Enhanced Ovarian Cancer Therapy with UltraCAR-T: Rapidly Manufactured Multigenic CAR-T Cells

Ovarian cancer remains a significant health challenge due to its high fatality rate among gynecological malignancies. The development of Chimeric Antigen Receptor (CAR)-T cell therapies has shown promise in treating blood cancers but has not been as effective against solid tumors. Traditional CAR-T cell production is time-consuming and costly, often resulting in cells with a diminished response.

A novel approach, the UltraCAR-T platform, has been introduced to address these issues. It uses a non-viral gene transfer method based on the Sleeping Beauty transposon system to efficiently deliver multiple genes, thereby accelerating the manufacturing process. This allows for the rapid production of UltraCAR-T cells at a medical center's facility and their return to the patient within a day of gene transfer.

The PRGN-3005 UltraCAR-T cells are engineered to co-express a CAR targeting MUC16, a protein highly present in ovarian tumors, membrane-bound IL-15 for enhanced survival and expansion, and a safety mechanism for controlled therapy. The cells were produced using a non-viral system and their transgene expression was validated through flow cytometry and western blotting. In vitro tests showed that PRGN-3005 cells were highly cytotoxic against MUC16-positive ovarian cancer cells.

These cells also displayed a stem-cell-like memory phenotype, improved survival without additional cytokines, and no autonomous proliferation without MUC16, highlighting the benefits of membrane-bound IL-15 on cell phenotype and longevity. The safety switch was proven effective in eliminating the cells through antibody-dependent cell-mediated cytotoxicity (ADCC).

In vivo studies using a MUC16-positive ovarian cancer model in mice demonstrated that a single dose of PRGN-3005 led to rapid expansion and a significant increase in UltraCAR-T cells, particularly the T stem cell memory population. The treatment showed a pronounced anti-tumor effect, leading to complete tumor regression in all treated mice, outperforming conventional CAR-T cells.

The FDA has granted approval for an Investigational New Drug (IND) application, and the PRGN-3005 Phase I clinical trial for advanced ovarian cancer is currently underway. The study's findings suggest that PRGN-3005 UltraCAR-T cells, with their enhanced efficacy and rapid manufacturing process, offer a promising new avenue for the treatment of ovarian cancer.