Bilal A. Siddiqui, MD, Clinical Innovator The University of Texas MD Anderson Cancer Center Area of Research: Prostate Cancer Metastatic castration-resistant prostate cancer (mCRPC) has low responses to immune checkpoint therapy (ICT) monotherapies due to an immunosuppressive tumor microenvironment (TME). The T cell bispecific antibody REGN5678, which co-targets the prostate specific membrane antigen and the CD28 costimulatory domain on T cells, in combination with anti-PD-1 has demonstrated promising efficacy in mCRPC, with ≥90% declines in serum prostate-specific antigen (PSA) levels in 83% (5/6) of patients treated at MD Anderson. However, a high rate of severe (≥Grade 3) immune-mediated toxicities has also been observed in 50% (3/6) of patients treated at MD Anderson. Thus, there is an unmet need to identify predictive, mechanistic biomarkers for efficacy and toxicity to optimize the therapeutic index of REGN5678 plus anti-PD-1 and achieve long-term clinical benefit in patients with lethal prostate cancer. Dr. Siddiqui proposes a biomarker-rich clinical trial of REGN5678 plus anti-PD-1 in patients with mCRPC to address this need. For this study they have developed a comprehensive toxicity mitigation strategy, including: (1) intensive toxicity monitoring measures and algorithms with low thresholds to hold dosing of the study drugs at the earliest sign of toxicity (e.g. elevations in liver enzymes or subtle neurologic symptoms); (2) a laboratory protocol incorporating a 24/7 remote monitoring service aimed at detecting early signs of toxicity; and (3) clinical algorithms for rapid escalation of immunosuppression in cases of severe toxicities. If successful, this study will help us to understand how the drug works and why it causes immune side effects in certain patients with prostate cancer. Dr. Siddiqui will be able to safely treat patients with prostate cancer with this promising immunotherapy. This work will help the development of the next generation of combinations to eventually cure this disease. Projects and Grants Optimizing risk benefit with a biomarker-rich phase Ib/II clinical trial of PSMAxCD28 (REGN5678) plus Cemiplimab (Anti-PD-1) in patients with metastatic castration-resistant prostate cancer The University of Texas MD Anderson Cancer Center | Prostate Cancer | 2024
