Image guided immunotherapy and targeted radionuclide therapy of metastatic melanoma

转移性黑色素瘤的图像引导免疫治疗和靶向放射性核素治疗

• 批准号: 10292356
• 负责人: Carolyn J. Anderson
• 金额: $ 22.01万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-09 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292356
• 关键词: Image; guided; immunotherapy; targeted; radionuclide

ABSTRACT Melanoma is the most lethal form of skin cancer. If discovered early, it is usually cured with surgery; however, treatment options are limited for metastatic melanoma, with a 5-year survival of only 15-20%. Although immunotherapy as a first-line treatment option has improved survival, individual response is uneven, possibly due in part to the quality of protective tumor infiltrating lymphocytes (TILs) impacted by treatment intervention. There is critical need to: 1) identify patients with an aggressive phenotype; 2) improve therapies to increase overall survival of such patients; and 3) develop improved monitoring means to discern whether patients are responding to therapy. Here we propose a multi-faceted approach for imaging and therapy of metastatic melanoma, to be tested in mouse models of primary and metastatic disease. There is great interest in targeting very late antigen-4 (VLA-4; also called integrin α4β1) for cancer imaging and therapy for multiple myeloma and melanoma, where it plays a facilitating role in tumor growth, angiogenesis and metastasis by promoting adhesion and migration of cancer cells. In humans, increased expression of VLA-4 in melanoma correlates with development of metastasis. We previously showed that high-affinity peptidomimetic VLA-4 targeted agents labeled with 68Ga (for Positron Emission Tomography (PET); T1/2 = 68 min) and 177Lu (for radionuclide therapy; T1/2 = 6.7 d) are avidly taken up by B16F10 melanoma tumors in mice. A recently published study showed dramatic efficacy from combining external beam irradiation (XRT) with the combination immunotherapy agents targeting CTLA-4 and PD1/PD-L1 therapy in B16F10 tumor-bearing mice. As XRT is not optimal for treating widely disseminated or micrometastatic disease, we aim to improve upon this important finding by investigating VLA-4 targeted, systemic, radiotherapy with 177Lu-DOTA-PEG4-LLP2A (177Lu-LLP2A), in combination with anti-CTLA-4 and anti-PD-1 immunotherapy. We will also develop PET imaging tracers targeting PD-L1 and CD8 to provide real-time, non-invasive monitoring of tumor cells, myeloid- derived cells and T cells in response to therapy. We hypothesize that targeted radiotherapy with 177Lu-LLP2A, combined with dual anti-CTLA-4 and anti-PD-1 immunotherapy, will be highly effective in treating melanoma tumor-bearing mice, and that imaging of PD-1 and CD8+ T-cells will allow the monitoring of early “clinical” responses to therapy. To address our hypotheses, we propose the following aims: 1) validate uptake of 68Ga- and 177Lu-labeled LLP2A in a mouse model of melanoma (BP20) where the tumors have the common BRAFV600E mutation, and in human tumors derived from patient melanoma metastases; 2) determine the optimal treatment strategy comparing 177Lu-LLP2A and XRT in combination with dual immunotherapy in B16F10 subcutaneous and disseminated tumors, and in BP20 tumors with the BRAFV600E mutation; and 3) develop and validate anti-mouse PD-L1 minibodies, and anti-mouse CD8 single domain antibody (sdAb) PET imaging agents labeled with 64Cu (T1/2 = 12.7 h) and 68Ga (T1/2 = 68 min), respectively. The combination therapy and PET imaging of early response will be performed. If successful, we will demonstrate that combining targeted radionuclide therapy and immunotherapy can effectively treat advanced-stage melanoma, while simultaneously identifying a panel of PET tracers for non-invasive monitoring of treatment efficacy.

抽象的 黑色素瘤是最致命的皮肤癌，如果早期发现，通常可以通过手术治愈。 转移性黑色素瘤的治疗选择有限，5 年生存率仅为 15-20%。 免疫疗法作为一线治疗选择可以提高生存率，但个体反应可能不均匀 部分原因是保护性肿瘤浸润淋巴细胞（TIL）的质量受到治疗干预的影响。 迫切需要：1）识别具有侵袭性表型的患者；2）改进治疗以增加 此类患者的总体生存率；3) 开发改进的监测手段来辨别患者是否 在这里，我们提出了一种针对转移性影像学和治疗的多方面方法。 黑色素瘤，将在原发性疾病和转移性疾病的小鼠模型中进行测试。 靶向非常晚期抗原 4（VLA-4；也称为整合素 α4β1），用于癌症成像和多种癌症治疗 骨髓瘤和黑色素瘤，它通过促进肿瘤生长、血管生成和转移发挥促进作用 促进人类癌细胞的粘附和迁移，增加黑色素瘤中 VLA-4 的表达。 我们之前表明高亲和力的拟肽 VLA-4 与转移的发展相关。 标有 68Ga（用于正电子发射断层扫描 (PET)；T1/2 = 68 分钟）和 177Lu（用于 放射性核素疗法；T1/2 = 6.7 d) 最近被小鼠 B16F10 黑色素瘤肿瘤广泛采用。 已发表的研究表明，将外部光束照射 (XRT) 与 针对 B16F10 荷瘤小鼠的 CTLA-4 和 PD1/PD-L1 联合免疫治疗药物治疗。 由于 XRT 并不是治疗广泛播散或微转移性疾病的最佳选择，我们的目标是改进这一点 通过研究 177Lu-DOTA-PEG4-LLP2A 的 VLA-4 靶向、全身放疗的重要发现 （177Lu-LLP2A），与抗CTLA-4和抗PD-1免疫疗法相结合，我们还将开发PET。 针对 PD-L1 和 CD8 的成像示踪剂可提供对肿瘤细胞、骨髓细胞的实时、非侵入性监测 我们挑战了 177Lu-LLP2A 的靶向放射治疗， 联合抗CTLA-4和抗PD-1双重免疫治疗，治疗黑色素瘤效果显着 荷瘤小鼠，PD-1 和 CD8+ T 细胞成像将允许监测早期“临床” 为了解决我们的假设，我们提出以下目标：1）验证 68Ga- 的摄取。 和 177Lu 标记的 LLP2A 在黑色素瘤小鼠模型 (BP20) 中，其中肿瘤具有共同点 2) 确定源自患者黑色素瘤转移的人类肿瘤中的 BRAFV600E 突变； 比较 177Lu-LLP2A 和 XRT 联合双重免疫治疗的最佳治疗策略 B16F10 皮下和播散性肿瘤，以及具有 BRAFV600E 突变的 BP20 肿瘤；3) 开发并验证抗小鼠 PD-L1 微型抗体和抗小鼠 CD8 单域抗体 (sdAb) PET 显像剂分别标记为 64Cu (T1/2 = 12.7 h) 和 68Ga (T1/2 = 68 min) 联合治疗。 如果成功的话，我们将进行早期反应的 PET 成像，以证明两者的结合。 靶向放射性核素治疗和免疫治疗可以有效治疗晚期黑色素瘤，同时 同时识别一组 PET 示踪剂，用于非侵入性监测治疗效果。