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：
8760163
负责人：
Michael James Gough
金额：
$ 32.16万
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 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8760163
关键词：
Acute Adjuvant Animals Antigens Back Cancer Model Cancer Patient Cessation of life Chronic Clinical Clinical Research Conformal Radiotherapy Cytotoxic Chemotherapy Data Diagnosis Disease Distant Metastasis Dose Dose Fractionation Environment Excision Fractionation Image Immune Immune response Immunotherapy Individual Inflammation Inflammatory Link Lymphocyte Malignant neoplasm of pancreas Modeling Mus Neoadjuvant Therapy Operative Surgical Procedures Pancreas Pancreatic Adenocarcinoma Patients Population Pre-Clinical Model Process Radiation Radiation therapy Recurrence Research Research Design Resectable Residual Cancers Residual Tumors Resolution Sampling Site Survival Rate T cell response T-Lymphocyte Testing Time Translating Tumor Antigens Unresectable Vaccine Therapy Vaccines Work adaptive immunity cancer cell chemokine chemoradiation design follow-up immune function immunoregulation killings novel open label pre-clinical prevent public health relevance radiation effect repaired response tissue repair treatment site tumor

项目摘要

DESCRIPTION (provided by applicant): Radiation therapy is a highly effective means to kill cancer cells; unfortunately tumors can grow back from small pockets of residual disease. We propose that immune responses initiated by radiation therapy have the potential to control residual disease in the treatment site and distant metastases. Our research thus far has demonstrated three main points: first, that radiation therapy induces tumor antigen-specific T cell responses that are required for the full efficacy of radiation therapy; second, that high dose radiation therapy releases adjuvants that are required to prime adaptive responses to tumor antigens; and third, a negative fact, that the tissue repair response activated by radiation damage limits immune responses at the tumor. The aim of this proposal is to understand the relationship between radiation dose and the positive and negative immune responses to tumors. We hypothesize that hypofractionated radiation therapy would result in superior adaptive immune responses to tumor antigens. We further examine how radiation interacts with immunotherapies to extend inflammation in the tumor and target residual disease. The specific aims of this study are to 1: Test the hypothesis that hypofractionated radiation therapy would result in superior adaptive immune responses to tumor antigens; 2: Test the hypothesis that vaccine therapies synergize with hypofractionated radiation therapy to boost and target T cell responses, and extend inflammatory destruction in the tumor; 3: Test the hypothesis that hypofractionated radiation therapy is a superior partner for clinical vaccine therapies in neoadjuvant chemoradiation for pancreatic cancer. Our study design incorporates preclinical radiation therapy of spontaneous models of pancreatic cancer using an advanced imaging and treatment platform. In addition, we use two matching clinical studies of immunomodulation combined with neoadjuvant chemoradiation therapy for locally advanced and borderline resectable pancreatic cancer to examine the effect of radiation fractionation on T cell immune responses. We and others are designing and conducting clinical studies combination immunotherapy and radiation: these data will be key to the design of an effective combination.

描述（由申请人提供）：放射治疗是杀死癌细胞的高效手段；不幸的是，肿瘤可以从小部分残留疾病中重新生长。我们认为，放射治疗引发的免疫反应有可能控制治疗部位的残留疾病和远处转移。迄今为止，我们的研究已经证明了三个要点：首先，放射治疗会诱导肿瘤抗原特异性T细胞反应，这是放射治疗充分发挥功效所必需的；其次，高剂量放射治疗会释放出启动对肿瘤抗原的适应性反应所需的佐剂；第三，一个消极的事实是，辐射损伤激活的组织修复反应限制了肿瘤的免疫反应。该提案的目的是了解辐射剂量与肿瘤的阳性和阴性免疫反应之间的关系。我们假设大分割放射治疗将导致对肿瘤抗原的优异适应性免疫反应。我们进一步研究辐射如何与免疫疗法相互作用，以扩大肿瘤中的炎症并针对残留疾病。本研究的具体目的是 1：检验大分割放射治疗会导致针对肿瘤抗原的优异适应性免疫反应的假设； 2：检验疫苗疗法与大分割放射疗法协同作用的假设，以增强和靶向 T 细胞反应，并延长肿瘤中的炎症破坏；图 3：检验大分割放射治疗是胰腺癌新辅助放化疗临床疫苗治疗的最佳伴侣这一假设。我们的研究设计结合了使用先进的成像和治疗平台对自发性胰腺癌模型进行临床前放射治疗。此外，我们还利用两项免疫调节联合新辅助放化疗治疗局部晚期和临界可切除胰腺癌的匹配临床研究来检验放射分割对 T 细胞免疫反应的影响。我们和其他人正在设计和开展免疫疗法和放射组合的临床研究：这些数据将是设计有效组合的关键。