Clinical and Immunological Effects of SBRT and IL-2 in Metastatic Melanoma

描述(由申请人提供)：项目概述我们已经完成了一项高剂量焦点放射(SBRT)联合高剂量IL-2治疗转移性黑色素瘤和肾癌患者的I期研究。这项研究显示，联合治疗的应答率为66.6%，远高于IL-2单独报告的应答率15%。初步的免疫原性研究发现，在这些患者中，T细胞的效应记忆群体与临床反应有关。为了验证这些I期结果，我们将在转移性黑色素瘤患者中进行大剂量IL-2与大剂量IL-2联合局部SBRT的随机II期临床试验。我们假设，与接受放射治疗的患者相比，接受SBRT和IL-2联合治疗的患者将产生更有效的抗肿瘤免疫反应，从而控制未照射的转移灶。 转移性黑色素瘤患者单独使用IL-2。我们认为，高剂量/分次(10-15GY)的局部照射结合IL-2免疫治疗将增强针对残留病的免疫反应。我们认为，辐射增强抗肿瘤免疫反应的机制是通过释放肿瘤抗原和内源性佐剂以及调节局部肿瘤环境。我们认为，在接受SBRT和IL-2治疗的患者中，以下是控制非靶向转移灶的关键组件：1)SBRT导致肿瘤破裂，为自身疫苗接种提供抗原源，2)SBRT破坏肿瘤转移将与增强抗肿瘤免疫反应的佐剂释放有关，以及3)联合方法将增强全身T细胞介导的针对肿瘤相关抗原的效应反应。为了验证我们的假设，我们将在Aim1：在转移性黑色素瘤患者中进行大剂量IL-2与大剂量IL-2联合局部SBRT的随机II期临床试验；在AIM2：评估接受SBRT和大剂量IL-2联合治疗的患者血液中肿瘤溶解、炎症和免疫激活的标志物。这项研究测试了一种非常有希望的放射和免疫疗法组合治疗黑色素瘤，这将代表着放射医学和免疫疗法在患者治疗方面的重大进步。此外，它还产生了解决放射医学中一些公开问题的机械数据，这些数据可以用来指导未来癌症治疗的放射和免疫联合治疗方法。

DESCRIPTION (provided by applicant): Project Summary We have completed a phase I study of high-dose focal radiation (SBRT) in combination with high- dose IL-2 for patients with metastatic melanoma and renal cell carcinoma. This study demonstrated response rates of 66.6% with the combined approach that is well above reported response rates for IL-2 alone of 15%. Preliminary immunogenicity studies identified an effector memory population of T cells associated with clinical response in these patients. To validate these Phase I results, we will perform a randomized phase II clinical trial of high-dose IL-2 versus high-dose IL-2 in combination with focal SBRT in patients with metastatic melanoma. We hypothesize that SBRT administered in combination with IL-2 will generate more effective anti-tumor immune responses that will result in control of un-irradiated metastatic lesions when compared to patients receiving IL-2 alone in patients with metastatic melanoma. We propose that high-dose per fraction (10-15 Gy) focal radiation combined with IL-2 immunotherapy will enhance immune responses that target residual disease. We propose that the mechanism for this enhanced anti-tumor immune response associated with radiation is through release of tumor antigen and endogenous adjuvants as well as modulation of the local tumor environment. We propose the following are key components in control of non-targeted metastatic lesions in patients receiving SBRT and IL-2: 1) SBRT results in tumor breakdown providing a source of antigen for self-vaccination, 2) SBRT destruction of tumor metastasis will be associated with adjuvant release that will enhance anti-tumor immune responses, and 3) the combined approach will enhance systemic T-cell mediated effector responses against tumor associated antigen. To test our hypothesis we will in Aim1: Perform a randomized phase II clinical trial of high-dose IL-2 versus high-dose IL-2 in combination with focal SBRT in patients with metastatic melanoma; and in Aim2: Evaluate markers of tumor lysis, inflammation and immune activation in the blood of patients receiving combined modality therapy with SBRT and high-dose IL-2 therapy. This study tests a highly promising combination of radiation and immunotherapy for the treatment of melanoma that would represent a significant advance in radiation medicine and immunotherapy in patient treatment. Additionally it generates mechanistic data that addresses some of the open questions in radiation medicine, which can be used to direct future combined radiation and immunotherapy approaches for cancer treatment.