Abstract 4988: Responders to combination radiation and PD-1 blockade demonstrate reduced myeloid immunosuppression and enhanced interferon signaling in oligometastatic prostate cancer patients

Abstract Background: Prostate cancer is unresponsive to current immunotherapies such as checkpoint inhibitors. Overcoming this “cold” environment requires rational combination of therapeutic modalities that can prime anti-tumor immunity. Radiation is a potential candidate; however it remains unclear how it should be most productively combined with immunotherapies. Methods: We completed an investigator-initiated clinical trial of newly diagnosed men with oligometastatic, hormone-sensitive prostate cancer (mHSPC, NCT03007732). Patients were randomized to receive anti-PD-1 x 13 cycles (pembrolizumab, Arm 1, n=12), or anti-PD-1 with intraprostatic injections of TLR9 agonist SD-101 (Arm 2, n=11). All patients received SBRT to the prostate tumor during cycle 1, and concomitant hormonal therapy with a GnRH agonist and abiraterone. Response was assessed as PSA nadir + 2 ng/mL at 15 months after ceasing all cancer therapies. For unbiased correlative immune interrogation of these patients, fresh paired biopsies of primary prostate tumor and PBMCs both before and after radiation and immunotherapy were analyzed by multi-omic single-cell genomics to assess changes with treatment, including T cell repertoire changes. Results: Fourteen of 21 evaluable patients responded by PSA criteria with 3 patients not yet reaching 15 months of post-treatment follow-up. Adverse events included expected IRAEs from anti-PD-1, and flu-like symptoms from SD-101, with no unexpected AEs. Single-cell analysis of tumor biopsies reveals treatment-induced decreases in cytotoxic T cell populations and increases in both immunostimulatory LAMP3+ dendritic cells and immunosuppressive SPP1+ myeloid populations. Treatment increased interferon (IFN) signaling in most myeloid subsets while strongest in LAMP3+ DCs. Compared to non-responders, responders showed less immunosuppression at baseline with depletion of myeloid cells and enhanced IFN activity on LAMP3+ DCs, and treatment-induced IFN activity on cytotoxic T cells. TLR9 agonism also specifically enhanced IFN responses, persistence of cytotoxic T cell clonotypes, and enhanced antigen presentation in tumor cells. Circulating T cells in blood detected shared clones with tissue showing enrichment in cytotoxic phenotype and association with responders. Conclusions: Responders to combination radiation and anti-PD-1 blockade have decreased myeloid immunosuppression and enhanced IFN activity prior to treatment in oligometastatic prostate cancer. This may identify patients likely to respond, and baseline immune setpoints that can be enhanced with improved immunotherapy strategies. Acknowledgements: This work was supported by the Prostate Cancer Foundation and Merck. Merck Sharp Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4988.