Pre-clinical Development of a Novel CAR-T Therapy Targeting TIM-1 for Treating Solid Tumors 2309293

Abstract

Abstract Introduction Chimeric antigen receptor (CAR)-based therapy represents a major advancement in cancer treatment, especially in hematopoietic malignancies. However, it faces many challenges in treating solid tumors, including the lack of tumor-specific antigens and on-target, off-tumor effects. We have developed a novel CAR-T cell therapy, designed to target a specific tumor antigen (TIM-1) in renal cell carcinoma (RCC) and ovarian clear cell carcinoma (OCCC). Expression of TIM-1 in healthy tissues is limited to absent. This tumor-specific expression makes TIM-1 an ideal target for CAR-based approaches. Methods TIM-1-specfic response of the CAR-T cells was validated by IFN-γ production upon recombinant TIM-1 stimulation and in vitro cytotoxicity against TIM-1-expressing tumor cells. Therapeutic efficacy of TIM-1 CAR-T cells was evaluated in xenograft models. Both tumor growth and survival of the mice were monitored. Moreover, possible toxicity of TIM-1 CAR-T cells in treating RCC was examined in a human TIM-1 knock-in mouse kidney ischemia/reperfusion model. Results TIM-1 CAR-T cells had significantly increased IFN-γ production in response to recombinant TIM-1 stimulation and TIM-1-expressing tumor cells. TIM-1-specific cytotoxicity was observed with TIM-1 CAR-T cells against TIM-1-expressing RCC and OCCC tumor cells. TIM-1 CAR-T cell treatment showed 100% survival in an RCC model, and 90% survival in an OCCC model. Tumor growth was significantly suppressed by TIM-1 CAR-T cell treatment in both models. Minimal toxicity was observed with up to 5*107 CAR-T cells in a human TIM-1 knock in mouse kidney ischemia/reperfusion model. There was no increase in kidney and liver toxicity markers with TIM-1 CAR-T treatment after ischemia/reperfusion injury. Conclusion TIM-1 CAR-T cell therapy is efficacious and safe in treating RCC and OCCC in pre-clinical models. The pre-IND development is underway in advancing this novel therapy to the clinic. Funding Source SBIR Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)