Revised. Metastatic melanoma is a lethal disease because low response rates (near 50%), acquired resistance, and severe adverse side effects limit long-term quality of life for these patients (5-yr. survival <30%). Radiopharmaceutical therapies are emerging as an exciting alternative in oncology and systemic receptor- targeted alpha-particle therapy (a-RT) is emerging as particularly transformative due to recent reports of complete responses in early trials. Viewpoint is introducing an MC1R-targeted peptide-based a-RT ([212Pb]VMT01) for Stage III/IV metastatic melanoma and has received IND approval (#152145) to begin [203Pb]VMT01 imaging trials (Mayo Clinic) to prepare for [212Pb]VMT01 monotherapy trials. However, our now published predicate R&D (PMID 34359580) revealed a combination of [212Pb]VMT01 a-RT and immunotherapy (ICI) that achieved a 43% complete response rate in an immune-competent mouse melanoma model and a tumor-specific immune response to [212Pb]VMT01. This is significant because this model is unresponsive to ICI alone, which suggests that combining ICIs with a-RT could improve outcomes for thousands of melanoma patients who are unresponsive to current standard of care treatment with single or dual agent ICI blockade. Thus, there is a rigorous scientific basis to develop combined ICI therapy and [212Pb]VMT01 for metastatic melanoma. PHASE I MILESTONES: >$13M Series A secured; IND for [203Pb]VMT01 Phase 1 melanoma imaging trial secured (Mayo Clinic; IND#152145); completed pre-IND consultation with for [212Pb]VMT01 monotherapy and Agency is in support of Viewpoint approach (IND#156357; see letters); IP licensed (exclusive); isotope supply 203Pb/212Pb secured; prototype 212Pb production device (VMT-a-GEN) completed; established VMT-a-GEN mfg facilities to control 212Pb supply. Pharm/tox/dosimetry in mice for VMT01 complete. Completing the revised Specific Aims readies Viewpoint for combined [212Pb]VMT01 a-RT with ICI clinical trials for metastatic melanoma. AIM 1 (Viewpoint Lab): Develop a detailed understanding of the regimens of [212Pb]VMT01 plus immune checkpoint inhibitors that maximize complete responses with minimal toxicities in immune-competent mice. Revised includes toxicity response to ICI’s, timing of administrations, and abscopal effects. AIM 2 (Morris Lab/University of Wisconsin): Develop a detailed understanding of the immunomodulating effect of [212Pb]VMT01 in two syngeneic melanoma models with heterogenous expression of MC1R. IMPACT AND SIGNIFICANCE: By completing this project, we expect to have identified dosing regimens for systemic [212Pb]VMT01 α-RT with immune checkpoint inhibitors that maximize complete responses, while minimizing toxicities in 4 immune-competent mouse models. We further expect to have developed understanding of the systemic anti-tumor immune response for primary and metastatic tumors that captures known intertumoral heterogeneity of metastatic melanoma. We anticipate that this will lead to clinica...