Ablating Liver Metastases with SBRT to Enhance Immune Checkpoint Blockade in Melanoma

用 SBRT 消融肝转移以增强黑色素瘤的免疫检查点封锁

• 批准号: 10562707
• 负责人: Michael Daniel Green
• 金额: $ 59.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-05 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562707
• 关键词: Address; Adenosine; Adoptive Transfer; Antigens; Apoptosis; Biological Markers; CD8-Positive T-Lymphocytes; Caring; Cell Count; Cell Survival; Cells; Circulation; Clinical; Clinical Trials; Colorectal; Combined Modality Therapy; Companions; Data; Disease; Evaluation; Flow Cytometry; Goals; Hepatic; Immune; Immune System Diseases; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immunologics; Immunosuppression; Immunotherapy; Knock-out; Liver; Macrophage; Measures; Metabolic; Metastasis Induction; Metastatic Melanoma; Metastatic Neoplasm to the Liver; Modeling; Myelogenous; Nivolumab; Pathway interactions; Patient Care; Patients; Peripheral; Pharmacogenomics; Pre-Clinical Model; Preclinical Testing; Production; Publishing; Purines; Radiation therapy; Research Personnel; Resistance; Role; Safety; Signal Transduction; T cell receptor repertoire sequencing; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-cell diversity; Testing; Work; adaptive immunity; biomarker development; combinatorial; effector T cell; immune checkpoint blockade; immunomodulatory therapies; improved; insight; intrahepatic; ipilimumab; irradiation; liver ablation; liver biopsy; lymph nodes; melanoma; metabolomics; mouse model; new therapeutic target; novel; overexpression; participant enrollment; patient population; peripheral blood; pre-clinical; prospective test; purine metabolism; randomized trial; response; response biomarker; single cell sequencing; single-cell RNA sequencing; subcutaneous; therapeutic target; tumor

ABSTRACT Immune checkpoint inhibitors (ICI) have revolutionized the care of patients with metastatic melanoma. Unfortunately, not all patients benefit from this therapy, and rational combinatorial strategies to enhance ICI efficacy in therapy non-responders are needed. We and others have shown that patients with liver metastases derive limited clinical benefit from ICI across a wide variety of disease types. In preclinical colorectal and melanoma models, we discovered that liver metastases cause immunotherapy resistance by siphoning tumor- specific T cells from systemic circulation. Within the liver, activated antigen-specific CD8+ T cells undergo apoptosis. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy reduces and metabolically refines immunosuppressive hepatic macrophages, increases hepatic T cell survival, and reduces hepatic siphoning of T cells. The central hypothesis of this proposal is that liver SBRT address ICI resistance in melanoma patients with liver metastases. We are now prospectively testing this strategy of combining liver SBRT with ipilimumab and nivolumab in melanoma patients with liver metastases. In Aim 1, we will determine whether liver SBRT combined with ipilimumab and nivolumab reverses hepatic and systemic immune dysfunction in patients enrolled on our investigator initiated clinical trial by correlating tumoral and peripheral blood immune changes with response. In Aim 2, we will determine how liver SBRT combined with ipilimumab and nivolumab reverses hepatic and systemic immune dysfunction in preclinical models of liver metastases. In Aim 3, we will determine whether liver SBRT modulates hepatic myeloid purine production and signaling to promote immune responses in metastatic melanoma. The completion of these aims as well as the associated clinical trial will establish the safety of liver SBRT with ipilimumab and nivolumab, provide preliminary efficacy measures of combination therapy, allow the development of biomarkers of response in preclinical models of liver metastases, and evaluate biomarkers of response in patients. The ultimate goal of this work is to test rationally-developed novel combination of radiotherapy and ICI in hopes of improving the care of melanoma patients with liver metastases who are resistant to immunotherapy.

摘要 免疫检查点抑制剂(ICI)已经彻底改变了转移性黑色素瘤患者的治疗。 不幸的是，并不是所有的患者都能从这种疗法中受益，合理的组合策略可以增强ICI。 治疗中的疗效需要无应答者。我们和其他人已经证明，肝转移患者 从各种疾病类型的ICI中获得有限的临床益处。在临床前结直肠和 黑色素瘤模型，我们发现肝转移通过虹吸肿瘤而导致免疫治疗抵抗- 来自体循环的特定T细胞。在肝脏内，活化的抗原特异性CD8+T细胞经历 细胞凋亡。因此，在临床前模型中，肝转移造成了全身免疫沙漠。同样， 肝转移患者外周T细胞数量减少，肿瘤T细胞多样性降低 和功能。在临床前模型中，肝脏定向放射治疗减少和代谢细化 免疫抑制肝巨噬细胞，增加肝T细胞存活率，减少肝虹吸 T细胞。这一建议的中心假设是肝脏SBRT解决了黑色素瘤患者对ICI的抵抗 有肝转移。我们现在正在前瞻性地测试这种联合肝脏SBRT和ipilimumab的策略。 和nivolumab用于黑色素瘤肝转移患者。在目标1中，我们将确定肝脏SBRT 联合应用ipilimumab和nivolumab可逆转患者的肝脏和全身免疫功能障碍 登记参加我们的研究人员启动的临床试验，将肿瘤和外周血免疫变化联系起来 并作出回应。在目标2中，我们将确定肝脏SBRT联合ipilimumab和nivolumab是如何逆转的 临床前肝转移模型中的肝脏和全身免疫功能障碍。在目标3中，我们将确定 肝脏SBRT是否调节肝脏髓系嘌呤的产生和信号以促进免疫反应 转移性黑色素瘤。这些目标的完成以及相关的临床试验将建立 肝SBRT联合ipilimumab和nivolumab的安全性，提供联合治疗的初步疗效措施 治疗，允许在肝转移的临床前模型中开发反应的生物标记物，以及 评估患者反应的生物标志物。这项工作的最终目标是检验理性发展的小说 放射治疗联合ICI希望改善黑色素瘤肝转移患者的护理 对免疫疗法有抵抗力的人。