Designing Rational Combinations to Improve CAR T Cell Therapy for Prostate Cancer

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PROJECT SUMMARY Chimeric antigen receptor (CAR) T cell therapy is a type of immunotherapy that has shown clinical success in treating hematological malignancies but faces multiple barriers in the treatment of solid tumors, including an immunosuppressive tumor microenvironment (TME) that hampers therapeutic responses to immunotherapies and heterogeneous antigen expression, which reduces the efficacy of CAR T cells that function primarily through specific targeting of an antigen. Both challenges may be overcome using rationally designed combination therapies that allow for greater stimulation of innate immunity, T cell infiltration, and CAR T cell efficacy. Our group has developed CAR T cells targeting the prostate stem cell antigen (PSCA) overexpressed in prostate cancer and is currently testing them in an ongoing phase 1 trial to treat patients with metastatic castration- resistant prostate cancer (mCRPC). To further examine the therapy in preclinical models, we developed an immunocompetent mouse model using mouse prostate tumors that are targeted with PSCA-CAR engineered mouse T cells. We found that preconditioning tumor-bearing mice with lymphodepleting agent cyclophosphamide (Cy) beneficially enhanced the TME, allowing for greater intra-tumoral infiltration of both endogenous and CAR T cells. However, additional modifications are needed to further alter the TME and achieve more durable responses. To this end, focal radiotherapy (RT) has been found to induce changes in the TME that largely activate the endogenous immune system and trigger anti-tumor responses by T cells, prompting studies to combine focal RT with other immune-based strategies. Perplexingly, RT is also known to induce several immune suppressive effects, which may be particularly magnified in antigen-heterogenous tumor models that limit CAR T cell efficacy. Using our preclinical model, we plan to develop and optimize this combination of focal RT with PSCA-CAR T cells to characterize these potentially complimentary therapeutic strategies. We also plan to unravel these complex effects of radiation on the combination therapy, which will be essential for maximizing the anti-tumor effects of CAR T cells against prostate cancer. Aim 1: I aim to understand how the immunomodulatory effects of focal RT on the TME and systemic immunity may synergize with CAR T cells to develop highly effective treatments against prostate tumors. Aim 2: I plan to identify and overcome resistance mechanisms against this combination therapy using prostate tumors with heterogeneous antigen expression. With the training and expertise provided by my research sponsor Dr. Saul Priceman, an expert in developing CAR T cell therapies for solid tumor treatment, my clinical co-sponsor Dr. Tanya Dorff, the clinical investigator in charge of our phase 1 trial, and the graduate school at City of Hope, an NCI-designated comprehensive cancer center, I will be able to achieve these goals set forth in this F31 Predoctoral Fellowship application.