Developing MRI-Guided Preventive Dendritic Cell Vaccination Strategy to Avoid Post-surgical Pancreatic Cancer Recurrence and Metastasis

项目摘要 胰腺导管腺癌（PDAC）是美国癌症死亡率的第三大原因。手术 切除术是唯一的治愈性治疗，由于复发率高（60%），只有20%的生存五年。 年手术切除后的化疗和放疗只能提供适度的生存改善。一 迫切需要新的方法来预防PDAC患者的肿瘤复发。 我们将比较肿瘤切除术后联合树突状细胞（DC） 通过改进的腹膜内，i.p.，给药途径，联合当前治疗（吉西他滨），与 单独使用预防性DC疫苗接种或单独使用吉西他滨（目的1）。 考虑到向淋巴结（LN）的迁移与抗肿瘤免疫应答之间的关系， DC疫苗迁移的定量可以作为预测纵向应答的早期生物标志物 (OS)并阐明了患者之间反应率差异的原因。了解那些 影响DC疫苗应答率将使疫苗剂量滴定能够优化个体的结局， 患者因此，我们将通过定量磁化率映射（QSM）和超短脉冲成像来验证磁成像。 用于跟踪临床适用的磁标记DC疫苗至引流的回波时间（UTE）R2* 技术 腹部淋巴结（目标2）。 我们将测试是否先进的MRI跟踪DC疫苗归巢淋巴结可以作为早期成像 在一些实施方案中，使用生物标志物来预测DC疫苗接种和吉西他滨治疗的组合在手术后的OS（目的3）。 所提出的工作将满足对癌症治疗的新型DC疫苗接种策略的显著需求， 可以迅速转化为临床，以防止胰腺肿瘤手术后复发，同时增加成像， 生物标志物作为一种潜在的强大的方法，同时预测对治疗的反应。 提出的预防性DC疫苗接种策略的成功和对治疗反应的预测可以 作为对其他实体器官系统的临床延伸具有广泛的影响（例如，胃，肝，结肠直肠，肾， 或子宫肿瘤）作为预防手术后复发的新的辅助免疫疗法。

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer mortality in the US. Surgical resection is the only curative treatment, and due to the high recurrence rate (60%), only 20% survive five years. Chemotherapy and radiotherapy after surgical resection only offer modest improvements in survival. A new approach to prevent tumor recurrence in PDAC patients is urgently needed. We will compare overall survival (OS) after tumor resection between the combination of dendritic cell (DC) vaccination via an improved intraperitoneal, i.p., route, combined with current therapy (gemcitabine), versus the use of preventive DC vaccination alone or gemcitabine alone (Aim 1). Given the relationship between migration to lymph nodes (LNs) and anti-tumor immune response, accurate quantification of DC vaccine migration could serve as an early biomarker for predicting longitudinal response (OS) and elucidating the cause of differential response rates between patients. Understanding factors that affect DC vaccine response rates will enable the titration of vaccine doses to optimize outcomes for individual patients. Thus, we will validate magnetic imaging via quantitative susceptibility mapping (QSM) and ultrashort echo time (UTE) R2* techniques for tracking clinically applicable magnetic-labeled DC vaccines to draining abdominal LNs (Aim 2). We will test whether advanced MRI-tracked DC vaccine homing to LNs can be used as an early imaging biomarker to predict OS of the combination of DC vaccination and gemcitabine treatment post-surgery (Aim 3). The proposed work will meet the significant demand for a novel DC vaccination strategy of cancer therapy that can rapidly be translated to the clinic to prevent relapse after pancreatic tumor surgery while adding an imaging biomarker as a potentially powerful method to simultaneously predict response to the therapy. The success of the proposed preventive DC vaccination strategy and prediction of response to treatment could have a broad impact as a clinical extension to other solid organ systems (e.g., stomach, liver, colorectal, renal, or uterine tumors) as novel adjuvant immunotherapy to prevent relapse after surgery.