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局灶性放疗（SBRT）联合高剂量IL-2治疗转移性黑色素瘤和肾细胞癌患者的I期研究。该研究表明，联合方法的应答率为66.6%，远高于单独IL-2的应答率15%。初步免疫原性研究确定了与这些患者的临床应答相关的效应记忆T细胞群。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高剂量IL-2与高剂量IL-2联合局灶性SBRT的随机II期临床试验。我们假设SBRT与IL-2联合给药将产生更有效的抗肿瘤免疫应答，与接受化疗的患者相比，这将导致未照射转移性病变的控制。 IL-2单独治疗转移性黑色素瘤患者我们提出，高剂量每部分（10-15戈伊）局灶性辐射与IL-2免疫治疗相结合，将增强免疫反应的目标残留疾病。我们提出，这种增强的抗肿瘤免疫反应与辐射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。我们提出以下是控制接受SBRT和IL-2的患者的非靶向转移性病变的关键组成部分：1）SBRT导致肿瘤分解，为自身接种提供抗原来源，2）SBRT对肿瘤转移的破坏将与佐剂释放相关，这将增强抗肿瘤免疫应答，和3）组合的方法将增强针对肿瘤相关抗原的系统性T细胞介导的效应子应答。为了检验我们的假设，我们将在目标1中：在转移性黑色素瘤患者中进行高剂量IL-2与高剂量IL-2联合局灶性SBRT的随机II期临床试验;以及在目标2中：评价接受SBRT和高剂量IL-2联合治疗的患者血液中肿瘤溶解、炎症和免疫活化的标志物。这项研究测试了一种非常有前途的放射和免疫疗法组合，用于治疗黑色素瘤，这将代表放射医学和免疫疗法在患者治疗中的重大进展。此外，它还生成了机制数据，解决了放射医学中的一些悬而未决的问题，这些数据可用于指导未来联合放射和免疫治疗癌症的方法。

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.