A single-arm phase II study to evaluate the safety and efficacy of combination systematic chemotherapy and multiple rounds of endoscopic ultrasound-guided radiofrequency ablation in pancreatic cancer

项目总结/摘要 胰腺导管腺癌（PDAC）的特征是对治疗的抵抗，通常在 晚期，限制了治疗方案。导致治疗失败的一个因素是严重的结缔组织增生， 一个充分记录的缺氧和免疫抑制肿瘤微环境（TME）。在PDAC中， 治疗方法，包括单独的化疗和放疗或与免疫检查点联合 抑制剂，已经显示出最小的治疗成功。超声内镜引导下射频消融 （EUS-RFA）是治疗PDAC的一种有前途的局部消融、基质和免疫调节剂治疗。我们建立 评价EUS-RFA在可切除肿瘤患者中的治疗获益的综合研究项目 PDAC。与此同时，我们发布了一个临床前模型来测试RFA治疗如何改变当地的TME 消融部位或通过评价对侧肿瘤（远位效应）进行全身性治疗。成功 我们的临床和小鼠数据的合并将揭示对RFA介导的免疫应答的机制的理解。 刺激、免疫抑制检查点和RFA-免疫治疗组合策略，以改善PDAC 生存结果。我们最近建立了一个安全性和可行性的微创，可重复 可与全身化疗联合使用的技术：EUS-RFA。我们的II期临床试验（PANCARDINAL- 1），12例入组患者，证明了重复EUS-RFA的耐受性、安全性和可行性， 可切除PDAC的标准化疗。我们进一步发现患者血清中的CD40在EUS后升高- RFA，表明免疫激活和抗肿瘤免疫。使用我们的临床前模型，我们还表明， CD73或PD-L1抑制增强RFA介导的肿瘤生长减少。鉴于这些发现，我们 假设一种靶向免疫检查点阻断和免疫抑制的多管齐下的方法， 联合RFA将改善未来EUS-RFA的临床试验设计，并改善PDAC生存率 成果。我们提出以下具体目的：目的1：评价化疗的效果， EUS-RFA对可切除PDAC中肿瘤生长、长期结局和抗肿瘤免疫机制的影响 患者（PANCARDINAL-1试验）和目标2：确定重复RFA治疗对维持抗 肿瘤免疫和改善药物递送，有和没有新的联合免疫疗法。影响和 创新：该提案是第一个执行EUS-RFA临床试验以改善化疗的提案- 基于PDAC的治疗。通过补充纳入临床相关的动物模型， 为未来的研究确定新的治疗策略。这笔资金将巩固建立一个 PANCARDINAL网络作为一个管道，正在进行的板凳到床边的方法，以建立一个新的 治疗PDAC的标准护理。

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to therapy and is often diagnosed at a late stage, limiting treatment options. A contributing factor to therapeutic failure is profound desmoplasia and a well-documented hypoxic and immunosuppressive tumor microenvironment (TME). In PDAC, several therapeutic approaches, including chemotherapy and radiation alone or combined with immune checkpoint inhibitors, have shown minimal therapeutic success. Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising local ablative, stromal and immunomodulator therapy for PDAC. We have established a comprehensive research program to evaluate therapeutic benefits of EUS-RFA in patients with resectable PDAC. In tandem, we have published a preclinical model to test how RFA treatment alters the TME in the local ablation site or systemically through evaluation of contralateral tumors (abscopal effect). Successful amalgamation of our clinical and murine data will reveal mechanistic understanding of RFA-mediated immune stimulation, immune inhibitory checkpoints, and RFA-immunotherapy combination strategies to improve PDAC survival outcomes. We recently established the safety and feasibility of a minimally invasive, repeatable technique that can be used with systemic chemotherapy: EUS-RFA. Our phase II clinical trial (PANCARDINAL- 1), with 12 enrolled patients, demonstrates the tolerability, safety, and feasibility of repeated EUS-RFA with standard chemotherapy for resectable PDAC. We further found CD40 in patient serum is elevated post EUS- RFA, indicating immune activation and anti-tumor immunity. Using our preclinical model, we have also shown CD73 or PD-L1 inhibition augments RFA-mediated tumor growth reduction. Given these findings, we hypothesize that a multipronged approach that targets immune checkpoint blockade and immunosuppression in combination with RFA will improve future clinical trial design with EUS-RFA and improve PDAC survival outcomes. We propose the following Specific Aims: Aim 1: Evaluate effects of chemotherapy with repeated EUS-RFA on tumor growth, long-term outcomes, and anti-tumor immunity mechanisms in resectable PDAC patients (PANCARDINAL-1 Trial) and Aim 2: Determine impact of repeated RFA treatment in sustaining anti- tumor immunity and improving drug delivery with and without novel combined immunotherapies. Impact and Innovation: This proposal is the first to execute a clinical trial examining EUS-RFA for improving chemotherapy- based treatment of PDAC. Through complementary incorporation of clinically relevant animal models, we will identify novel therapeutic strategies for future studies. This funding will solidify establishment of a PANCARDINAL Network to serve as a pipeline for ongoing bench-to-bedside approaches to establish a new standard of care for the treatment of PDAC.