High dose radiation therapy to direct immune responses to pancreatic cancer

高剂量放射治疗引导胰腺癌的免疫反应

基本信息

批准号：
9815641
负责人：
Michael James Gough
金额：
$ 39.19万
依托单位：
PROVIDENCE PORTLAND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9815641
关键词：
Animal Model Antigen Presentation Bioinformatics Cells Cellular immunotherapy Clinical Clinical Research Combination immunotherapy Cross Presentation Data Dendritic Cells Development Disease Distant Dose Fractionation Environment Failure Genetic Engineering Goals Growth and Development function Head and Neck Squamous Cell Carcinoma Immune Immune response Immunity Immunology Immunotherapy In Situ Knowledge Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Mus Neoplasm Metastasis Organ Preservation Outcome Patient-Focused Outcomes Patients Phenotype Play Population Pre-Clinical Model Radiation Radiation Dose Unit Radiation therapy Regulation Research Design Resectable Residual state Role Sampling Site T cell response T-Lymphocyte Testing Time Tumor Antigens Tumor Immunity Tumor-infiltrating immune cells Vaccines anti-tumor immune response antigen-specific T cells base cancer cell checkpoint therapy functional restoration genetic analysis immunogenic implantation improved improved outcome lymph nodes novel pre-clinical prevent radiation effect radiation response response success therapy outcome tumor tumor growth

项目摘要

PROJECT SUMMARY The critical preliminary data for this proposal is that in preclinical models, pre-existing tumor-resident T cells are both necessary and sufficient for tumor control by radiation therapy and immunotherapy. We demonstrate that in poorly immunogenic tumors, cross-presenting dendritic cells in the tumor-draining lymph node may be playing no significant role in tumor control. In these models, radiation and immunotherapy are an effective means of local control but fail to engender new systemic immunity. The aim of this proposal is to understand how radiation interacts with tumor resident T cells for local control, and how to restore cross-presentation of tumor-associated antigens to generate new systemic anti-tumor immune responses. We hypothesize that the endogenous vaccine effect of radiation therapy is limited in poorly immunogenic tumors, and current success relies on amplifying pre-existing anti-tumor immunity. The specific aims of this study are to 1: Test the hypothesis that in the presence of pre-existing immunity, tumor control by radiation therapy and immunotherapy occurs independent of cross-presentation and new immune responses; 2: Test the hypothesis that deficient DC cross-presentation limits the ability of radiation therapy to initiate new systemic anti-tumor immune responses; 3: Test the hypothesis that regulation of antigen presentation and cross-presenting DC can be assessed in patient tumors using genetic analysis. Our study design incorporates CT-guided radiation therapy and results are validated in multiple tumor models including those from genetically engineered spontaneous models, using a range of RT doses and fractionations. Our analyses of clinical samples use high quality bioinformatic approaches that allow us to evaluate the infiltrating immune cells and antigen presentation in patient tumors. These are applied to a unique clinical study that allows us to validate our preclinical observations in patients.

项目概要该提案的关键初步数据是，在临床前模型中，预先存在的肿瘤驻留 T 细胞对于通过放射治疗和免疫治疗控制肿瘤来说既是必要的也是充分的。我们展示在免疫原性较差的肿瘤中，肿瘤引流淋巴结中交叉呈递的树突状细胞可能是对肿瘤控制无明显作用。在这些模型中，放射和免疫疗法是有效的局部控制手段，但无法产生新的系统免疫力。该提案的目的是了解辐射如何与肿瘤驻留 T 细胞相互作用以进行局部控制，以及如何恢复 T 细胞的交叉呈递肿瘤相关抗原产生新的全身抗肿瘤免疫反应。我们假设放射治疗的内源性疫苗效果在免疫原性差的肿瘤中有限，目前的成功依赖于增强已有的抗肿瘤免疫力。本研究的具体目的是 1：测试假设在存在预先存在的免疫力的情况下，通过放射治疗和免疫治疗的发生独立于交叉呈递和新的免疫反应； 2：检验假设 DC交叉呈递缺陷限制了放射治疗启动新的全身抗肿瘤的能力免疫反应； 3：检验抗原呈递调节和交叉呈递 DC 的假设可以使用遗传分析对患者肿瘤进行评估。我们的研究设计结合了 CT 引导辐射治疗和结果在多种肿瘤模型中得到验证，包括基因工程模型自发模型，使用一系列放疗剂量和分次。我们对临床样本的分析使用高高质量的生物信息学方法使我们能够评估浸润的免疫细胞和抗原呈递在患者肿瘤中。这些应用于独特的临床研究，使我们能够验证我们的临床前研究对患者的观察。