644 Combining radiopharmaceutical ligand therapy with CAR T cells to overcome the heterogeneous immunosuppressive prostate tumor microenvironment
Year: 2026
Type: conference-abstract
Abstract: Background 177Lu-PSMA-617 is an FDA-approved targeted radiopharmaceutical therapy (RPT) for metastatic castration-resistant prostate cancer (mCRPC), but durable responses remain limited. While chimeric antigen receptor (CAR) T cell therapy has transformed treatment of hematologic malignancies, its efficacy in mCRPC is constrained by antigen heterogeneity and an immunosuppressive tumor microenvironment (TME). In a phase 1 clinical trial ( NCT03873805) of PSCA-targeted CAR T cells, we observed favorable safety and evidence of activity following cyclophosphamide (Cy) lymphodepletion. Preclinical studies suggest radiation can enhance CAR T cell efficacy through TME remodeling; however, focal radiation cannot effectively target disseminated metastatic disease. Here, we investigate the combination of systemic 177Lu-PSMA-617 RPT and PSCA-CAR T cells to overcome immune suppression and tumor heterogeneity in prostate cancer. By leveraging therapies that are FDA-approved or already in clinical development, this strategy offers a clear path toward rapid clinical translation and may provide proof-of-concept for combining RPT with cellular therapy in immunologically cold tumors.Methods Using human PSCA knock-in (hPSCA-KI) syngeneic mouse models, we evaluated the immunomodulatory and therapeutic effects of combining 177Lu-PSMA-617 RPT, Cy, and PSCA-CAR T cells. Murine prostate cancer cell lines engineered to express human PSMA and/or PSCA were implanted subcutaneously and treated with RPT, Cy, and CAR T cells. Tumors and tumor-draining lymph nodes were analyzed by flow cytometry and single-cell RNA sequencing to characterize immune responses. Tumor growth, survival, body weight, and blood chemistry were monitored to assess efficacy and safety.Results We evaluated the efficacy and safety of combining Lu-177 RPT with PSCA-CAR T cell therapy in both xenograft and syngeneic prostate cancer models. Integrated flow cytometry and single-cell transcriptomic analyses revealed significant immunologic remodeling following combination treatment. Sequential administration of Lu-177 RPT followed by PSCA-CAR T cells improved survival and anti-tumor responses compared with either therapy alone. Mechanistically, the combination addressed antigen heterogeneity while promoting a more favorable immune microenvironment that supported sustained anti-tumor activity. Similar findings were observed with 225Ac-PSMA-617, suggesting broader applicability across radionuclide platforms.Conclusions Combining PSMA-targeted RPT with PSCA-CAR T cells enhances anti-tumor efficacy and durability in preclinical prostate cancer models. The use of clinically relevant therapies supports near-term translational potential. Extension of these findings to 225Ac-PSMA-617 further highlights the promise of integrating RPT and CAR T cell therapy as a next-generation treatment strategy for mCRPC and other immunologically cold cancers.Ethics Approval All animal studies were approved by the UCLA, USC, and City of Hope Institutional Animal Care and Use Committees (IACUC) and conducted in accordance with Animal Research: Reporting of In vivo Experiments (ARRIVE) guidelines (protocol no. 21666 and 21687, USC; no. 21025, COH).
Authors: Jiangyue Liu, John P Murad, Iveta Fajnorova, Yuwei Ren, Kofi Poku, Shuai Yang, Yu-Hsuan Fu, Cari Young, Lupita S Lopez, Reginaldo Rosa, Pauline Jeanjean, Ines Azrour, Ava Fakharpour, Lea Christian, Yukiko Yamaguchi, Laura H Porter, Vikram Adhikarla, Russell C Rockne, Stephen J Forman, Yun Rose Li, Tanya Dorff, Gail P Risbridger, Renea Taylor, Christine Mona, Saul J Priceman
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225304315