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 黑色素瘤是皮肤癌最致命的形式。如果发现的话，通常可以通过手术治愈。然而， 治疗选择受到转移性黑色素瘤的限制，仅5年生存率仅为15-20％。虽然 免疫疗法作为一线治疗方案的生存率提高了，个人反应不均匀，可能 部分是由于受到治疗干预影响的受保护肿瘤浸润淋巴细胞（TIL）的质量。 至关重要的是：1）确定具有侵略性表型的患者； 2）改善疗法以增加 此类患者的总体生存； 3）制定改进的监控意味着辨别患者是否是 回应治疗。在这里，我们提出了一种多方面的转移和治疗方法 黑色素瘤，将在原发性和转移性疾病的小鼠模型中进行测试。对 针对多种 骨髓瘤和黑色素瘤在肿瘤生长，血管生成和转移中起着支持作用 促进癌细胞的粘附和迁移。在人类中，VLA-4在黑色素瘤中的表达增加 与转移的发展相关。我们先前表明高亲和力肽映射VLA-4 标记为68GA的靶向剂（用于正电子发射断层扫描（PET）； T1/2 = 68分钟）和177LU（用于 放射性核素治疗； T1/2 = 6.7 d）在小鼠中被B16F10黑色素瘤肿瘤大量吸收。最近 发表的研究表明，将外束辐射（XRT）与 靶向CTLA-4和PD1/PD-L1治疗的组合免疫疗法在含B16F10肿瘤的小鼠中。 由于XRT并不是对广泛传播或微转移性疾病的最佳选择，因此我们旨在改善这一点 通过研究177lu-dota-peg4-llp2a的靶向系统性，全身放射疗法的重要发现 （177LU-LLP2A），结合抗CTLA-4和抗PD-1免疫疗法。我们还将发展宠物 靶向PD-L1和CD8的成像示踪剂可提供对肿瘤细胞的实时无创监测 响应治疗的细胞和T细胞。我们假设使用177lu-llp2a的靶向放疗， 结合双重抗CTLA-4和抗PD-1免疫疗法，将在治疗黑色素瘤方面非常有效 具有肿瘤的小鼠以及PD-1和CD8+ T细胞的成像将允许对早期的“临床”监测 对治疗的反应。为了解决我们的假设，我们提出以下目的：1）验证68GA- 和177LU标记的LLP2A在黑色素瘤（BP20）中具有常见的黑色素瘤模型（BP20） BRAFV600E突变，以及来自患者黑色素瘤转移的人类肿瘤； 2）确定 最佳治疗策略比较177LU-LLP2A和XRT与双重免疫疗法结合 B16F10皮下和弥散的肿瘤，在具有BRAFV600E突变的BP20肿瘤中； 3） 开发和验证抗小鼠PD-l1小型生物和抗小鼠CD8单域抗体（SDAB）PET 成像剂分别标记为64cu（T1/2 = 12.7 h）和68GA（T1/2 = 68分钟）。组合疗法 并将进行早期响应的宠物成像。如果成功，我们将证明该合并 有针对性的放射性治疗和免疫疗法可以有效治疗晚期黑色素瘤，而 同时识别一组宠物示踪剂，以无创监测治疗效率。