Combining receptor-targeted alpha particle therapy and immunotherapy to achieve complete responses in metastatic melanoma

修订。转移性黑色素瘤是一种致命的疾病，因为低反应率（近50%），获得性耐药性， 并且严重的不良副作用限制了这些患者的长期生活质量（5-yr.存活率<30%）。 放射性药物治疗正在成为肿瘤学和全身受体的一种令人兴奋的替代疗法， 靶向α粒子治疗（a-RT）由于最近的报道而成为特别具有变革性的治疗方法， 在早期试验中完全反应。Viewpoint正在引入一种基于MC 1 R靶向肽的a-RT （[212 Pb] VMT 01）治疗III/IV期转移性黑色素瘤，并已获得IND批准（#152145），开始 [203 Pb] VMT 01成像试验（马约诊所），为[212 Pb] VMT 01单药治疗试验做准备。然而，我们现在 已发表的同品种R&D（PMID 34359580）揭示了[212 Pb] VMT 01 a-RT和免疫疗法的组合 (ICI)在免疫活性小鼠黑色素瘤模型中达到43%的完全缓解率， 对[212 Pb] VMT 01的肿瘤特异性免疫应答。这一点很重要，因为该模型对ICI没有反应 这表明将ICIs与a-RT相结合可以改善数千例黑色素瘤患者的预后， 对目前采用单药或双药ICI阻滞的标准治疗无反应的患者。因此，在本发明中， 有严格的科学依据来开发用于转移性黑素瘤的ICI疗法和[212 Pb] VMT 01的组合。 I期里程碑：> 1300万美元的A轮融资获得批准;[203 Pb] VMT 01 1 1期黑色素瘤成像试验的IND 安全（马约诊所; IND编号152145）;完成[212 Pb] VMT 01单药治疗的IND前咨询， 监管机构支持Viewpoint方法（IND #156357;见信函）; IP许可（独家）;同位素供应 获得203 Pb/212 Pb;完成原型212 Pb生产装置（VMT-a-GEN）;建立VMT-a-GEN工厂 控制212 Pb供应。VMT 01的小鼠药理学/毒理学/剂量测定已完成。完成经修订的 Specific Aims准备Viewpoint进行[212 Pb] VMT 01 a-RT与ICI联合治疗转移性黑色素瘤的临床试验。 目的1（Viewpoint Lab）：详细了解[212 Pb] VMT 01+免疫治疗方案 检查点抑制剂，最大限度地提高完全反应，在免疫功能正常的小鼠中毒性最小， 小鼠修订内容包括ICI的毒性反应、给药时间和远位效应。 目标2（莫里斯实验室/威斯康星州大学）：详细了解免疫调节 [212 Pb] VMT 01在具有MC 1 R异质性表达的两种同源黑色素瘤模型中的作用。 影响和意义：通过完成本项目，我们预计将确定给药方案， 全身性[212 Pb] VMT 01 α-RT与免疫检查点抑制剂，最大限度地提高完全缓解， 最小化4种免疫活性小鼠模型中的毒性。我们还希望进一步了解 原发性和转移性肿瘤的系统性抗肿瘤免疫应答， 转移性黑素瘤的异质性。我们预计，这将导致临床试验和一种新的方法， 转移性黑色素瘤患者的护理，导致更完整的反应和更好的生活质量。

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 clinical trials and a new approach to metastatic melanoma patient care that results in more complete responses and better quality of life.