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

• 批准号: 10533342
• 负责人: David G DeNardo
• 金额: $ 43.58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10533342
• 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; Functional disorder; Genetic; ITGAM gene; Immune; Immunity; Immunologic Memory; Immunotherapy; Impairment; Infiltration; Inflammation; Inflammatory; Integrins; Intelligence; Macrophage; 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; Pathology; Patients; Phase; Phenotype; Pre-Clinical Model; Radiation therapy; Research Personnel; Resistance; STING agonists; Sampling; Signal Transduction; Survival Rate; T cell infiltration; 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; drug repurposing; granulocyte; improved; monocyte; novel strategies; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pharmacologic; pre-clinical; programs; recruit; response; small molecule; success; targeted agent; targeted treatment; tool; trafficking; translational approach; treatment response; tumor

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 检查点免疫疗法对抗癌症的潜力已经在几种癌症中得到证实。 类型然而，在胰腺导管腺癌（PDAC）中，检查点免疫治疗并没有导致 临床获益。虽然有多种因素可能起作用，但一个重要因素是， PDAC由多个免疫抑制性骨髓细胞谱系引起。因此，一种有前景的治疗策略 是靶向这些骨髓细胞来提高T细胞介导的免疫力。这些认识导致了一个 将髓样靶向剂与检查点免疫疗法相结合的大量临床试验。 然而，所有目前的治疗策略都受到非靶向亚群的代偿作用， 单核细胞、粒细胞和/或组织驻留巨噬细胞，这可能最终限制治疗功效。 为了克服这一限制，我们的团队开发了一种小分子CD11b变构激动剂ADH-503。 我们的数据将清楚地表明：1）CD11b激动剂快速复极化TAM以支持抗肿瘤 免疫力，同时减弱多个抑制性骨髓细胞谱系的募集 而没有其它髓样靶向药物的代偿机制。2)CD11b激动剂诱导 骨髓重编程重新唤醒T细胞免疫，这反过来又显著限制疾病进展。3)的 CD11b-激动剂与检查点免疫疗法的组合导致显著的肿瘤消退和长期的 PDAC模型中的长期存活率，否则对PD-1治疗完全耐药。这些惊人的数据 我们的假设是，CD11b激动剂重编程TME以克服对检查点的抗性， 免疫疗法。为了测试这一点，我们将： 目的1：确定CD11b激动直接影响骨髓细胞的分子机制。 目的2：确定CD11b激动增强T细胞免疫的细胞机制。 目的3：确定化疗或放疗是否能更好地最大化抗肿瘤免疫， ADH-503加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中的一种新方法，可以使PDAC 对免疫疗法有反应。