TARGETING CCR2 TO OVERCOME IMMUNOSUPPRESSION AND IMPROVE IMMUNOTHERAPY

描述(申请人提供)：胰腺癌(PC)患者的预后很差，5年生存率不到6%。这在一定程度上是由于PC倾向于 疾病检测之前的转移和对细胞毒治疗的抵抗力。胰腺癌的治疗抵抗很大一部分来自于独特的肿瘤微环境的支持。这种肿瘤微环境包括大量浸润性髓系细胞，包括肿瘤相关的巨噬细胞，这些细胞通过诱导免疫抑制来加剧对治疗的反应。因此，在临床可行的情况下，重新编程免疫微环境将改善对细胞毒治疗的反应，即使在耐药肿瘤中也是如此。解决这个问题的一个独特的方法是靶向C-C趋化因子受体2型(CCR2)。通过C-C趋化因子受体2型(CCR2)传递的信号对IM的动员及其在炎症组织中的募集至关重要。我们的初步和已发表的研究结果清楚地表明，在PC小鼠模型中，使用新型CCR2抑制剂PF-04136309阻断IM动员可以减缓肿瘤进展并防止转移。因此，选择性靶向炎性单核细胞对PC的治疗具有重要的前景。基于这些令人兴奋和具有挑衅性的初步数据，我们启动了一项针对局部晚期胰腺癌患者TH CCR2信号通路的Ib期临床试验。虽然靶向CCR2在支持细胞毒治疗方面具有很强的临床潜力，但它与免疫治疗相结合可能更有前景。值得注意的是，我们的研究发现，CCR2阻断克服了免疫抑制，重新启动了CD8+CTL的抗肿瘤反应。然而，抑制CCR2也会导致T细胞检查点通路的上调，如程序性细胞死亡1(PD1)配体和细胞毒性T淋巴细胞抗原4(CTLA4)。这些数据表明，CCR2抑制与基于抗CTLA4和/或PD1的免疫治疗相结合将在产生影响患者生存所必需的持久抗肿瘤免疫反应方面非常有效。因此，在我们已发表的工作、新的初步数据和我们现有临床试验的样本的基础上，这笔赠款将专注于了解和利用CCR2 BLOCK重新编程胰腺肿瘤微环境以增强抗肿瘤免疫的机制。我们的总体假设是，阻断CCR2信号对肿瘤微环境进行重新编程，以改善对免疫治疗的反应。为了测试这一点，我们将：1)确定靶向CCR2的最佳治疗方案，以改进免疫治疗。2)确定阻断CCR2对人胰腺癌T淋巴细胞反应的影响概述：拟议中的研究将评估靶向CCR2以改善免疫治疗的有效性，从而使这一策略能够整合到未来的临床试验中。同时，我们的研究将提高我们对CCR2阻断提高人和小鼠CTL应答的机制(S)的理解。

DESCRIPTION (provided by applicant): The prognosis for pancreatic cancer (PC) patients is dismal, with a 5-year survival rate of less than 6%. This is in part due to the propensity of PC to metastasize prior to disease detection and the resistance to cytotoxic therapies. A significant portion of therapeutic resistance in pancreatic cancers comes from the support of a unique tumor microenvironment. This tumor microenvironment includes significant numbers of infiltrating myeloid cells including tumor-associated macrophages, which exacerbate responses to therapy by inducing immunosuppression. Thus, where clinically feasible reprogramming the immune microenvironment would improve responses to cytotoxic therapy even in resistant tumors. One unique approach to this problem is to target the C-C chemokine receptor type 2 (CCR2). Signaling through C-C chemokine receptor type 2 (CCR2) is critical to the mobilization of IM and their recruitment to inflamed tissue. Our preliminary and published findings clearly show that blockade of IM mobilization using a novel CCR2 inhibitor, PF-04136309 slows tumor progression and prevents metastasis in mouse models of PC. Thus, selective targeting of inflammatory monocytes holds significant promise for the treatment of PC. Based on this exciting and provocative preliminary data, we have initiated a Phase Ib clinical trial targeting th CCR2 signaling pathway in patients with locally-advanced pancreas cancer. While targeting CCR2 holds strong clinical potential for bolstering cytotoxic therapy it may be even more promising in combination with immunotherapy. Strikingly, our studies have found that CCR2 blockade overcomes immune suppression to re-initiates anti- tumor responses by CD8+ CTLs. However, CCR2 inhibition also leads to up-regulation T cell checkpoint pathways such as Programmed Cell Death 1 (PD1) ligands and Cytotoxic T-Lymphocyte Antigen 4 (CTLA4). These data suggest that the combination of CCR2 inhibition and anti-CTLA4 and/or PD1 based immunotherapy would be highly effective at generating the type of durable anti-tumor immune responses necessary to impact patient survival. Thus, building on our published work, new preliminary data, and samples from our existing clinical trial this grant will focus on understanding and exploiting the mechanisms by which CCR2 blockade reprograms the pancreatic tumor microenvironment to bolster anti-tumor immunity. Our overall hypothesis is that blockade of CCR2 signaling reprograms the tumor microenvironment to improve responses to immunotherapy. To test this, we will: 1) Determine the optimum therapeutic regimen for targeting CCR2 to improve immunotherapy. 2) Determine the effect of CCR2 blockade on T lymphocyte responses in human pancreatic cancer Summary: The proposed research will assess the efficacy of targeting CCR2 to improve immunotherapy, thus allowing this strategy to be integrated into future clinical trials. At the same time our studies will improve our understanding of the mechanism(s) by which CCR2 blockade improves CTL responses in humans and mice.