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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的免疫检查点抑制剂（ICI）彻底改变了转移性黑色素瘤患者的护理。不幸的是，并非所有患者都能从这种疗法以及增强 ICI 的合理组合策略中受益需要治疗无反应者的疗效。我们和其他人已经证明，肝转移患者在多种疾病类型中从 ICI 中获得的临床益处有限。在临床前结直肠癌和在黑色素瘤模型中，我们发现肝转移通过虹吸肿瘤来引起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，肝转移在临床前模型中造成了全身免疫荒漠。相似地，肝转移患者外周 T 细胞数量减少，肿瘤 T 细胞多样性减少和功能。在临床前模型中，肝脏定向放射治疗可减少并改善代谢免疫抑制肝巨噬细胞，增加肝 T 细胞存活，并减少肝虹吸 T 细胞。该提案的中心假设是肝脏 SBRT 解决黑色素瘤患者的 ICI 耐药问题伴有肝转移。我们现在正在前瞻性地测试这种将肝脏 SBRT 与易普利姆玛 (ipilimumab) 相结合的策略和纳武利尤单抗用于治疗肝转移的黑色素瘤患者。在目标 1 中，我们将确定肝脏 SBRT 是否联合伊匹单抗和纳武单抗可逆转患者的肝脏和全身免疫功能障碍参加了我们的研究者通过关联肿瘤和外周血免疫变化发起的临床试验有回应。在目标 2 中，我们将确定肝脏 SBRT 联合伊匹单抗和纳武单抗如何逆转肝转移临床前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 是否调节肝髓细胞嘌呤产生和信号传导以促进免疫反应在转移性黑色素瘤中。这些目标以及相关临床试验的完成将确立伊匹单抗和纳武单抗肝脏 SBRT 的安全性，提供联合用药的初步疗效指标治疗，允许在肝转移的临床前模型中开发反应生物标志物，以及评估患者反应的生物标志物。这项工作的最终目标是测试合理开发的小说放疗和 ICI 相结合，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。