Combining receptor-targeted alpha particle therapy and immunotherapy to achieve complete responses in metastatic melanoma - 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 $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 a-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 clinical trials and a new approach to metastatic melanoma patient care that results in more complete responses and better quality of life.