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

项目总结/摘要 开发有效的治疗方法是胰腺导管炎患者迫切的、未满足的医疗需求 腺癌（PDAC）。免疫检查点拮抗剂的出现，如抗PD-1和抗CTLA 4 抗体已经彻底改变了一些癌症的治疗，但在PDAC中仍然不成功。我们和其他人 显示PDAC的肿瘤微环境（TME）充满髓源性抑制细胞， 包括炎性单核细胞（IM）和肿瘤相关巨噬细胞（TAM），它们抑制了 化疗和抗肿瘤免疫。PDAC中CCL 2的过量产生已显示导致肿瘤 生长、播散、局部免疫抑制和化疗耐药性。针对一个关键的趋化因子 C-C基序趋化因子配体2（CCL 2）/ C-C趋化因子受体2型（CCR 2）轴， 在临床前小鼠模型和临床试验中， 在我们的机构进行，为进一步确认和优化针对CCR 2的策略奠定了前提， PDAC。我们正在进行一项I/II期临床试验， 和抗PD-1剂。意识到并非所有患者都将受益于该方案，诊断工具能够 在预测和监测治疗反应的同时评估CCR 2丰度将是非常宝贵的。CCR2 抑制剂减缓肿瘤进展，防止PDAC小鼠模型中的转移，并增强PDAC小鼠模型中的作用。 边缘可切除或局部晚期PDAC患者（NCT 01413022）。我们开发了一个CCR 2- PET示踪剂（64 Cu-DOTA-ECL 1 i），并显示其在多个临床前病变中成像CCR 2的灵敏度和特异性。 炎性疾病模型和PDAC模型和PDAC人样本。我们的PDAC PET成像 遗传小鼠模型证实了肿瘤中CCR 2的早期、敏感和特异性检测。第一个- 人体成像显示64 Cu-DOTA-ECL 1 i在正常胰腺和肝脏中的低积累（常见的 转移性疾病的部位，其中携带CCR 2的IM和TAM在转移前部位浸润， 转移克隆的建立）具有快速的血液和肾脏清除，表明这种PET的潜力 用于PDAC患者中CCR 2检测的示踪剂。我们假设64 Cu-DOTA-ECL 1 i可以敏感地和 特异性检测PDAC中的CCR 2，跟踪CCR 2靶向治疗后的变化， PDAC患者接受CCR 2靶向治疗。我们建议评估肿瘤摄取64 Cu-DOTA-ECL 1 i是否 与PDAC患者中CCR 2的肿瘤表达和对标准化疗的反应相关。我们也 将评估64 Cu-DOTA-ECL 1 i的肿瘤摄取是否预测PDAC患者对CCR 2导向治疗的应答 接受CCR 2/5抑制剂和化学免疫疗法治疗的患者。成功完成这项赠款将 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.