Project 1: Employing CD11b-Agonists to Render PDAC 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类型中确立。 然而，在胰腺导管腺癌（PDAC）中，检查点免疫治疗尚未导致临床上的 效益尽管有多种因素可能导致检查点耐药，但一个重要因素是广泛的 PDAC被多个免疫抑制性骨髓细胞谱系浸润。这些骨髓细胞， 包括肿瘤相关巨噬细胞（TAM）和髓源性抑制细胞（MDSC），驱动T细胞 排斥和功能障碍。因此，一种有希望的治疗策略是重新编程这些骨髓细胞， 提高T细胞介导免疫力。我们的团队最近开发了一种CD 11b的变构激动剂GB 1275。 我们发表的数据表明，CD 11b激动作用可使TAM迅速复极化，以支持抗肿瘤免疫 CD 11b激动剂与检查点免疫疗法联合使用可导致肿瘤消退和长期生存 在临床前PDAC模型中。这些强有力的数据推动了我们的假设，即CD 11b激动剂重新编程了 PDAC肿瘤微环境，以克服对检查点免疫疗法的抗性。为了验证这一 假设，我们将： 目的1：确定GB 1275、吉西他滨和Abraxane以及PD-1阻滞剂在 转移性PDAC患者。 目的2：确定PDAC中GB 1275治疗的暴露、反应和耐药性的生物标志物 患者 目的3：确定肿瘤内在和外在因素如何调节CD 11b激动剂治疗的影响。 影响：这些研究将研究一种新的方法，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 yet led to clinical benefits. Although multiple factors likely contribute to checkpoint resistance, one significant factor is extensive infiltration of PDACs by multiple lineages of immunosuppressive myeloid cells. These myeloid cells, which include tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), drive T cell exclusion and dysfunction. Thus, one promising therapeutic strategy is to reprogram these myeloid cells to improve T cell-mediated immunity. Our team has recently developed an allosteric AGONIST of CD11b, GB1275. Our published data demonstrate that CD11b-agonism rapidly repolarizes TAMs to support anti-tumor immunity and combining CD11b-agonists with checkpoint immunotherapy leads to tumor regression and long-term survival in pre-clinical PDAC models. These strong data drive our hypothesis that CD11b agonism reprograms the PDAC tumor microenvironment to overcome resistance to checkpoint immunotherapy. To test this hypothesis, we will: Aim 1: Determine the safety and efficacy of GB1275, Gemcitabine and Abraxane and PD-1 blockade in metastatic PDAC patients. Aim 2: Determine the biomarkers of exposure, response, and resistance to GB1275 therapy in PDAC patients. Aim 3: Determine how tumor-intrinsic and extrinsic factors regulate the impact of CD11b agonist therapy. Impact: These studies will investigate a novel approach to render PDAC responsive to immunotherapy.