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

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 with low-dose TRT to propagate antitumor immunity. C57BL/6 mice were engrafted with primary and secondary tumors 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 with 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 responses in the primary and secondary tumors. Overall, these data highlight TRT + DCP + ISV as a promising approach to prime and propagate antitumor immunity and promote response to checkpoint inhibition.