Receptor-targeted radionuclide therapy combined with immunotherapies to improve metastatic melanoma tumor response.

黑色素瘤的发病率上升速度比任何其他癌症都快。手术可以在早期阶段治愈，但 转移性黑素瘤通常是致命的。对新的靶向和免疫疗法的反应可能是显着的， 选择病例，但应答率低，获得性耐药和严重的不良副作用（特别是对于 联合免疫疗法）限制了这些患者的长期生活质量。因此，尽管正确的 被视为晚期黑色素瘤治疗的一场革命，对所有疗法的总体反应率仍然是 5年生存率<25%。尽管有这些缺点，但有一个明确的和日益增长的 先进的黑色素瘤药物市场（2016年全球收入40亿美元;预计复合年增长率15%）。此外，受体- 靶向放射性核素疗法正在成为肿瘤学中有价值的产品。最近两次收购， 大型制药公司：2014年拜耳的Algeta（29亿美元）; 2017年诺华的Advanced Accelerator Applications （3.9亿美元）强调了这一价值。Viewpoint确定了其MCR 1靶向放射性核素的初步适应症 治疗进展性4期转移性黑色素瘤（潜在全球年收入6亿美元）。然而，在这方面， 新出现的证据表明，电离辐射（IR）与免疫疗法相结合， 促进免疫原性癌细胞死亡。目前的外部光束IR依赖于远位效应，因为IR 以这种方式递送的药物只能被引导到单个病变。由于已知的肿瘤间异质性， 对于黑色素瘤，全身性MC 1 R-RT的优点是在所有转移性病变中精确沉积放射， 其具有改善呈递给免疫系统的新抗原库的潜力。因此 是确定安全地将免疫疗法与MC 1 R-RT结合用于转移性肿瘤的可行性的关键需求。 黑素瘤概念验证研究结果支持这一假设，即这种组合可以扩大我们的 一线治疗的适应症爱荷华州将在该项目的奖励后匹配5万美元。 商业原理：成功将MC 1 R-RT与免疫疗法相结合，以安全地提高 恶性黑色素瘤的总体和完全缓解可能将我们的适应症扩展到一线 所有转移性黑色素瘤患者的联合治疗，这将大大提高我们的价值。 目的1：确定安全地将MC 1 R-RT（90 Y）与免疫疗法联合使用以改善 两种免疫活性小鼠黑色素瘤模型中的肿瘤反应率和存活率。 影响和意义：成功完成这一目标将确立安全 将Viewpoint专有的MCR 1靶向放射性核素疗法与免疫疗法相结合， 黑素瘤这项工作如果成功，也将建立一个强大的生物化学和免疫学原理， 在临床试验中进一步开发MC 1 R-RT，旨在克服低应答率，获得 耐药性和严重的副作用限制了目前的恶性黑色素瘤治疗。

Melanoma incidence is rising faster than any other cancer. Surgery can be curative at early stages, but metastatic melanoma is typically fatal. Responses to new targeted and immunotherapies can be remarkable in select cases, but low response rates, acquired resistance, and severe adverse side effects (particularly for combination immunotherapies) limit long-term quality of life for these patients. Thus, despite what is rightly seen as a revolution in advanced-stage melanoma treatment, the overall response rate to all therapies remains dismally near 50% and the 5-year survival is <25%. Despite these shortcomings, there is a clear and growing market for advanced melanoma drugs (2016 global revenues $4Bln; expected CAGR 15%). Further, receptor- targeted radionuclide therapies are emerging as valuable products in oncology. Two recent acquisitions by large pharma: Algeta by Bayer in 2014 ($2.9Bln); and Advanced Accelerator Applications by Novartis in 2017 ($3.9Bln) highlight this value. Viewpoint identified an initial indication for its MCR1-targeted radionuclide therapy of progressive stage 4 metastatic melanoma (potential global annual revenues $600Mln). However, emerging evidence suggests a synergistic role for ionizing radiation (IR) combined with immunotherapy to promote immunogenic cancer cell death. Current external beam IR relies on an abscopal effect because IR delivered in this way can only be directed to individual lesions. Because of known intertumoral heterogeneity of melanoma, the advantage of systemic MC1R-RT is precise deposition of radiation in all metastatic lesions, which has the potential to improve the repertoire of neoantigens presented to the immune system. Thus, there is a critical need to determine the feasibility of safely combining immunotherapies with MC1R-RT for metastatic melanoma. Proof-of-concept study results support the hypothesis that this combination can expand our indication to a front-line therapy. The State of Iowa will match $50k upon award for this project. BUSINESS RATIONALE: Success in combining MC1R-RT with immunotherapy to safely improve rates of overall and complete response for malignant melanoma potentially expands our indication to a frontline combination therapy for all metastatic melanoma patients, which would significantly increase our valuation. AIM 1: Determine the feasibility of safely combining MC1R-RT (90Y) with immunotherapies to improve tumor response rates and survival in two immune-competent mouse melanoma models. IMPACT and SIGNIFICANCE: Successful completion of this Aim will establish the feasibility of safely combining Viewpoint’s proprietary MCR1-targeted radionuclide therapy with immunotherapies for malignant melanoma. This work if successful will also establish a robust biochemical and immunological rationale for further development of MC1R-RT in clinical trials designed to overcome low response rates, acquired resistance, and serious side effects that limit current malignant melanoma therapies.