Enhancing CAR T-Cell Therapy for Metastatic Prostate Cancer: The AUTO7 Approach

A novel CAR T therapy for prostate cancer, AUTO7, has been developed, integrating six distinct functional modules to enhance treatment efficacy. The therapy is designed to target PSMA, a protein commonly found in prostate cancer cells, using a humanized antibody. The safety of the treatment is regulated by an incorporated switch, while the dnTGFβRII and dSHP2 modules work to counteract immunosuppressive effects caused by TGFβ1 and the PD1/PD-L1 pathway, respectively. The IL7R_CCR module promotes cell viability and proliferation without the need for external cytokines, and the IL12 module is engineered to stimulate lymphocyte recruitment and activation.

The PSMA-specific binder was created through CDR grafting from an antibody sourced from genetically vaccinated rats. T-cells were modified to carry the CAR and the six modules, and their performance was evaluated in vitro using PSMA positive cell lines. The modified T-cells demonstrated robust cytotoxicity, resistance to immunosuppression, and the ability to proliferate independently of cytokines. The IL12 module was particularly effective in activating fresh PBMCs to produce IFNγ.

In vivo testing in NSG mice with human xenografts showed that AUTO7 CAR T-cells were able to completely eliminate tumors without any observed toxicity. The study indicates that the inclusion of the IL7R_CCR, IL-12, dnTGFβRII, and dSHP2 modules significantly improved T cell functionality by enhancing their persistence, proliferation, activation, and resistance to immunosuppressive factors within the tumor microenvironment.

The research was presented by Marco Della Peruta et al. at the Annual Meeting of the American Association for Cancer Research in 2020, highlighting the potential of the AUTO7 product in treating metastatic castration-resistant prostate cancer (mCRPC).