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

肿瘤靶向 TLR5 激活在逆转免疫检查点治疗耐药中的作用

基本信息

批准号：
10090450
负责人：
Sarah E Glazer
金额：
$ 3.35万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090450
关键词：
4T1 Adaptive Immune System Affinity Aftercare Agonist Animal Model Antibodies Antineoplastic Agents Bacteria Biodistribution Biological Assay Bone Marrow Transplantation CD276 gene Cancer Center Cancer Patient Canis familiaris Cells Clinical Trials Data Development Drug Kinetics Evaluation Flagellin Foundations Genetic Transcription Goals Government Histology Human Immune Immune checkpoint inhibitor Immune response Immune system Injections Innate Immune System Intravenous Lead Malignant Neoplasms Mammary Neoplasms Mediating Methodology Methods Monitor Mus Myeloid Cells Myeloid-derived suppressor cells Normal tissue morphology Patients Persons Positron-Emission Tomography Primates Process Production Research Personnel Resistance Role Salmonella Signal Transduction Survival Analysis T cell response T-Cell Proliferation T-Lymphocyte TLR5 gene Testing Therapeutic Toll-like receptors Training Treatment Efficacy anti-cancer anti-cancer therapeutic antitumor effect cancer imaging cancer survival checkpoint therapy chemotherapy combat cytokine experimental study imaging system immune activation immunomodulatory therapies mouse model neoplastic cell novel novel therapeutic intervention radiotracer refractory cancer response subcutaneous targeted delivery therapy resistant training opportunity transplant model tumor tumor immunology tumor-immune system interactions

项目摘要

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.

项目概要/摘要免疫检查点疗法 (ICT) 证明了调节免疫疗法的令人兴奋的功效与通常全面扩展的传统化疗策略相比。生存期延长几个月，信息通信技术可以带来持久的抗癌反应，从而提高患者的总体生存率然而，60-80% 的患者对 ICT 没有反应，新的治疗策略正在出现。 ICT 通过作用于 T 细胞来调节适应性免疫系统。 Toll 样受体 (TLR) 激动剂作用于先天免疫系统，是一种尚未充分研究的机制当 TLR5 激动剂被证明是可耐受的时，它会驱动抗癌免疫反应。在临床试验中皮下和静脉注射，鞭毛蛋白（一种 TLR5 激动剂）已证明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。数据显示，肿瘤内注射鞭毛蛋白可以克服ICT抵抗，这种效果是由于局部肿瘤免疫微环境（TIME）的调节然而，并非所有患者肿瘤都可以进入。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，该提案的重点是开发一种将鞭毛蛋白直接递送至肿瘤的新方法隔室并了解肿瘤靶向 TLR5 激活克服 ICT 的机制该提议的中心假设是通过 NF- 肿瘤靶向激活 TIME 的 TLR5。 κB 信号传导将在 TIME 中重新编程 PMN-MDSC，缓解 T 细胞抑制以克服 ICT 耐药性。该假设将在以下目标中进行研究：目标 1：生物分布和药代动力学。在目标 2 中，鞭毛蛋白的肿瘤靶向递送将通过 PET 进行评估。 TLR5 激活将作为独立药物或与 ICT 联合治疗 ICT 耐药性进行评估最后，目标 3 将研究肿瘤靶向 TLR5 激活重编程的机制。 PMN-MDSC 在 TIME 中克服 ICT 阻力了解 TLR5 激活的机制。可以克服 ICT 阻力，开发一种将鞭毛蛋白直接递送至肿瘤的机制将提供对抗 ICT 耐药性并为患有以下疾病的患者开发易于转化的疗法的新方法此外，该提案由 MD 安德森癌症中心的申请人完成。癌症系统成像系的博士将为申请人提供特殊的培训机会在癌症免疫学和成像方面，以及提高申请人成为一名独立调查员。