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

项目摘要 涉及CD 8+细胞毒性T淋巴细胞（CTL）和/或自然杀伤细胞的急性免疫应答可 有效抑制肿瘤的发生和发展。不幸的是，迄今为止的免疫治疗尝试 作为PC中的单药，努力实现显著的临床获益。这很可能是由于存在一个 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（IM）和巨噬细胞（TAM）。因此，大量的这些细胞 与胰腺癌的早期转移复发和低生存率相关。因此， 重编程骨髓应答以增强保护性抗肿瘤免疫具有显著的治疗潜力。 靶向肿瘤浸润性骨髓细胞以改善治疗结果：我们和其他研究小组 证明了IM和TAM的动员和肿瘤浸润可以促进局部免疫抑制， 和对细胞毒性疗法的抗性。通过C-C趋化因子受体2（CCR 2）的信号传导对于免疫调节至关重要。 IM的动员及其向发炎组织的募集。我们最近发表的报告清楚地表明， 使用新的CCR 2抑制剂PF-04136309（CCR 2 i）阻断IM募集，减缓肿瘤进展， 改善对化疗的反应，并预防PC小鼠模型的转移1，13。基于这些 令人兴奋和挑衅性的数据，我们启动了一项针对CCR 2信号通路的Ib/II期临床试验， 局部晚期PC患者。在这项试验中，我们观察到48.5%的应答率， 33例接受CCR 2 i + FOLFIRINOX治疗的患者。此外，该方案耐受性良好（安全）。这些 缓解似乎与循环CCR 2 + IM的显著减少以及 免疫抑制基因在原发性肿瘤微环境中的表达谱。这些临床 数据，我们发表的临床前研究发现，CCR 2阻断克服了免疫抑制， 通过CD 8 + CTL的抗肿瘤应答。有趣的是，我们已经发现，CCR 2在两个人中的阻断， 患者和小鼠模型导致T细胞检查点途径的上调，包括程序化细胞 死亡-1（PD 1）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， CCR 2抑制和基于PD 1的免疫疗法。因此，我们提出以下目标： 目的1：探讨阻断CCR 2对PC患者T淋巴细胞反应的影响。 目的2：确定CCR 2抑制提高T细胞免疫的机制。 目的3：确定CCR 2抑制与PD 1阻断联合是否可以增强治疗效果 晚期PC患者的结局。 摘要：拟议的研究将评估靶向CCR 2改善PD 1的安全性和有效性。 基于免疫疗法。与此同时，我们将更好地了解 CCR 2阻断改善人和小鼠的CTL应答。

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.