"Combining radiation with TLR5 agonist based immunotherapy against liver metastases"

总结 本研究的长期目标是利用基于Toll样受体5（TLR5）激动剂的免疫疗法 与免疫调节放射治疗在发展一种安全有效的组合方法 控制肝脏转移性疾病该项目的目的是证明改善的治疗效果 使用这种新的治疗方法来治疗肝转移性疾病，并提供机制基础， 推动联合战略的进一步发展。这项研究的假设是，TLR5 激动剂介导的免疫反应在正常肝脏微环境中结合 肝脏放射治疗（RT）免疫调节作用产生有效的抗肿瘤免疫， 肝转移这一理论是基于最近的累积数据表明，肝脏微环境 具有独特的特性，其中TLR5激动剂引起显著的抗肿瘤免疫应答， 通过TLR5应答性肝细胞和中试实验，表明 应用于肝脏的电离辐射增强并扩展了TLR5激动剂的治疗范围 针对肝转移的免疫疗法。在这个项目中，假设将使用高度 侵袭性小鼠结肠直肠癌和葡萄膜黑色素瘤肝转移模型和新产生的 和最佳化的TLR5激动剂恩托莫德。研究计划包括测试不同的 联合治疗方案，并将其应用结果与肝放射和TLR5的结果进行比较 使用实验性结肠直肠癌单独刺激对肝转移性生长的抗肿瘤功效 癌症和自发性葡萄膜黑色素瘤肝转移模型（Aim 1）。单次给药和分次RT 将在相对于全身施用恩托莫德的不同时间（辅助和新辅助）施用， 确定联合治疗的最有效方案。免疫学变化在 在有效的抗肿瘤免疫应答的发展中的肝微环境将是 使用表型和功能测定确定（Aim 2）。研究结果将进一步推动 这一创新方法的临床方案。而小鼠结肠直肠癌和葡萄膜黑色素瘤肝 转移模型的选择是由于重要的医学需求，明确的转化途径和令人鼓舞的 通过这些模型获得的初步结果，这些结果将提供与其他癌症相关的信息 很容易转移到肝脏该项目的完成将为临床前 促进临床试验进展的疗效数据以及进一步基础的机制基础 研究负责这种创新治疗的抗肿瘤活性的分子机制 这是对抗肝转移所急需的方法。

Summary The long term goal of this research is to utilize toll-like receptor 5 (TLR5) agonist based immunotherapy with immunomodulatory radiation treatment in the development of a safe and effective combinatorial approach to control liver metastatic disease. The objective of this project is to demonstrate improved therapeutic efficacy against liver metastatic disease using this novel treatment approach and to provide a mechanistic foundation to advance further development of the combined strategy. The hypothesis underlying this research is that TLR5 agonist mediated immune response in the normal liver microenvironment combined with the immunomodulatory effects of liver radiation treatment (RT) generate potent antitumor immunity to eliminate liver metastases. This theory is based on recent cumulative data indicating that the liver microenvironment possesses a unique character in which TLR5 agonists elicit a significant antitumor immune response mediated by TLR5 responsive hepatocytes and on pilot experiments illustrating that the immune stimulatory effects of ionizing radiation applied to the liver enhance and extend the therapeutic reach of TLR5 agonist immunotherapy against liver metastases. In this project, the hypothesis will be tested using the highly aggressive murine colorectal cancer and uveal melanoma liver metastasis models and the newly generated and pharmacologically optimized TLR5 agonist, entolimod. The research plan includes testing different combination therapy regimens and comparing the results of their application to that of liver radiation and TLR5 stimulation individually for antitumor efficacy against liver metastatic growth using the experimental colorectal cancer and spontaneous uveal melanoma liver metastasis models (Aim 1). Single dose and fractionated RT will be applied at different times (adjuvant and neoadjuvant) relative to systemic entolimod administration to determine the most efficacious regimens of the combined therapy. The role of the immunological changes in the hepatic microenvironment in the development of an efficacious antitumor immune response will be determined using phenotypic and functional assays (Aim 2). The results will further the development of a clinical protocol for this innovative approach. While the murine colorectal cancer and uveal melanoma liver metastasis models were chosen due to the significant medical need, clear translational path and encouraging preliminary results obtained with these models, the results will provide information relevant to other cancers with a high propensity to metastasize to the liver. Completion of this project will provide supporting pre-clinical efficacy data to facilitate advancement to clinical trials and a mechanistic foundation on which to base further investigation of the molecular mechanisms responsible for the antitumor activity of this innovative therapeutic approach that is critically needed against liver metastasis.