The Role of Tumor-Targeted TLR5 Activation in Reversing Immune Checkpoint Therapy Resistance

项目总结/摘要 免疫检查点疗法（ICT）证明了调节免疫检查点的疗法的令人兴奋的疗效。 系统对抗癌症。与传统的化疗策略相比， 如果患者的生存期缩短了几个月，ICT可以产生持久的抗癌反应，从而提高患者的总体生存率， 几年或更长时间。然而，60-80%的患者对ICT无反应，新的治疗策略 治疗这些ICT耐药肿瘤所必需的。ICT通过作用于T细胞来调节适应性免疫系统。 Toll样受体（TLR）的激动剂作用于先天性免疫系统，并且是一种未充分探索的机制， 从而驱动抗癌免疫反应。TLR 5激动剂已显示在以下情况下是可耐受的： 在临床试验中皮下和静脉注射，鞭毛蛋白，一种TLR 5激动剂，已经证明 当通过肿瘤内注射给药时，在动物模型中具有有效的抗肿瘤作用。此外，初步 数据显示，肿瘤内注射鞭毛蛋白可以克服ICT抗性，并且这种效果是由于局部 调节肿瘤免疫微环境（TIME）。然而，由于并非所有患者的肿瘤都是可触及的， 通过直接注射，需要新的方法来配制和递送鞭毛蛋白作为抗癌治疗剂。 因此，该提议集中于开发一种将鞭毛蛋白直接递送至肿瘤的新方法 了解肿瘤靶向TLR 5激活克服ICT的机制 阻力这一建议的中心假设是，肿瘤靶向激活TLR 5的时间，通过NF-κ B， κB信号传导将在TIME中重编程PMN-MDSC，缓解T细胞抑制以克服ICT抗性。 这一假设将在以下目标中进行研究。在目标1中，研究了以下药物的生物分布和药代动力学： 通过PET评估鞭毛蛋白的肿瘤靶向递送。在目的2中，肿瘤靶向的化疗药物的治疗功效是通过观察肿瘤靶向的化疗药物的治疗功效来确定的。 TLR 5活化将作为单独的试剂或与ICT组合通过治疗ICT耐药的肿瘤来评估。 肿瘤的最后，目标3将研究肿瘤靶向TLR 5激活重编程的机制 PMN-MDSC在克服ICT阻力的时间。了解TLR 5激活的机制 可以克服ICT抗性，并开发一种将鞭毛蛋白直接递送到肿瘤的机制， 对抗ICT耐药性的新方法，并为患有 抗ICT肿瘤。此外，申请人在MD安德森癌症中心完成本提案 在癌症系统成像部门将为申请人提供特殊的培训机会 在癌症免疫学和成像，以及提高申请人的培训目标，成为一个 独立调查员

PROJECT SUMMARY/ABSTRACT Immune checkpoint therapies (ICTs) demonstrate the exciting efficacy of therapies that modulate the immune system to combat cancer. Compared to traditional chemotherapeutic strategies, which typically extend overall survival by a few months, ICTs can lead to durable anti-cancer responses that increase overall patient survival by years or more. However, 60-80% of patients are unresponsive to ICTs and new therapeutic strategies are necessary to treat these ICT-resistant tumors. ICTs modulate the adaptive immune system by acting on T cells. Agonists of toll like receptors (TLRs) act on the innate immune system and are an underexplored mechanism by which to drive an anti-cancer immune response. TLR5 agonists have been shown to be tolerable when administered subcutaneously and intravenously in clinical trials and flagellin, a TLR5 agonist, has demonstrated potent anti-tumor effects in animal models when administered by intra-tumoral injection. In addition, preliminary data has shown that intra-tumoral injection of flagellin can overcome ICT resistance and this effect is due to local modulation of the tumor immune microenvironment (TIME). However, as not all patient tumors are accessible by direct injection, new methodologies are needed to formulate and deliver flagellin as an anti-cancer therapeutic. As such, this proposal is focused on the development of a novel method to deliver flagellin directly to the tumor compartment and understanding the mechanisms by which tumor-targeted TLR5 activation overcomes ICT resistance. The central hypothesis of this proposal is that tumor-targeted activation of TLR5 of the TIME, via NF- κB signaling, will reprogram PMN-MDSCs in the TIME, relieving T cell suppression to overcome ICT resistance. This hypothesis will be investigated in the following aims. In Aim 1, the bio-distribution and pharmacokinetics of tumor-targeted delivery of flagellin will be assessed by PET. In Aim 2, the therapeutic efficacy of tumor-targeted TLR5 activation will be assessed as a standalone agent or in combination with ICT by treating ICT-resistant tumors. Finally, Aim 3 will investigate, the mechanisms by which tumor-targeted TLR5 activation reprograms PMN-MDSCs in the TIME to overcome ICT resistance. Understanding the mechanisms by which TLR5 activation can overcome ICT resistance and developing a mechanism to deliver flagellin directly to tumors will provide novel methodologies to combat ICT resistance and develop readily translatable therapeutics for patients with ICT-resistant tumors. In addition, completion of this proposal by the applicant at the MD Anderson Cancer Center in the Department of Cancer Systems Imaging will provide the applicant with exceptional training opportunities in cancer immunology and imaging, as well as enhance the applicant's training goals of becoming an independent investigator.