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Local Radiation as an Adjuvant for Immunotherapy

局部放射作为免疫治疗的辅助剂

基本信息

批准号：
8020091
负责人：
Sandra Demaria
金额：
$ 31.24万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8020091
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-Free Survival Effectiveness Failure Fluorescence Future Image Immune Immune Cell Activation Immunologic Adjuvants Immunotherapy Inflammation Investigation Ionizing radiation Liver Localized Malignant Neoplasm Lung Mediating Modeling Mus Natural Killer Cells Neoplasm Metastasis Primary Neoplasm Process Prostate carcinoma Prostatic Proteins RNA Interference Radiation Radiation therapy Reporter Role Site Solid Neoplasm T cell response T-Cell Depletion T-Lymphocyte Testing Therapeutic Transgenic Mice Tumor Antigens Tumor Burden Tumor Immunity cancer therapy carcinogenesis chemokine in vivo innovation intravital microscopy lymph nodes malignant breast neoplasm migration mouse model neoplastic cell novel therapeutics pre-clinical receptor response trafficking tumor uptake vaccination strategy

项目摘要

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 mechanismswhereby 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.

CD 8 + T细胞介导的免疫可以消除大的肿瘤负荷。然而，癌症患者和具有已建立的血管化肿瘤的小鼠难以用大多数疫苗接种来实现战略布局肿瘤部位免疫细胞的运输和活化不足被认为是，至少在部分，负责免疫疗法（IT）破坏实体瘤失败。电离辐射治疗（RT）是一种重要的局部癌症治疗方法。作为杀细胞剂，RT还可以改变肿瘤的生长，微环境和产生炎症。在转移性乳腺癌的4 T1小鼠模型中，显示RT与CTLA-4阻断剂组合可增强抑制CD 8 + T细胞介导应答转移和诱导原发性肿瘤消退。积累的数据支持RT的假设可用作免疫佐剂以增强IT的有效性。然而，电离辐射促进抗肿瘤免疫的机制仍存在争议，大部分未定义。拟议的研究将确定RT促进抗肿瘤的机制通过分析该过程的关键步骤来提高免疫力。首先，RT促进交叉启动的能力将使用4 T1肿瘤模型及其表达报告抗原的衍生物来确定。呈现肿瘤特异性T细胞的活化、传播和持续存在将被分析。第二，RT对肿瘤内效应T细胞运输和功能的影响将被进一步研究。测定CXCR 6/CXCL 16相互作用在CD 8 + T细胞募集到辐照肿瘤中的作用将被进一步研究。在CXCR 6基因座小鼠中使用EGFP敲入和RNA干扰来沉默CXCL 16。在此外，活体显微镜将用于研究CXCR 6 + T细胞在肿瘤中的动态行为。已建立的4 T1肿瘤的微环境及其对局部辐射的反应。第三，RT的能力与另一种免疫刺激抗体（抗4-1BB/CD 137）组合诱导抗肿瘤应答将进行测试并与CTLA-4阻断进行比较。这些发现将在转基因小鼠中得到证实自发致癌模型。RT可用作免疫学方法的创新概念辅助信息技术的有效性的提高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。