Novel CCR2 PET for Pancreatic Cancer Imaging and Prediction of Response to Standard and CCR2-Targeted Therapy

项目摘要/摘要 开发有效的治疗方法是胰腺导管患者迫切而未得到满足的医疗需求。 腺癌(PDAC)。抗PD-1和抗CTLA4等免疫检查点拮抗剂的问世 抗体已经使一些癌症的治疗发生了革命性的变化，但在PDAC治疗中仍然不成功。我们和其他人 显示PDAC的肿瘤微环境(TME)中充满了髓系来源的抑制细胞。 包括炎性单核细胞(IMS)和肿瘤相关巨噬细胞(TAMs)，它们抑制了 化疗和抗肿瘤免疫。PDAC中CCL2的过度产生已被证明会导致肿瘤 生长、扩散、局部免疫抑制和对化疗的耐药性。靶向一种关键的趋化物质 机制，C-C基序趋化因子配体2(CCL2)/C-C趋化因子受体2型(CCR2)轴， 这些细胞对TME增强化疗疗效的临床前小鼠模型和临床试验 在我们机构进行，为进一步确认和优化针对CCR2的战略奠定了前提 PDAC。我们正在开始一项I/II期临床试验，结合CCR2/5抑制剂、化疗 和抗PD-1试剂。意识到并不是所有的患者都会从这种方案中受益，这是一种能够 在预测和监测治疗反应的同时评估CCR2的丰度将是非常宝贵的。CCR2 抑制剂延缓肿瘤进展，防止PDAC小鼠模型的转移，并增强 边界可切除或局部晚期PDAC的患者(NCT01413022)。我们已经开发了CCR2- PET示踪剂(64Cu-DOTA-ECL1i)在多发性临床前CCR2显像中的敏感性和特异性 炎症性疾病模型、PDAC模型和PDAC人标本。我们的PDAC PET成像 小鼠遗传模型显示了CCR2在肿瘤中的早期、灵敏和特异的检测。第一个-- In-man成像显示64Cu-DOTA-ECL1i在正常胰腺和肝脏(一种常见的 转移性病变的部位，携带CCR2的IMS和TAMs在转移前病变部位 转移性克隆的建立)，具有快速的血液和肾脏清除，表明这种PET的潜力 PDAC患者CCR2检测的示踪剂。我们假设64Cu-DOTA-ECL1i可以灵敏和 在PDAC中专门检测CCR2，跟踪CCR2靶向治疗后的变化，并可能进行预筛查 PDAC患者接受CCR2靶向治疗。我们建议评估肿瘤对64Cu-DOTA-ECL1i的摄取 PDAC患者CCR2的表达和对标准化疗的疗效相关。我们也 将评估肿瘤摄取64Cu-DOTA-ECL1i是否可以预测PDAC对CCR2指导治疗的反应 接受CCR2/5抑制剂和化学免疫治疗的患者。这笔赠款的成功完成将 促进临床数据解释、患者分层和治疗指导的创新手段。

PROJECT SUMMARY/ABSTRACT Development of effective therapies is an urgent, unmet medical need for patients with pancreatic ductal adenocarcinoma (PDAC). The advent of immune checkpoint antagonists such as anti-PD-1 and anti-CTLA4 antibodies has revolutionized treatment of some cancers but remains unsuccessful in PDAC. We and others showed that the tumor microenvironment (TME) of PDAC is rife with myeloid-derived suppressor cells including inflammatory monocytes (IMs) and tumor-associated macrophages (TAMs) that stifle the effect of chemotherapy and anti-tumor immunity. Excessive production of CCL2 in PDAC has shown to result in tumor growth, dissemination, local immunosuppression, and resistance to chemotherapy. Targeting a key chemotactic mechanism, the C-C motif chemokine ligand 2 (CCL2)/ C-C chemokine receptor type 2 (CCR2) axis, that draws these cells to the TME potentiates the efficacy of chemotherapy in preclinical mouse model and a clinical trial conducted at our institution, setting the premise to further confirm and optimize CCR2-targeted strategies in PDAC. We are in the process of opening a phase I/II clinical trial combining a CCR2/5 inhibitor, chemotherapy and anti-PD-1 agent. Realizing that not all patients will benefit from this regimen, a diagnostic tool capable of assessing CCR2 abundance while predicting and monitoring treatment response will be invaluable. CCR2 inhibitor slows tumor progression, prevents metastasis in mouse models of PDAC, and potentiates effect in patients with border-line resectable or locally-advanced PDAC (NCT01413022). We have developed a CCR2- PET tracer (64Cu-DOTA-ECL1i) and shown its sensitivity and specificity in imaging CCR2 in multiple preclinical inflammatory disease models and PDAC models and PDAC human specimens. Our PDAC PET imaging in genetic mouse model demonstrated early, sensitive, and specific detection of CCR2 in tumors. The first- in-man imaging showed low accumulation of 64Cu-DOTA-ECL1i in normal pancreas and liver (a common site of metastatic disease where CCR2-bearing IMs and TAMs infiltrate the pre-metastatic sites prior to establishment of metastatic clones) with rapid blood and renal clearance, indicating the potential of this PET tracer for CCR2 detection in PDAC patients. We hypothesize that 64Cu-DOTA-ECL1i can sensitively and specifically detect CCR2 in PDAC, track the variation following CCR2-targeted treatment, and likely prescreen PDAC patients for CCR2-targeted therapy. We propose to evaluate whether tumor uptake of 64Cu-DOTA-ECL1i correlates with tumor expression of CCR2 and response to standard chemotherapy in PDAC patients. We also will evaluate whether tumor uptake of 64Cu-DOTA-ECL1i predicts response to CCR2-directed therapy in PDAC patients treated with CCR2/5 inhibitor and chemo-immunotherapy. The successful completion of this grant will facilitate innovative means for clinical data interpretation, patient stratification, and therapy guidance.