In Situ Vaccination, Low-Dose Targeted Radionuclide Therapy, and Immune Checkpoint Inhibition Eradicate Poorly Immunogenic Metastatic Tumors in Murine Cancer Models

作者：Trishna Debnath, Won Jong Jin, Ravi B. Patel, Peter M. Carlson, Md. Mahfuzur Rahman, Tracy J. Berg, Caroline P. Kerr, Rene Welch, Yujuan Wang, Meredith Hyun, Irene M. Ong, Jamey P. Weichert, Reinier Hernandez, Paul M. Sondel, Zachary S. Morris · 发表于：Cancer Immunology Research · 年份：2026 · DOI：10.1158/2326-6066.cir-25-1475 · 研究领域：Radiopharmaceutical Chemistry and Applications、Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses

Focal radiotherapy can provide an in situ vaccine (ISV) effect that may prime adaptive antitumor immunity, which can be augmented by combination with intratumoral immune adjuvants and systemic immune checkpoint inhibition. However, propagation of an antitumor immune response is not consistently achieved in metastatic disease. Delivery of low-dose targeted radionuclide therapy (TRT) can promote clonal expansion and propagation of antitumor immune responses. Therefore, in this study, we combined dual immune checkpoint blockade (DCP; anti-PD-L1 and anti-CTLA-4) with ISV (focal radiotherapy with intratumoral injection of tumor-specific monoclonal antibody and IL2) to prime and low-dose TRT to propagate antitumor immunity. C57BL/6 mice were engrafted with a primary and secondary tumor, and intravenously injected with tumor cells to model advanced metastatic disease. Mice with poorly immunogenic, syngeneic MOC2 head and neck squamous cell carcinomas or B78 melanomas received monotherapy or double or triple combinations of: low-dose TRT; DCP; and primary tumor-targeted ISV. When compared to dual or monotherapies, TRT+DCP+ISV eradicated bulky well-established tumors, prevented development of lung metastases from circulating tumor cells, and extended survival (p< 0.01). TRT+DCP+ISV conferred tumor-specific immune memory, enabling uniform rejection of tumor re-engraftment. TRT+DCP+ISV activated innate and adaptive immune response in the primary and secondary tumors. Overall, these data...