Exploiting Integrin Signaling to Overcome Resistance to Immunotherapy

利用整合素信号传导克服免疫治疗耐药性

基本信息

批准号：
10057373
负责人：
David G DeNardo
金额：
$ 44.47万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057373
关键词：
Agonist Cancer Model Cellular Immunity Chemotherapy and/or radiation Clinic Clinical Clinical Trials Combined Modality Therapy Data Disease Disease Progression Disease model Exclusion Genetic ITGAM gene Immune Immunity Immunologic Memory Immunotherapy Impairment Infiltration Inflammation Inflammatory Integrins Intelligence Macrophage Colony-Stimulating Factor Receptor Malignant Neoplasms Malignant neoplasm of pancreas Molecular Molecular Mechanisms of Action Myelogenous Myeloid Cells Myeloid-derived suppressor cells Neoplasm Metastasis Pancreatic Ductal Adenocarcinoma Patients Pharmacology Phase Phenotype Pre-Clinical Model Radiation therapy Research Personnel Resistance STING agonists Signal Transduction Survival Rate T cell response T-Lymphocyte TNFRSF5 gene Testing Therapeutic Therapeutic Agents Tissues Translating Treatment Efficacy Tumor Immunity Tumor-associated macrophages anti-PD1 therapy beta-Chemokines cancer clinical trial cancer type checkpoint therapy chemokine receptor clinical development combat granulocyte improved macrophage monocyte novel strategies pancreatic cancer patients pancreatic ductal adenocarcinoma model pre-clinical programmed cell death protein 1 recruit response small molecule success targeted agent targeted treatment tool trafficking translational approach tumor

项目摘要

PROJECT SUMMARY The potential of checkpoint immunotherapy to combat cancer has been established in several cancer types. However, in pancreatic ductal adenocarcinoma (PDAC), checkpoint immunotherapy has not led to clinical benefit. Although multiple factors likely contribute, one significant factor is the extensive infiltration of PDAC by multiple lineages of immunosuppressive myeloid cells. Therefore, one promising therapeutic strategy is the targeting these myeloid cells to improve T cell-mediated immunity. These realizations have led to a significant number of clinical trials combining myeloid targeted agent with checkpoint immunotherapy. However, all current therapeutic strategies are subject to compensatory actions by untargeted subsets of monocytes, granulocytes, and/or tissue resident macrophages, which may ultimately limit therapeutic efficacy. To overcome this limitation, our team has developed a small molecule allosteric agonist of CD11b, ADH-503. Our data will clearly demonstrate: 1) CD11b-agonism both rapidly repolarizes TAMs to support anti-tumor immunity while simultaneously blunting the recruitment of multiple lineages of suppressive myeloid cells without the compensatory mechanisms seen with other myeloid-targeting agents. 2) CD11b-agonist-induce myeloid reprograming reawakens T cell immunity that in-turn significantly limit disease progression. 3) The combination of CD11b-agonist with checkpoint immunotherapy leads to dramatic tumor regression and long- term survival in PDAC models that are otherwise completely resistant to PD-1 therapy. These stunning data drive our hypothesis that CD11b agonism reprograms the TME to overcome resistance to checkpoint immunotherapy. To test this, we will: Aim 1: Determine the molecular mechanisms by which CD11b-agonism directly impacts myeloid cells. Aim 2: Determine the cellular mechanism(s) by which CD11b-agonism enhances T cell immunity. Aim 3: Determine if chemotherapy or radiation therapy better maximize the anti-tumor immunity and the efficacy generated by ADH-503 plus checkpoint immunotherapy. Impact: These studies investigate a new approach in current clinical development that can render PDACs responsive to immunotherapy.

项目摘要在几种癌症中已经建立了检查点免疫疗法对抗癌症的潜力类型。但是，在胰腺导管腺癌（PDAC）中，检查点免疫疗法并未导致临床益处。尽管多个因素可能是造成的，但一个重要因素是广泛的渗透 PDAC由免疫抑制髓样细胞的多个谱系。因此，一种有希望的治疗策略是靶向这些髓样细胞以改善T细胞介导的免疫力的。这些实现导致了将髓样靶标和检查点免疫疗法相结合的大量临床试验。但是，所有当前的治疗策略均通过不固定的子集采取补偿性行动单核细胞，粒细胞和/或组织驻留巨噬细胞，最终可能限制治疗功效。为了克服这一限制，我们的团队开发了一个小分子变构激动剂，即CD11b，ADH-503。我们的数据将清楚地证明：1）CD11b-agyism均快速重新振动TAM以支持抗肿瘤免疫力同时使抑制性髓样细胞的多个谱系募集没有其他粒细胞靶向剂的补偿机制。 2）CD11b激动剂诱导髓样重编程会唤起T细胞免疫，从而明显限制疾病进展。 3） CD11B激动剂与检查点免疫疗法的组合导致巨大的肿瘤回归和长期 PDAC模型中的术语生存期，否则对PD-1治疗具有完全抗性。这些令人惊叹的数据推动我们假设CD11b激动剂对TME进行重新编程以克服对检查点的抗性免疫疗法。为了测试这一点，我们将： AIM 1：确定CD11b-启动直接影响髓样细胞的分子机制。 AIM 2：确定CD11b-agenism增强T细胞免疫力的细胞机制。目标3：确定化学疗法或放射治疗是否更好地最大化抗肿瘤免疫力和 ADH-503加上检查点免疫疗法产生的功效。影响：这些研究调查了当前临床开发的一种新方法，可以使PDAC呈现PDAC 对免疫疗法的反应。