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

项目摘要/摘要 免疫检查点疗法(ICT)展示了调节免疫的疗法令人兴奋的疗效 抗击癌症的系统。与传统的化疗策略相比，传统的化疗策略通常会全面扩展 生存时间延长几个月，信息通信技术可以产生持久的抗癌反应，从而提高患者的总体生存时间 几年或更长时间。然而，60%-80%的患者对信息通信技术没有反应，新的治疗策略是 是治疗这些对ICT具有抵抗力的肿瘤所必需的。ICT通过作用于T细胞来调节适应性免疫系统。 Toll样受体(TLRs)激动剂作用于先天性免疫系统，是一种尚未被研究的机制，通过 来驱动抗癌免疫反应。TLR5激动剂已被证明在以下情况下是可以耐受的 在临床试验中，皮下和静脉注射TLR5激动剂鞭毛素已经证明 瘤内注射对动物模型的有效抗肿瘤作用。此外，初步的 有数据表明，瘤内注射鞭毛蛋白可以克服ICT耐药性，这种效果是由于局部 肿瘤免疫微环境的调节(时间)。然而，由于并不是所有的患者都可以接触到肿瘤 通过直接注射，需要新的方法来配制和传递鞭毛蛋白作为抗癌治疗药物。 因此，这项提议的重点是开发一种新的方法，将鞭毛蛋白直接输送到肿瘤中。 了解肿瘤靶向TLR5激活克服ICT的机制 抵抗。这一建议的中心假设是，肿瘤靶向激活TLR5的时间，通过核因子- κB信号，将及时重新编程PMN-MDSCs，缓解T细胞抑制，以克服对ICT的抵抗力。 这一假说将从以下几个方面进行研究。目标1：阿司匹林的生物分布和药代动力学 肿瘤靶向的鞭毛蛋白输送将通过PET进行评估。在目标2中，肿瘤靶向治疗的疗效 TLR5激活将作为单独的试剂进行评估，或者通过治疗ICT耐药与ICT结合进行评估 肿瘤。最后，Aim 3将研究肿瘤靶向TLR5激活重新编程的机制 PMN-MDSCs在克服ICT阻力的时候。了解TLR5激活的机制 能够克服ICT耐药性并开发一种机制将鞭毛蛋白直接输送到肿瘤将提供 对抗ICT耐药性的新方法，并为患者开发易于翻译的治疗方法 对ICT具有抵抗性的肿瘤。此外，申请者在MD Anderson癌症中心填写此建议书 将为申请者提供特殊的培训机会 在癌症免疫学和成像方面，以及加强申请人的培训目标，成为 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.