Exploiting Integrin Signaling to Overcome Resistance to Immunotherapy

项目总结 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，检查点免疫治疗并未导致 临床益处。尽管多种因素可能起到了作用，但一个重要因素是 PDAC由多个免疫抑制的髓系细胞组成。因此，一种有希望的治疗策略 靶向这些髓系细胞以提高T细胞介导的免疫力。这些认识导致了一种 大量临床试验将髓系靶向制剂与检查点免疫疗法相结合。 然而，所有当前的治疗策略都受到非靶向亚群的补偿行动的影响。 单核细胞、粒细胞和/或组织驻留的巨噬细胞，最终可能限制治疗效果。 为了克服这一限制，我们团队开发了CD11b的小分子变构激动剂ADH-503。 我们的数据将清楚地证明：1)CD11b激动剂既能迅速重新极化TAM，又能支持抗肿瘤 免疫同时钝化多系抑制性髓系细胞的招募 没有其他髓系靶向药物的补偿机制。2)CD11b激动剂-诱导 髓系重新编程可重新唤醒T细胞免疫，进而显着限制疾病的进展。3) CD11b激动剂与检查点免疫治疗相结合可导致肿瘤显著消退和长期存活。 对PD-1治疗完全抵抗的PDAC模型的长期存活率。这些令人震惊的数据 推动我们的假设，CD11b激动剂重新编程TME以克服对检查点的抵抗 免疫疗法。为了测试这一点，我们将： 目的1：确定CD11b激动剂直接作用于髓系细胞的分子机制。 目的：探讨CD11b激活增强T细胞免疫功能的细胞机制(S)。 目的3：确定化疗或放射治疗哪个更好地最大化抗肿瘤免疫和 ADH-503加检查点免疫治疗的疗效。 影响：这些研究在当前的临床开发中探索了一种新的方法，可以使PDAC 对免疫疗法有反应。

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.