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

Relapsing or persistent acute myeloid leukemia (AML) represents a severe form of cancer that is difficult to treat and has a grim outlook. The necessity for innovative treatments is evident due to the scarcity of effective options. The conventional production of CAR-T cells is a time-consuming and costly process that involves significant ex vivo cell expansion after viral transduction, which is not ideal for patients who require prompt treatment.

The UltraCAR-T platform is a novel approach that aims to overcome these challenges by offering a quicker, more local manufacturing process that can be executed in a hospital's GMP-compliant facility immediately after patient apheresis. This platform uses Precigen's cutting-edge non-viral multi-gene delivery system and maintains high cell viability, enabling the rapid delivery of autologous CAR-T cells just one day post gene transfer.

The PRGN-3006 UltraCAR-T cells, developed using Precigen's UltraVector platform, are engineered to express 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 longevity in the presence of tumor antigens without the need for additional cytokines. This feature also negates the requirement for T cell expansion before administration. The kill switch co-expression offers a method for controlled elimination of the cells post-treatment, enhancing safety and therapeutic control.

The PRGN-3006 UltraCAR-T cells were successfully manufactured using a non-viral gene transfer method and a streamlined production process from various donor T cells. Flow cytometry and western blot analyses confirmed the co-expression of the CAR, mbIL15, and kill switch. In vitro tests showed robust expansion in the presence of the CD33 antigen, no autonomous expansion without CD33, and sustained persistence without exogenous cytokines. The cells demonstrated specific killing of CD33+ tumor cells and released significant levels of inflammatory cytokines like IFNγ when co-cultured with AML tumor cells. The kill switch activator antibody was also shown to specifically eliminate PRGN-3006 cells.

In an in vivo aggressive AML xenograft model using immunocompromised mice, a single administration of PRGN-3006 UltraCAR-T cells, given just one day after gene transfer, effectively reduced tumor burden and significantly improved survival rates compared to conventional CAR-T cells lacking mbIL15 expression (p<0.01). The PRGN-3006 cells showed better engraftment, expansion, and persistence in the mice.

The promising pre-clinical results support the initiation of clinical trials for PRGN-3006 UltraCAR-T in treating AML. The FDA has granted approval for an investigational new drug application, and a Phase 1 clinical trial for patients with relapsed/refractory AML and high-risk myelodysplastic syndrome is underway (ClinicalTrials.gov Identifier: NCT03927261).