TARGETING CCR2 TO OVERCOME IMMUNOSUPPRESSION AND IMPROVE IMMUNOTHERAPY

靶向 CCR2 克服免疫抑制并改善免疫治疗

• 批准号: 8749794
• 负责人: David G DeNardo
• 金额: $ 12.34万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8749794
• 关键词: Acute; Apoptosis; CD8B1 gene; Cancer Patient; Cell Count; Clinical; Clinical Data; Clinical Trials; Cytotoxic Chemotherapy; Cytotoxic T-Lymphocyte-Associated Protein 4; Cytotoxic T-Lymphocytes; Data; Detection; Development; Diagnosis; Disease; Future; Gene Expression; Grant; Human; ImProv; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Infiltration; Inflammatory; Inflammatory Infiltrate; Leukocytes; Ligands; Maintenance; Malignant neoplasm of pancreas; Mediating; Medical; Molecular Profiling; Mus; Myelogenous; Myeloid Cells; Natural Killer Cells; Neoplasm Metastasis; Outcome; PC6 extract; Pancreas; Pathway interactions; Patients; Phase; Primary Neoplasm; Proprotein Convertase 1; Publishing; Regimen; Relapse; Reporting; Research; Resistance; Sampling; Signal Pathway; Signal Transduction; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Tumor Immunity; Up-Regulation; Work; base; beta-Chemokines; chemokine receptor; clinical application; cytotoxic; effective therapy; gamma-Chemokines; improved; inhibitor/antagonist; killings; macrophage; monocyte; mouse model; neoplastic cell; novel; outcome forecast; palliative; pancreatic neoplasm; preclinical study; prevent; public health relevance; response; tumor; tumor growth; tumor microenvironment; tumor progression

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.

描述（由申请人提供）：胰腺癌（PC）患者的预后很差，5年生存率低于6%。这部分是由于PC的倾向， 在疾病检测之前转移和对细胞毒性疗法的抗性。胰腺癌的治疗耐药性很大一部分来自独特的肿瘤微环境的支持。这种肿瘤微环境包括大量的浸润性骨髓细胞，包括肿瘤相关巨噬细胞，其通过诱导免疫抑制而加剧对治疗的反应。因此，在临床上可行的情况下，重编程免疫微环境将改善对细胞毒性疗法的应答，即使在抗性肿瘤中也是如此。解决这个问题的一种独特方法是靶向C-C趋化因子受体2（CCR 2）。通过C-C趋化因子受体2（CCR 2）的信号传导对于IM的动员及其向炎症组织的募集至关重要。我们的初步和已发表的研究结果清楚地表明，使用新型CCR 2抑制剂PF-04136309阻断IM动员可减缓PC小鼠模型中的肿瘤进展并预防转移。因此，选择性靶向炎性单核细胞对于PC的治疗具有重要的前景。基于这一令人兴奋和挑衅性的初步数据，我们已经启动了一项针对局部晚期胰腺癌患者的CCR 2信号通路的Ib期临床试验。虽然靶向CCR 2在支持细胞毒性疗法方面具有强大的临床潜力，但与免疫疗法结合可能更有前途。引人注目的是，我们的研究已经发现，CCR 2阻断克服了免疫抑制以通过CD 8 + CTL重新启动抗肿瘤应答。然而，CCR 2抑制也导致上调T细胞检查点途径，如程序性细胞死亡1（PD 1）配体和细胞毒性T淋巴细胞抗原4（CTLA 4）。这些数据表明，CCR 2抑制和基于抗CTLA 4和/或PD 1的免疫疗法的组合在产生影响患者存活所必需的持久抗肿瘤免疫应答类型方面将是高度有效的。因此，基于我们已发表的工作，新的初步数据和我们现有临床试验的样本，该资助将专注于理解和利用CCR 2阻断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CCR 2信号转导可以重新编程肿瘤微环境，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CCR 2的最佳治疗方案，以改善免疫治疗。2)确定CCR 2阻断对人类胰腺癌T淋巴细胞反应的影响摘要：拟议的研究将评估靶向CCR 2改善免疫治疗的疗效，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CCR 2阻断改善人类和小鼠CTL应答的机制的理解。