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

SBRT 和 IL-2 对转移性黑色素瘤的临床和免疫学影响

• 批准号: 8493114
• 负责人: BRENDAN D CURTI
• 金额: $ 19.31万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8493114
• 关键词: Address; Adjuvant; Antigens; Autoantigens; Biological; Biological Markers; Blood; Blood specimen; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Death; Cells; Clinical; Clinical Research; Combined Modality Therapy; Cytolysis; Data; Dose; Environment; Future; Immune; Immune response; Immune system; Immunologic Markers; Immunotherapy; Inflammation; Interleukin-2; Life; Lytic; Measures; Mediating; Medicine; Melanoma Cell; Memory; Metastatic Lesion; Metastatic Melanoma; Molecular; Monitor; Neoplasm Metastasis; Patients; Pattern; Peptide Library; Phase; Phase II Clinical Trials; Phenotype; Population; Radiation; Radiation therapy; Randomized; Renal Cell Carcinoma; Reporting; Research; Residual Tumors; Serum; Source; T cell response; T memory cell; T-Lymphocyte; Testing; Time; Toxic effect; Tumor Antigens; Tumor Markers; Uric Acid; Vaccination; arm; cancer therapy; candidate marker; chemokine; cytokine; design; immune activation; immunogenicity; improved; melanoma; neoplastic cell; peripheral blood; phase 1 study; preclinical study; procalcitonin; public health relevance; response; tumor

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.

描述（由申请人提供）： 项目摘要 我们已经完成了高剂量局灶放疗 (SBRT) 与高剂量 IL-2 联合治疗转移性黑色素瘤和肾细胞癌患者的 I 期研究。这项研究表明，联合方法的缓解率为 66.6%，远高于报道的单独使用 IL-2 的缓解率 15%。初步免疫原性研究确定了与这些患者的临床反应相关的 T 细胞效应记忆群体。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 联合局部 SBRT 的随机 II 期临床试验。我们假设，与接受 SBRT 治疗的患者相比，SBRT 与 IL-2 联合治疗将产生更有效的抗肿瘤免疫反应，从而控制未照射的转移性病灶。 转移性黑色素瘤患者单独使用 IL-2。我们建议每次分次高剂量（10-15 Gy）局部放疗与 IL-2 免疫治疗相结合将增强针对残留疾病的免疫反应。我们认为，这种与辐射相关的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。我们提出以下是接受 SBRT 和 IL-2 的患者控制非靶向转移病灶的关键组成部分：1) SBRT 导致肿瘤破裂，为自我疫苗接种提供抗原来源，2) SBRT 对肿瘤转移的破坏将与佐剂释放相关，从而增强抗肿瘤免疫反应，3) 联合方法将增强全身 T 细胞介导的效应器 针对肿瘤相关抗原的反应。为了检验我们的假设，我们将在目标 1 中：对转移性黑色素瘤患者进行高剂量 IL-2 与高剂量 IL-2 联合局部 SBRT 的随机 II 期临床试验；目标 2：评估接受 SBRT 和高剂量 IL-2 联合治疗的患者血液中肿瘤溶解、炎症和免疫激活的标志物。这项研究测试了一种非常有前途的放射和免疫疗法组合治疗黑色素瘤的方法，这将代表放射医学和免疫疗法在患者治疗中的重大进步。此外，它还生成解决放射医学中一些悬而未决问题的机制数据，可用于指导未来癌症治疗的放射和免疫治疗组合方法。