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

摘要 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，并不是所有的患者都能从这种治疗中获益， 需要治疗无应答者的功效。我们和其他人已经证明，肝转移患者 ICI在多种疾病类型中的临床获益有限。在临床前结直肠和 在黑色素瘤模型中，我们发现肝转移瘤通过虹吸肿瘤引起免疫治疗抗性， 体循环中的特异性T细胞。在肝脏内，活化的抗原特异性CD8+ T细胞经历了 凋亡因此，肝转移在临床前模型中产生全身免疫沙漠。同样地， 肝转移患者外周血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，肝脏定向放射治疗减少并代谢改善 免疫抑制性肝巨噬细胞，增加肝T细胞存活，并减少肝细胞的虹吸， T细胞。该建议的中心假设是肝脏SBRT解决了黑色素瘤患者的ICI耐药 肝转移我们现在正在前瞻性地测试这种将肝脏SBRT与易普利姆玛相结合的策略 和纳武单抗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逆转患者的肝脏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， 有回应。在目标2中，我们将确定肝脏SBRT联合ipilimumab和nivolumab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SBRT是否调节肝髓样嘌呤产生和信号传导以促进免疫应答 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 易普利姆玛和纳武单抗肝SBRT的安全性，提供联合治疗的初步疗效指标 治疗，允许开发肝转移临床前模型中的反应生物标志物，以及 评估患者的反应生物标志物。这项工作的最终目的是测试理性发展的小说 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

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.