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

已修订。转移性黑色素瘤是一种致命的疾病，因为低应答率(近50%)、获得性耐药性、 严重的副作用限制了这些患者的长期生活质量(5年。存活率为30%)。 放射性药物疗法正在成为肿瘤学和全身受体领域的一种令人兴奋的替代疗法。 靶向阿尔法粒子疗法(a-RT)由于最近的报道而变得特别具有变革性。 在早期试验中完成反应。观点正在引入一种以MC1R为靶点的多肽a-RT ([212Pb]VMT01)用于III/IV期转移性黑色素瘤，并已获得IND批准(#152145)开始 [203Pb]VMT01成像试验(梅奥诊所)，为[212Pb]VMT01单一疗法试验做准备。然而，我们现在 发表的Predicate R&D(PMID 34359580)揭示了[212Pb]VMT01a-RT和免疫治疗的组合 (ICI)在免疫活性小鼠黑色素瘤模型中获得43%的完全应答率 [212Pb]VMT01的肿瘤特异性免疫应答这一点很重要，因为此模型对ICI没有响应 单独，这表明ICIS与a-RT相结合可以改善数千例黑色素瘤的预后 对目前的护理标准无效的患者，使用单药或双药ICI阻断治疗。因此， ICI联合[212Pb]VMT01治疗转移性黑色素瘤有严格的科学依据。 第一阶段里程碑：&gt；1300万美元的A系列安全；[203Pb]VMT01第一阶段黑色素瘤成像试验的IND Secure(梅奥诊所；IND#152145)；完成了[212Pb]VMT01单一疗法的IND前咨询和 机构支持观点方法(IND#156357；见信函)；知识产权许可(独家)；同位素供应 确保203铅/212铅安全；完成212铅生产装置原型(VMT-a-Gen)；建立VMT-a-Gen MFG 控制~(212)Pb供应的设施。小鼠VMT01药物/毒性/剂量测定完成。完成修订后的 [212Pb]VMT01a-RT联合ICI治疗转移性黑色素瘤的临床试验 目标1(观点实验室)：详细了解[212Pb]VMT01加免疫的治疗方案 检查点抑制剂，最大限度地提高免疫能力的完全反应和最小的毒性 老鼠。修订包括对ICI的毒性反应、给药时机和异常影响。 目标2(莫里斯实验室/威斯康星大学)：详细了解免疫调节 [212Pb]VMT01在两种MC1R异源表达的同基因黑色素瘤模型中的作用 影响和意义：通过完成这个项目，我们预计将确定用于治疗的剂量方案 系统[212Pb]VMT01α-RT，带有免疫检查点抑制剂，最大限度地提高完全反应，同时 在4种免疫能力强的小鼠模型中将毒性降至最低。我们还希望进一步加深对 捕获已知肿瘤间质的原发和转移性肿瘤的系统抗肿瘤免疫反应 转移性黑色素瘤的异质性。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.