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

项目总结 胰腺导管腺癌(PDAC)是美国第三大癌症死亡原因。外科手术 切除是唯一的根治方法，由于复发率很高(60%)，只有20%的人能存活五年 好几年了。手术切除后的化疗和放射治疗仅能适度提高存活率。一个 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后的总存活率(OS)和树突状细胞(DC)的组合 通过改进的腹膜内注射途径接种疫苗，结合目前的治疗方法(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(目标1)。 鉴于转移到淋巴结(LNS)和抗肿瘤免疫反应之间的关系，准确的 DC疫苗迁移的量化可作为预测纵向应答的早期生物标志物 (OS)和阐明患者之间应答率不同的原因。了解以下因素 影响DC疫苗应答率将使疫苗剂量的滴定能够优化个人结果 病人。因此，我们将通过定量磁化率图(QSM)和超短波来验证磁成像 用于跟踪临床适用的磁标记DC疫苗直到排出的回声时间(UTE)R2*技术 腹部淋巴结(AIM 2)。 我们将测试先进的MRI追踪的DC疫苗归巢到LNS是否可以用作早期成像 预测DC疫苗和吉西他滨联合治疗术后OS的生物标志物(目标3)。 拟议的工作将满足对新的DC癌症治疗疫苗接种策略的重大需求 可以快速转化到临床，防止胰腺肿瘤手术后复发，同时增加成像 生物标记物作为一种潜在的强有力的方法来同时预测治疗的反应。 拟议的预防性DC疫苗接种战略的成功和治疗反应的预测可能 作为临床扩展到其他固体器官系统(例如，胃、肝、结直肠、肾、 或子宫肿瘤)作为预防术后复发的新型辅助免疫疗法。

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.