Abstract B040: Development of an immunocompetent murine model of PSMA-positive metastatic prostate cancer to study the impact of PSMA-targeted therapies on the immune response

Abstract Background: Prostate cancer (PC) is the second leading cause of cancer-related death in men, with metastatic castration-resistant PC (mCRPC) remaining largely incurable. Prostate-specific membrane antigen (PSMA) is a validated target, with PSMA-directed radioligand therapy demonstrating survival benefit in mCRPC. Targeted alpha therapies (TAT) with isotopes Lead-212 (212Pb) and Actinium-225 (225Ac) are in clinical development and deliver high-linear-energy-transfer radiation, inducing potent cytotoxicity and potentially enhancing anti-tumour immunity. Current PSMA-positive preclinical models rely on xenografts or engineered murine cells, limiting evaluation of TAT-induced immune modulation thus far. Objective: To investigate the immune-modulatory effects of 212Pb-TAT in metastatic PC, we sought to establish (i) a syngeneic murine model of metastatic PC expressing murine PSMA (mPSMA), and (ii) a PSMA-directed TAT tool compound with high affinity for mPSMA. Methodology: Murine metastatic PC cells (RM1-BM), which recapitulate late-stage TP53-mutant disease, were engineered to express murine FOLH1 (mPSMA) using a PiggyBac transposon system. Expression of mPSMA was confirmed both in vitro and in vivo by western blotting and immunohistochemistry. The TAT agent 212Pb-PS0001 (AdvanCell) was assessed in biodistribution and efficacy studies in immunocompetent C57Bl/6 mice. Results: RM1-BM-mFolh1 cells expressed mPSMA comparably to human PSMA-positive C4-2 cells. 212Pb-PS0001 showed selective tumour uptake in RM1-BM-mFolh1 models, with minimal off-target accumulation. Therapeutic evaluation demonstrated that a single dose of 212Pb-PS0001 significantly suppressed RM1-BM-mFolh1 tumour growth in immunocompetent mice, while untreated controls exhibited progressive disease. Notably, several animals achieved durable tumour control, suggesting potential activation of an anti-tumour immune response. Conclusion: We established a syngeneic mPSMA-positive metastatic PC model suitable for studying the immune-modulatory effects of PSMA-targeted therapies. This model represents a robust platform for assessing therapeutic efficacy, elucidating immune mechanisms of action, and evaluating rational combination strategies, including integration with immune checkpoint blockade. Preliminary studies with 212Pb-PS0001 demonstrated selective PSMA targeting, rapid clearance, and potent anti-tumour activity, supporting its use as PSMA-TAT tool compound. Citation Format: Melissa Monterosso, Aneesha Jones, Kayden Kwah, Anna Amiss, Abby Sydes, Didier Boucher, Aimee Horsfall, Heather Green, Johannes Koehbach, Ralph Huebner, Yaowu He, Stephen Rose, Gary Li, Feifei Liu, Simon Puttick, Anna Karmann, John Hooper, Thomas Kryza. Development of an immunocompetent murine model of PSMA-positive metastatic prostate cancer to study the impact of PSMA-targeted therapies on the immune response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B040.