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

用于胰腺癌成像和预测标准和 CCR2 靶向治疗反应的新型 CCR2 PET

基本信息

批准号：
10534151
负责人：
FARROKH DEHDASHTI
金额：
$ 16.85万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10534151
关键词：
Aftercare Animal Model Biology Biopsy Blood Cells Clinical Data Clinical Treatment Clinical Trials Conduct Clinical Trials Data Data Analyses Detection Development Disease Disease Progression Disease model Future Genetic Grant Human Image Immuno-Chemotherapy Immunohistochemistry Immunosuppression Infiltration Inflammatory Institution Life Ligands Liver Macrophage Malignant Neoplasms Malignant neoplasm of pancreas Medical Monitor Morbidity - disease rate Myeloid-derived suppressor cells Neoplasm Metastasis Pancreas Pancreatic Ductal Adenocarcinoma Patient Selection Patient imaging Patients Peptides Phase Phase I/II Clinical Trial Positron-Emission Tomography Process Production Radiolabeled Regimen Renal clearance function Resectable Resistance Safety Science Screening procedure Sensitivity and Specificity Signal Transduction Site Specimen Testing Therapeutic Toxic effect Tracer Tumor Immunity Tumor-associated macrophages Update Variant Work antagonist anti-CTLA4 antibodies anti-PD-1 anti-PD1 therapy beta-Chemokines cancer imaging cancer immunotherapy cancer type chemokine chemokine receptor chemotherapy clinical biomarkers detection sensitivity diagnostic tool early phase clinical trial effective therapy first-in-human gamma-Chemokines human tissue image guided imaging agent immune checkpoint in vivo ineffective therapies inhibitor innovation monocyte mouse model novel pancreatic ductal adenocarcinoma model pancreatic neoplasm participant enrollment patient stratification pre-clinical preclinical study predicting response prevent radiological imaging radiotracer response targeted treatment treatment response tumor tumor growth tumor microenvironment tumor progression uptake

项目摘要

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.

项目概要/摘要开发有效的治疗方法是胰导管患者迫切且未得到满足的医疗需求腺癌（PDAC）。免疫检查点拮抗剂如抗PD-1和抗CTLA4的出现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。我们和其他人研究表明 PDAC 的肿瘤微环境 (TME) 中充满了骨髓源性抑制细胞包括抑制炎症单核细胞（IM）和肿瘤相关巨噬细胞（TAM）的作用化疗和抗肿瘤免疫。 PDAC 中 CCL2 的过量产生已被证明会导致肿瘤生长、传播、局部免疫抑制和化疗耐药。靶向关键的趋化因子机制，C-C 基序趋化因子配体 2 (CCL2)/C-C 趋化因子受体 2 型 (CCR2) 轴，绘制这些细胞对 TME 增强了临床前小鼠模型和临床试验中化疗的功效在我们机构进行的，为进一步确认和优化 CCR2 目标策略奠定了前提 PDAC。我们正在开展一项结合 CCR2/5 抑制剂和化疗的 I/II 期临床试验和抗PD-1剂。认识到并非所有患者都会从这种治疗方案中受益，一种能够在预测和监测治疗反应的同时评估 CCR2 丰度将是非常有价值的。 CCR2 抑制剂可减缓肿瘤进展，防止 PDAC 小鼠模型中的转移，并增强在患有临界可切除或局部晚期 PDAC 的患者 (NCT01413022)。我们开发了 CCR2- PET 示踪剂 (64Cu-DOTA-ECL1i) 并在多个临床前研究中显示了其在 CCR2 成像中的敏感性和特异性炎症性疾病模型和 PDAC 模型以及 PDAC 人体标本。我们的 PDAC PET 成像遗传小鼠模型证明了肿瘤中 CCR2 的早期、灵敏和特异性检测。第一个—— 人体成像显示，正常胰腺和肝脏（常见的胰腺和肝脏）中 64Cu-DOTA-ECL1i 的积累量较低。转移性疾病部位，其中携带 CCR2 的 IM 和 TAM 在转移前浸润到转移前部位转移克隆的建立）具有快速的血液和肾脏清除率，表明该 PET 的潜力用于 PDAC 患者 CCR2 检测的示踪剂。我们假设 64Cu-DOTA-ECL1i 可以敏感且专门检测 PDAC 中的 CCR2，跟踪 CCR2 靶向治疗后的变化，并可能进行预筛选 PDAC 患者接受 CCR2 靶向治疗。我们建议评估肿瘤是否摄取 64Cu-DOTA-ECL1i 与 CCR2 的肿瘤表达和 PDAC 患者对标准化疗的反应相关。我们也将评估肿瘤对 64Cu-DOTA-ECL1i 的摄取是否可以预测 PDAC 中 CCR2 导向治疗的反应使用 CCR2/5 抑制剂和化疗免疫疗法治疗的患者。本次赠款的顺利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。