Advancements in AML and MDS Treatment: The Rapid and Efficient UltraCAR-T Therapy with PRGN-3006

Relapsing or treatment-resistant acute myeloid leukemia (AML) is a severe cancer with few treatment options, highlighting the urgent need for innovative therapies. The conventional process for creating CAR-T cells is time-consuming and costly due to the need for ex vivo expansion and viral vector transduction, which is not ideal for patients with advanced cancer who require prompt treatment.

The UltraCAR-T platform offers a solution by simplifying the manufacturing process, allowing local production in a hospital's GMP facility immediately after apheresis. This platform uses Precigen's cutting-edge non-viral gene delivery system and a rapid manufacturing method that ensures high cell viability, enabling the administration of autologous CAR-T cells just one day post gene transfer.

PRGN-3006 UltraCAR-T cells, developed with Precigen's UltraVector platform, feature the co-expression of CD33 CAR, membrane-bound IL-15 (mbIL15), and a kill switch. The inclusion of mbIL15 provides the cells with an internal cytokine source, enhancing their expansion and persistence without the need for additional cytokines. This also negates the need for ex vivo T cell expansion before administration. The kill switch co-expression offers a mechanism for the controlled elimination of PRGN-3006 post-treatment, enhancing therapeutic safety.

Manufactured using a non-viral method and a streamlined process, PRGN-3006 UltraCAR-T cells were confirmed to express CAR, mbIL15, and the kill switch through flow cytometry and western blot analysis. In vitro tests showed robust expansion in the presence of the CD33 antigen, no autonomous expansion without it, and sustained persistence without exogenous cytokines. The cells demonstrated specific killing of CD33+ tumor cells and released inflammatory cytokines when co-cultured with AML tumor cells. The kill switch activator antibody treatment effectively eliminated PRGN-3006 cells.

In an aggressive AML xenograft model using immunocompromised mice, a single administration of PRGN-3006 UltraCAR-T cells one day after gene transfer significantly reduced tumor burden and improved survival rates compared to conventional CAR-T cells lacking mbIL15 expression. The cells also showed higher engraftment, expansion, and persistence in the mice.

The FDA has granted approval for an investigational new drug application for PRGN-3006 UltraCAR-T, and a Phase 1 clinical trial for treating relapsed/refractory AML and high-risk myeloid dysplastic syndrome patients is underway (ClinicalTrials.gov Identifier: NCT03927261).

Disclosures indicate that several individuals are employed by Precigen, Inc., and one has equity ownership in Intrexon Corp., while another has a board membership with Celyad.