Project 1: Overcoming Tumor-Induced Immune Suppression to Improve Responses to Immunotherapy

项目总结 涉及CD8+细胞毒性T淋巴细胞(CTL)和/或自然杀伤细胞的急性免疫反应可以 有效抑制肿瘤的发展和进展。不幸的是，到目前为止，免疫治疗的尝试 作为PC中的单一药物，努力实现显著的临床益处。这很可能是由于存在 免疫抑制肿瘤微环境。这种免疫抑制微环境的关键驱动因素是 肿瘤浸润性炎性单核细胞(IMS)和巨噬细胞(TAM)。因此，大量的这些细胞 与胰腺癌早期转移复发和生存不良有关。因此，方法是 重新编程髓系反应以增强保护性抗肿瘤免疫具有显著的治疗潜力。 靶向肿瘤浸润性髓系细胞以改善治疗结果：我们和其他小组 证明IMS和TAMS的动员和肿瘤侵袭可以促进局部免疫抑制， 以及对细胞毒治疗的抵抗力。通过C-C趋化因子受体2型(CCR2)的信号转导对 IMS的动员及其在炎症组织中的募集。我们最近发布的报告清楚地说明了 使用新型CCR2抑制剂PF-04136309(CCR2i)阻断IM募集，可以减缓肿瘤的进展， 改善PC1，13小鼠模型对化疗的反应并防止转移。 令人兴奋和挑衅性的数据，我们启动了一项针对CCR2信号通路的Ib/II期临床试验 在局部晚期PC患者中。在这项试验中，我们观察到48.5%的应答率 CCR2i+FOLFIRINOX治疗33例。此外，该方案耐受性良好(安全)。这些 反应似乎与循环中CCR2+IMS的显著减少以及 原发肿瘤微环境中免疫抑制基因的表达谱。与这些临床应用相对应 数据，我们发表的临床前研究发现，CCR2阻断克服了免疫抑制重新启动 CD8+CTL的抗肿瘤效应。有趣的是，我们发现CCR2在人类 患者和小鼠模型导致T细胞检查点通路上调，包括编程细胞 死亡-1(PD1)及其配体。这些数据表明，我们可能会发现独特的治疗协同作用 CCR2抑制和基于PD1的免疫治疗。因此，我们提出以下目标： 目的1：探讨CCR2受体阻滞剂对PC患者T淋巴细胞反应的影响。 目的2：探讨CCR2抑制提高T细胞免疫功能的机制。 目的3：确定CCR2抑制和PD1阻断联合使用是否能提高治疗效果 晚期PC患者的预后。 摘要：拟议的研究将评估靶向CCR2以改善PD1的安全性和有效性 基础免疫疗法。同时，我们将提高对(S)通过 CCR2阻断可改善人和小鼠的CTL反应。

PROJECT SUMMARY Acute immune responses involving CD8+ cytotoxic T lymphocytes (CTLs) and/or natural killer cells can effectively restrain tumor development and progression. Unfortunately, immunotherapy attempts to date have struggled to achieve significant clinical benefit as single agents in PC. This is likely due to the presence of an immunosuppressive tumor microenvironment. Critical drivers of this immunosuppressive microenvironment are tumor-infiltrating inflammatory monocytes (IMs) and macrophages (TAMs). Thus, high numbers of these cells correlate with early metastatic relapse and poor survival in pancreatic cancer. Therefore, approaches that reprogram myeloid responses to potentiate protective antitumor immunity hold significant therapeutic potential. Targeting tumor-infiltrating myeloid cells to improve therapeutic outcomes: We and other groups have demonstrated that mobilization and tumor infiltration of IMs and TAMs can promote local immunosuppression, and resistance to cytotoxic therapy. Signaling through C-C chemokine receptor type 2 (CCR2) is critical for the mobilization of IMs and their recruitment to inflamed tissues. Our recently published reports clearly illustrate that blockade of IM recruitment using a novel CCR2 inhibitor, PF-04136309 (CCR2i), slows tumor progression, improves responses to chemotherapy and prevents metastasis in mouse models of PC1,13. Based on these exciting and provocative data, we initiated a Phase Ib/II clinical trial targeting the CCR2 signaling pathway in patients with locally advanced PC. In this trial, we have observed a remarkable 48.5% response rate in the 33 patients treated with CCR2i + FOLFIRINOX. Additionally, this regimen was well tolerated (safe). These responses appear to be correlated with a marked reduction in circulating CCR2+ IMs as well as decreased immune suppressive gene expression profiles in the primary tumor microenvironment. Paralleling these clinical data, our published pre-clinical studies found that CCR2 blockade overcomes immune suppression to reinitiate anti-tumor responses via CD8+ CTLs. Intriguingly, we've discovered that CCR2 blockade in both human patients and mouse models leads to the upregulation of T cell checkpoint pathways, including programmed cell death-1 (PD1) and its ligands. These data suggest that we might find unique therapeutic synergy between CCR2 inhibition and PD1-based immunotherapies. Thus, we propose the following aims: Aim 1: Determine the effects of CCR2 blockade on T lymphocyte responses in patients with PC. Aim 2: Determine the mechanisms by which CCR2 inhibition improves T cell immunity. Aim 3: Determine whether combining CCR2 inhibition with PD1 blockade can enhance therapeutic outcomes in patients with advanced PC. Summary: The proposed research will assess the safety and efficacy of targeting CCR2 to improve PD1 based immunotherapy. At the same time, we will improve our understanding of the mechanism(s) by which CCR2 blockade improves CTL responses in humans and mice.