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，并非所有患者都从这种疗法中受益，以及提高ICI的合理组合策略需要在治疗无反应方面的功效。我们和其他人表明肝转移的患者从ICI中获得有限的临床益处，多种疾病类型。在临床前结直肠和黑色素瘤模型，我们发现肝转移通过卷入肿瘤引起免疫疗法的抗性特定的T细胞来自全身循环。在肝脏内，活化的抗原特异性CD8+ T细胞经历凋亡。因此，肝转移在临床前模型中产生系统性免疫沙漠。相似地，肝转移的患者的周围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，肝脏定向的放射疗法会减少和代谢优化免疫抑制性肝巨噬细胞，增加肝T细胞的存活，并减少肝si鼻 T细胞。该提议的中心假设是肝脏SBRT解决了黑色素瘤患者的ICI耐药性与肝转移。我们现在正在前瞻性测试将肝脏SBRT与ipilimumab结合的策略黑色素瘤转移患者的nivolumab。在AIM 1中，我们将确定是否肝脏SBRT 与ipilimumab和nivolumab相结合的患者肝和全身免疫功能障碍通过将肿瘤和外周血免疫变化相关联的研究者开始了临床试验有回应。在AIM 2中，我们将确定肝脏SBRT如何与ipilimumab和nivolumab相反肝转移临床前模型中的肝和全身免疫功能障碍。在AIM 3中，我们将确定肝SBRT是否调节肝髓嘌呤的产生和信号传导以促进免疫反应在转移性黑色素瘤中。这些目标的完成以及相关的临床试验将确定用ipilimumab和nivolumab的肝脏SBRT安全，提供组合的初步疗效治疗，允许在肝转移的临床前模型中发展反应的生物标志物，并评估患者反应的生物标志物。这项工作的最终目标是测试理性发达的小说放疗和ICI的组合，希望改善肝转移的黑色素瘤患者的护理对免疫疗法有抵抗力的人。