Combinations of Receptor-Targeted Alpha Radionuclide Therapy and Immune Checkpoint Inhibitors for Melanoma Treatment

摘要 恶性黑色素瘤是最致命的皮肤癌，其发病率在美国呈上升趋势。 各州。不幸的是，转移性黑色素瘤还没有根治方法。尽管取得了重大进展 分子靶向治疗(BRAF、CTLA-4和PD-1靶向治疗)在治疗转移瘤中的应用 黑色素瘤近十年来，转移性黑色素瘤患者的5年生存率仅为35%。因此，在那里 迫切需要开发转移性黑色素瘤的替代治疗策略。 黑素皮质激素-1受体(MC1R)是一个独特的分子靶点，因为它在&gt；80%的细胞中高表达。 黑素性和无色素性人类转移性黑色素瘤。我们在人类中第一次取得的显著成果显然 MC1R靶向68Ga-DOTA-GGNle-CycMSHhex治疗人黑色素瘤的可行性研究 成像。最近，我们发现DOTA-GGNle-CycMSHhex(KD)多肽与0.12 nM的MC1R结合 亲和力比DOTA-GGNle-CycMSHhex显著提高8.3倍。此外， 用8-氨基辛酸(-AOC-)接头取代-GG-进一步提高了MC1R与MC1R的亲和力 DOTA-AocNle-CycMSHhex(KD)是DOTA-GGNle-CycMSHhex(KD)的3.8倍。因此，我们 建议开发用于成像的新型203Pb/212Pb-DOTA-Linker-NLE-CycMSHhex(KD)多肽 引导的MC1R靶向α-核素治疗(MC1R-ART)，并与免疫检查点相结合 该项目中用于黑色素瘤治疗的抑制剂(ICIS)。我们推测这种新型的~(203)Pb/~(212)Pb- DOTA-Linker-NLE-CycMSHhex(KD)多肽可用于成像引导的MC1R-TART，并且 联合应用MC1R-TART和ICIS治疗黑色素瘤比单独使用MC1R-TART更有效。 本项目的目标是开发新型的~(203)Pb/~(212)Pb-DOTA-Linker-NLE-CycMSHhex(KD) 多肽成像引导MC1R-START，将MC1R-START与ICIS联合治疗黑色素瘤。我们的 获得的美国专利清楚地表明了这个项目的独创性和新颖性。我们积极的初步结果 研究结果有力地支持了我们的假设和研究设计。重要的是，我们已经集结了一支强大的 拥有成熟专业知识的研究团队，非常适合执行这一令人兴奋的翻译项目。 该项目的积极结果将证明MC1R-ART和MC1R-TART相结合的可行性和有效性 ICIS用于黑色素瘤的治疗，并为设计新的转移治疗方法提供了新的见解 黑色素瘤。该项目的成功将为临床医生提供一种新的有价值的成像工具(~(203)Pb-多肽)来 确定将从治疗中受益的MC1R阳性患者，确定患者特定的剂量学 安全有效的剂量，并监测患者对MC1R-TART和ICIS治疗的反应。成功之路 该项目的实施将为在FDA批准的未来临床试验中评估这种新疗法铺平道路。 为患者提供个性化的诊断和治疗，增加治愈到转移的机会 黑色素瘤患者。

ABSTRACT Malignant melanoma is the most lethal form of skin cancer with an increasing incidence in the United States. Unfortunately, no curative treatment exists for metastatic melanoma. Despite the significant advances of molecularly targeted treatments (BRAF-, CTLA-4- and PD-1-targeted therapies) in treating metastatic melanoma over the past decade, the 5-year survival is only 35% for metastatic melanoma patients. Thus, there is an urgent need to develop alternative treatment strategies for metastatic melanoma. Melanocortine-1 receptor (MC1R) is a distinct molecular target due to its high expression in >80% of melanotic and amelanotic human metastatic melanoma. Our remarkable first-in-human results clearly demonstrate the feasibility of using MC1R-targeted 68Ga-DOTA-GGNle-CycMSHhex for human melanoma imaging. Recently, we have identified DOTA-GGNle-CycMSHhex(KD) peptide with 0.12 nM MC1R binding affinity which is dramatically improved by 8.3-fold as compared to DOTA-GGNle-CycMSHhex. Moreover, the replacement of -GG- with 8-Aminooctanoic acid (-Aoc-) linker further improves the MC1R binding affinity of DOTA-AocNle-CycMSHhex(KD) peptide by 3.8-fold as compared to DOTA-GGNle-CycMSHhex(KD). Thus, we propose to develop novel theranostic 203Pb/212Pb-DOTA-Linker-Nle-CycMSHhex(KD) peptides for imaging- guided MC1R-targeted alpha radionuclide therapy (MC1R-TART), and combine them with immune checkpoint inhibitors (ICIs) for melanoma treatment in this project. We hypothesize that novel theranostic 203Pb/212Pb- DOTA-Linker-Nle-CycMSHhex(KD) peptides can be used for imaging-guided MC1R-TART, and the combinations of MC1R-TART and ICIs can treat melanoma more effectively than MC1R-TART only. The objective of this project is to develop novel theranostic 203Pb/212Pb-DOTA-Linker-Nle-CycMSHhex(KD) peptides imaging-guided MC1R-TART, and combine MC1R-TART with ICIs for melanoma treatment. Our awarded US patents clearly demonstrate the originality and novelty of this project. Our positive preliminary results strongly support our hypothesis and research design. Importantly, we have assembled a strong research team with established expertise that is uniquely suited to carry out this exciting translational project. The positive results of this project will demonstrate the feasibility and efficacy of combining MC1R-TART and ICIs for melanoma treatment, and provide a new insight into the design of novel treatments for metastatic melanoma. The success of this project will provide clinicians a novel valuable imaging tool (203Pb-peptide) to identify MC1R-positive patients who will benefit from the treatments, determine patient-specific dosimetry for safe and efficacious doses, and monitor patients’ responses to MC1R-TART and ICIs treatments. The success of this project will pave the way for evaluating this novel treatment in future FDA-approved clinical trials, provide patients with personalized diagnoses and treatments, enhancing the opportunity for cure to metastatic melanoma patients.