Project 3: Modulating Androgen Receptor Signaling to Enhance the Efficacy of CAR T Cell Therapy for Advanced Prostate Cancer

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PROJECT SUMMARY Adoptive cell transfer in the form of chimeric antigen receptor T cell (CART) therapy has revolutionized the treatment of hematologic malignancies and is slowly making inroads into solid tumors. Challenges to the efficacy and safety of CARTs in prostate cancer include antigen heterogeneity, an immunologically “cold” tumor microenvironment, poor persistence, and exhaustion. We have developed a novel CART therapy targeting six transmembrane epithelial antigen of the prostate 1 (STEAP1) which we found to be expressed more broadly than prostate-specific membrane antigen (PSMA) in over 87% of lethal metastatic prostate cancers. In preclinical human-in-mouse and mouse-in-mouse studies, STEAP1 CART demonstrated 1) specificity and antitumor activity in multiple prostate cancer models with varying levels of STEAP1 antigen density and 2) preliminary evidence of safety. The STEAP1 CART program has been accepted into the NCI Experimental Therapeutics (NExT) Program to support clinical translation to a first-in-human study in men with metastatic castration- resistant prostate cancer (mCRPC). Furthermore, androgens are well known to be immunosuppressive, yet CART therapy is used without consideration of local androgen concentrations or the sex of the patient. We present evidence that targeting the androgen receptor is necessary for effective T cell-specific immunotherapy and enhances the function of adoptive cell therapy products. In addition, we demonstrate that androgen receptor signaling inhibitors (ARSI) improve antigen presentation and promote T cell function within the prostate tumor microenvironment. Together, our observations suggest that combining CART therapy with ARSI could improve therapeutic outcomes in advanced prostate cancer patients. To the best of our knowledge this is the first combination of preclinical studies and a CART clinical trial to target STEAP1 in advanced prostate cancer patients. The goal of this proposal is to understand if we can improve CART function by perturbing androgen receptor signaling with an ARSI. We hypothesize that we can improve STEAP1 CART cell persistence and function by combining it with ARSI treatment. We will test this hypothesis in the following Aims: 1) Evaluate the effect of AR modulation on STEAP1 CART phenotype and function; 2) Investigate whether inflammation and ARSI impacts safety and toxicity of STEAP1 CART therapy; and 3) Conduct a phase I clinical trial to assess the feasibility, safety, and efficacy of STEAP1 CART therapy alone and in combination with enzalutamide in men with STEAP1+ mCRPC. These studies provide the preclinical framework for understanding how ARSI and/or AR deletion impacts the function of a novel prostate CART product. Importantly, these studies will provide critical insight into the safety and toxicity of STEAP1 CART therapy alone or with ARSI and reveal potential therapeutic toxicity.