Mary “Nora” Disis, MD, director, University of Washington (UW) Institute of Translational Health Science, Center for Translational Medicine in Women's Health, dean, Research and Graduate Education, associate dean, Translational Science, Helen B. Slonaker Endowed Professor for Cancer Research, professor, medicine and oncology, adjunct professor, Obstetrics & Gynecology and Pathology, UW School of Medicine, discusses the rationale for investigating the efficacy and optimal delivery of PRGN-3005 autologous UltraCAR T cells in patients with advanced stage platinum-resistant ovarian cancer.

Although CAR T-cell therapies have shown substantial efficacy in hematologic diseases, attempts to utilize this drug class in solid tumors have been less successful, Disis begins. Challenges associated with the implementation of CAR T-cell therapy in this disease space include issues with T-cell penetration and limited T-cell persistence, she states. 

In order to address these unmet needs, investigator's launched a phase 1/1b study (NCT03907527) to assess PRGN-3005, Disis states. PRGN-3005 is a novel therapy that targets the tumor antigen MUC16, which is commonly expressed in advanced ovarian cancers, Disis explains. PRGN-2005 was engineered to express MUC16, as well as a cytokine promoting T-cell longevity, she notes.

The trial enrolled patients with cisplatin-refractory ovarian cancer, Disis continues, noting that this disease subtype is often challenging to treat. PRGN-3005 autologous UltraCAR T-cells were administered with or without lymphodepletion, demonstrating tolerability and a reduction in overall tumor burden in heavily pretreated patients, Disis reports.

Intravenous delivery of PRGN-3005 led to dose-dependent T-cell expansion regardless of subsequent lymphodepletion. However, combining lymphodepletion with PRGN-3005 notably stabilized or decreased CA125 levels in 89% of patients.

The study also highlighted the effectiveness of PRGN-3005, with a single intravenous infusion after lymphodepletion resulting in a 67% reduction in tumor burden, while 2 infusions led to a 28% reduction. Importantly, PRGN-3005 exhibited an excellent safety profile, with no dose-limiting toxicities, neurotoxicity, or ophthalmologic adverse effects noted.

These results suggest that PRGN-3005 CAR T-cell therapy, with its engineered cytokine for prolonged T-cell activity, could overcome current limitations associated with the treatment of patients with difficult-to-treat ovarian cancer, Disis concludes.

Videos

Mary “Nora” Disis, MD, discusses the rationale for investigating the efficacy and optimal delivery of PRGN-3005 autologous UltraCAR T cells in patients with advanced stage platinum-resistant ovarian cancer.

Dr. Disis on the Rationale For Investigating PRGN-3005 With/Without Lymphodepletion in Ovarian Cancer

Mary “Nora” Disis, MD, director, University of Washington (UW) Institute of Translational Health Science, Center for Translational Medicine in Women's Health, associate dean, UW School of Medicine, dean, Research and Graduate Education, associate dean, Translational Science, Helen B. Slonaker Endowed Professor for Cancer Research, professor, medicine and oncology, adjunct professor, Obstetrics & Gynecology and Pathology, UW School of Medicine, discusses the results of a phase 1/1b study of PRGN-3005 autologous UltraCAR T cells in patients with advanced stage platinum-resistant ovarian cancer .

At the 2023 ASCO Annual Meeting, investigators presented the results of this phase 1/1b study, which evaluated the safety and efficacy of intraperitoneal and intravenous administration of PRGN-3005 with and without lymphodepletion, Disis begins. Although many CAR T-cell therapies can be associated with severe cytokine release syndrome (CRS), investigators reported only mild cases of grade 1/2 CRS, Disis explains. Overall, the safety profile of the agent was favorable, with no dose-limiting toxicities, no neurotoxicity, no ophthalmologic adverse effects, and no use of kill switch.

Investigators also evaluated T-cell persistence with the agent and demonstrated that T cells persisted for weeks following infusion. Data will continue to be collected to evaluate the long-term durability of T-cell persistence with the agent, Disis expands.

Investigators also evaluated optimal delivery techniques with the agent. Ovarian cancer is typically an intra-abdominal tumor, leading investigators to look at intraperitoneal delivery (n = 12), intravenous delivery (n = 6), and intravenous delivery with lymphodepleting chemotherapy (n = 9). The latter approach was included because it is known that lymphodepletion can cause CAR T cells to expand even more in the body, Disis says. Finally, investigators evaluated response with the agent. Notably, a single intravenous infusion of PRGN-3005 following lymphodepletion led to a 67% reduction in tumor burden. Additionally, administration of two infusions led to a 28% reduction in tumor burden, Disis concludes.

Mary “Nora” Disis, MD, discusses the results of a phase 1/1b study of PRGN-3005 autologous UltraCAR T cells in patients with advanced stage platinum-resistant ovarian cancer.


Dr Disis on the Investigation of the CAR T-Cell Therapy PRGN-3005 in Ovarian Cancer

Mary L. (Nora) Disis, MD, professor of Medicine, Department of Medicine, University of Washington School of Medicine, discusses immunotherapy for patients with breast cancer.

Immunotherapy is now being tested in breast cancer to determine how it can work more efficiently since it doesn’t seem to be as effective as it is in other cancers, explains Disis.

For the majority of patients with breast cancer, investigators must determine a way to start the correct immune response in order to have an impact on the tumor, states Disis.

Mary L. (Nora) Disis, MD

Articles

Dr. Disis on the Rationale For Investigating PRGN-3005 With/Without Lymphodepletion in Ovarian Cancer

Dr Disis on the Investigation of the CAR T-Cell Therapy PRGN-3005 in Ovarian Cancer

Dr. Disis on Immunotherapy in Breast Cancer