High dose radiation therapy to direct immune responses to pancreatic cancer

描述（由申请人提供）： 放射治疗是杀死癌细胞的一种非常有效的手段;不幸的是，肿瘤可以从残留疾病的小口袋中重新生长。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。到目前为止，我们的研究已经证明了三个要点：第一，放射治疗诱导肿瘤抗原特异性T细胞反应，这是放射治疗完全有效所必需的;第二，高剂量放射治疗释放了引发对肿瘤抗原的适应性反应所需的佐剂;第三，一个负面的事实，即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上级适应性免疫应答。我们进一步研究了放射如何与免疫疗法相互作用，以延长肿瘤中的炎症并靶向残留疾病。本研究的具体目的是：1：检验大分割放射治疗将导致对肿瘤抗原的上级适应性免疫应答的假设; 2：检验疫苗疗法与大分割放射治疗协同作用以增强和靶向T细胞应答并延长肿瘤中的炎性破坏的假设; 3：检验大分割放射治疗是胰腺癌新辅助放化疗中临床疫苗治疗的上级伙伴的假设。我们的研究设计采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，我们使用两个匹配的临床研究免疫调节结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细胞免疫应答的影响。我们和其他人正在设计和进行免疫疗法和放射疗法的临床研究：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.