CAR T platform to treat solid tumors

SUMMARY Cancer is one of the leading causes of death worldwide. Over the years, several treatment approaches have been developed. However, their effectiveness is severely limited by the heterogeneity of cancer cells. Thus, there is a constant need for development of therapeutic approaches with improved outcome, such as immunotherapy that utilizes and enhances the normal capacity of the patient's immune system. Of note, renal cell carcinoma and ovarian cancer are considered immunogenic, or “hot” cancers, in that tumors are infiltrated with T cells. This provides optimism that the immune system can be harnessed to be a potent and durable weapon against these cancers. Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy against hematologic tumors. Yet, CAR T cells fail against solid tumors due to key obstacles presented by the tumor microenvironment (TME). We propose in this application to demonstrate proof-of-concept of a novel platform that can overcome the current barrier to CAR T cell therapy in solid tumors. Our strategy combines the specificity of anti-TIM1 CAR with modulation of the TME by a combination of two cytokines, leading to a shift from immunosuppressive to a cytotoxic environment. Our approach capitalizes on the recruitment and activation of a broad repertoire of endogenous innate and adaptive immune cells, including tumor-specific T cells. Super2 and IL-33 CAR T cells promote antitumor immunity in multiple murine solid tumor models and is impervious to antigen loss, highlighting its potential as a universal CAR T cell platform for treatment of solid tumors. Aims will include the following: Aim 1. Design and evaluate human constructs expressing anti-TIM1 CAR, Super2 and IL-33 in vitro. Aim 2. Demonstrate proof of concept (POC) of efficacy of a dual cytokine delivery by anti-TIM1 CAR T cells in a humanized model of Renal cell carcinoma (RCC).