] diseases, but that has not translated to solid tumors for a lot of reasons. [This includes the fact that] the tumors can’t be penetrated by the T cells, and most importantly, that the T cells don’t persist long enough to do damage against these solid tumors.

The rationale of this study was [to evaluate] a novel construct for CAR T cells targeting a very important antigen that’s expressed on the tumor: MUC16, which is expressed on virtually all advanced-stage ovarian cancers. This CAR T-cell product 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 one of the main reasons why CAR T cells may not work in solid tumors.

What was the safety and efficacy of PRGN-3005 as reported at the 2023 ASCO Annual Meeting? Which delivery method of this agent was associated with superior outcomes?

The results of the phase 1 study were presented. [The trial] looked at a few things. First of all, [it looked at] the safety of the CAR T-cell therapy because many CAR T-cell therapies are associated with severe cytokine release syndrome [CRS]. We fortunately did not see that here. We saw CRS, but it was quite mild. The safety of the infusions was quite favorable.

The second thing the study looked at was whether the T cells did persist, and they did. They persisted for weeks and weeks after infusion. We’re still collecting 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-cell therapy. Ovarian cancer is generally an intra-abdominal tumor, so we looked at intraperitoneal delivery and intravenous delivery. [We also evaluated] intravenous delivery with chemotherapy to lymphodeplete T cells because we know that lymphodepletion can make the CAR T cells expand even more in the body.

The final thing [we did was] follow the patients for some type of response rate. In the arm that received the intravenous CAR T cells with lymphodepletion, over two-thirds of patients showed some disease reduction.

What next steps are planned for this research?

Next steps [include] a phase 2 clinical trial, which is already underway. We’ve been able to establish a dose and establish [the agent’s] safety. [We] have [also observed] some early, encouraging clinical activity. This next, larger trial will be directed toward expanding the number of patients and nailing the clinical activity of the approach.

Based on these results, how might intravenous delivery of CAR T-cell therapy after lymphodepletion improve the efficacy of this drug class—not only in ovarian cancer, but in other solid tumors?

This study represents a novel method of the delivery of CAR T-cell therapy in the sense that we take the blood from the patients, we transfect the cells in the blood overnight, and we infuse the CAR T cells back into the patient the next day. It’s a very rapid way to generate the cells and infuse them.

[Additionally], these new generations of CAR T cells—not only the ones we are testing—don’t seem to have the significant AEs that we’ve seen with first-generation CAR T cells.I hope that [novel delivery] strategies like this will allow CAR T-cell delivery to occur in any hospital anywhere, as long as it shows efficacy.

What other research in ovarian cancer were you excited to see presented at the 2023 ASCO Annual Meeting, and why?

I’m excited to see combination immunotherapy treatments. There are a lot of posters and presentations suggesting that combination approaches [given] over extended periods of time may benefit the patient in terms of prolonged disease stabilization or pushing more patients into remission. As [we] begin to combine immune checkpoint inhibitors with CAR T-cell therapy and with cancer vaccines, we’re pushing ever closer to getting the full extent of immune therapies to patients—especially those with solid tumors.

Dr Disis reports having received institutional research funding from Aston Sci., Bavarian Nordic, Precigen and Veana Therapeutics; she has stock and other ownership interests with Epithany; she is an inventor on patents held by the University of Washington.

Reference

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. J Clin Oncol. 2023;41(suppl 16):5590. doi:10.1200/JCO.2023.41.16_suppl.5590