High dose radiation therapy to direct immune responses to pancreatic cancer

描述(由申请人提供)： 放射治疗是一种非常有效的杀死癌细胞的方法；不幸的是，肿瘤可以从小块残留的疾病中生长出来。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。到目前为止，我们的研究证明了三个主要观点：第一，放射治疗诱导肿瘤抗原特异性T细胞反应，这是充分发挥放射治疗效果所必需的；第二，高剂量放射治疗释放启动对肿瘤抗原的适应性反应所需的佐剂；第三，负面事实，即由辐射损伤激活的组织修复反应限制了肿瘤的免疫反应。这项建议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，低分割放射治疗将导致对肿瘤抗原的更好的适应性免疫反应。我们进一步研究了放射与免疫疗法如何相互作用，以延长肿瘤中的炎症并针对残留疾病。这项研究的具体目标是：1：检验低分割放射治疗将导致对肿瘤抗原的卓越适应性免疫反应的假设；2：检验疫苗治疗与低分割放射治疗协同作用以增强和靶向T细胞反应并扩大肿瘤炎症破坏的假设；3：检验低分割放射治疗是胰腺癌新辅助化疗中临床疫苗治疗的更好合作伙伴的假设。我们的研究设计包括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，我们使用了两项相匹配的临床研究，即免疫调节联合新辅助放化疗治疗局部晚期和边缘可切除的胰腺癌，以检查放射分割对T细胞免疫反应的影响。我们和其他人正在设计和进行结合免疫治疗和放射治疗的临床研究：这些数据将是设计有效组合的关键。

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.