Local Radiation as an Adjuvant for Immunotherapy

局部放射作为免疫治疗的辅助剂

• 批准号: 7263431
• 负责人: Sandra Demaria
• 金额: $ 31.93万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7263431
• 关键词: Adjuvant; Antibodies; Antigen Presentation; Antigens; Behavior; Breast Carcinoma; CD8B1 gene; CXCR6 gene; Cancer Patient; Carcinoma; Cells; Cellular Immunity; Cessation of life; Clinical; Clinical Data; Clinical Trials; Cross-Priming; Data; Dendritic cell activation; Disease; Disease regression; Disease-Free Survival; Effectiveness; End Point; Failure; Fluorescence; Future; Image; Immune; Immune Cell Activation; Immunologic Adjuvants; Immunotherapy; Inflammation; Investigation; Ionizing radiation; Liver; Localized Malignant Neoplasm; Lung; Mammary gland; Mediating; Modeling; Mus; Natural Killer Cells; Neoplasm Metastasis; Numbers; Primary Neoplasm; Process; Prostate carcinoma; Prostatic; Proteins; RNA Interference; Radiation; Radiation therapy; Reporter; Role; Site; Solid Neoplasm; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Thinking; Transgenic Mice; Transgenic Organisms; Tumor Antigens; Tumor Burden; Tumor Immunity; cancer therapy; carcinogenesis; chemokine; concept; in vivo; innovation; intravital microscopy; lymph nodes; malignant breast neoplasm; migration; mouse model; neoplastic cell; novel therapeutics; pre-clinical; radiation effect; receptor; response; trafficking; tumor; uptake; vaccination strategy

DESCRIPTION (provided by applicant): CD8+ T-cell mediated immunity can eliminate large tumor burdens. However, significant clinical responses of cancer patients and mice with established vascularized tumors are difficult to achieve with most vaccination strategies. Insufficient trafficking and activation of immune cells at tumor sites are thought to be, at least in part, responsible for the failure of immunotherapy (IT) to destroy solid tumors. Ionizing radiation therapy (RT) is an important local cancer treatment. Used as cytocidal agent, RT can also alter the tumor microenvironment and generate inflammation. In the 4T1 mouse model of metastatic breast cancer we have shown that RT in combination with CTLA-4 blockade elicits a CD8+ T cell-mediated response inhibiting metastases and inducing regression of primary tumors. Accumulated data support the hypothesis that RT can be used as an immunological adjuvant to enhance the effectiveness of IT. However, the ability of ionizing radiation to promote anti-tumor immunity is still controversial, and mechanisms involved remain largely undefined. Proposed studies will determine the mechanisms whereby RT promotes anti-tumor immunity by analyzing the critical steps of this process. First, the ability of RT to promote cross-priming will be determined using the 4T1 tumor model and its derivative expressing a reporter antigen. Presentation of tumor antigens by dendritic cells and activation, dissemination and persistence of tumor-specific T cells will be analyzed. Second, the effect of RT on effector T cell trafficking and function within tumors will be determined. The role of CXCR6/CXCL16 interactions in CD8+ T cell recruitment to irradiated tumors will be established employing EGFP-knockin in the CXCR6 locus mice, and RNA interference to silence CXCL16. In addition, intravital microscopy will be used to study the dynamic behavior of CXCR6+ T cells in the microenvironment of established 4T1 tumors and their response to local radiation. Third, the ability of RT to induce anti-tumor responses in combination with another immune stimulatory antibody (anti-4-1BB/CD137) will be tested and compared to CTLA-4 blockade. Findings will then be confirmed in a transgenic mouse model of spontaneous carcinogenesis. The innovative concept that RT can be used as an immunological adjuvant to enhance the effectiveness of IT will open a new field of investigation. Overall, these studies will provide the pre-clinical data necessary for testing this novel therapeutic strategy in future clinical trials.

描述（由申请人提供）：CD8+ t细胞介导的免疫可以消除大的肿瘤负担。然而，大多数疫苗接种策略很难实现癌症患者和已建立血管化肿瘤的小鼠的显著临床反应。免疫细胞在肿瘤部位的运输和激活不足被认为是，至少在一定程度上，免疫疗法（IT）破坏实体瘤失败的原因。电离放射治疗是一种重要的局部肿瘤治疗方法。作为杀细胞剂，RT还能改变肿瘤微环境，产生炎症。在转移性乳腺癌的4T1小鼠模型中，我们已经证明RT联合CTLA-4阻断可引发CD8+ T细胞介导的反应，抑制转移并诱导原发肿瘤的消退。积累的数据支持RT可以作为免疫佐剂来增强IT的有效性的假设。然而，电离辐射促进抗肿瘤免疫的能力仍然存在争议，所涉及的机制在很大程度上仍未确定。拟议的研究将通过分析这一过程的关键步骤来确定RT促进抗肿瘤免疫的机制。首先，RT促进交叉启动的能力将通过4T1肿瘤模型及其表达报告抗原的衍生物来确定。将分析树突状细胞呈递肿瘤抗原和肿瘤特异性T细胞的活化、传播和持久性。其次，将确定RT对肿瘤内效应T细胞运输和功能的影响。CXCR6/CXCL16相互作用在CD8+ T细胞募集到受照射肿瘤中的作用将在CXCR6基因座小鼠中使用egfp敲除蛋白，并通过RNA干扰来沉默CXCL16。此外，活体显微镜将用于研究CXCR6+ T细胞在已建立的4T1肿瘤微环境中的动态行为及其对局部辐射的反应。第三，RT与另一种免疫刺激抗体（抗4- 1bb /CD137）联合诱导抗肿瘤反应的能力将被测试，并与CTLA-4阻断进行比较。研究结果将在自发癌变的转基因小鼠模型中得到证实。RT可以作为免疫佐剂来增强IT的有效性，这一创新概念将开辟一个新的研究领域。总的来说，这些研究将为在未来的临床试验中测试这种新的治疗策略提供必要的临床前数据。