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

项目摘要/摘要 胰腺导管腺癌(PDAC)的特点是对治疗耐药，常被诊断为 晚期，限制了治疗选择。导致治疗失败的一个因素是深度促结缔组织增生症和 一个公认的低氧和免疫抑制肿瘤微环境(TME)。在PDAC中，有几个 治疗方法，包括单独或联合免疫检查站的化疗和放射治疗 抑制剂的治疗效果微乎其微。内窥镜超声引导射频消融术 (EUS-RFA)是治疗PDAC的一种有前景的局部消融、间质和免疫调节剂治疗方法。我们已经确立了 评估EUS-RFA对可切除肿瘤患者疗效的综合研究计划 PDAC。同时，我们已经发布了一个临床前模型来测试RFA治疗如何改变当地的TME 消融部位或系统地通过评估对侧肿瘤(非内窥镜效应)。成功 我们的临床和小鼠数据的融合将揭示RFA介导的免疫的机制理解 刺激、免疫抑制检查点和RFA-免疫治疗相结合的策略以改善PDAC 生存结果。我们最近确定了一种安全可行的微创、可重复的 可用于全身化疗的技术：EUS-RFA。我们的II期临床试验(潘卡地诺- 1)，有12名登记的患者，证明了重复EUS-RFA的耐受性、安全性和可行性 可切除的PDAC的标准化疗。我们进一步发现患者血清中CD40在EUS后升高。 RFA，提示免疫激活和抗肿瘤免疫。使用我们的临床前模型，我们还展示了 抑制CD73或PD-L1可增强RFA介导的肿瘤生长抑制。鉴于这些发现，我们 假设以免疫检查点阻断和免疫抑制为目标的多管齐下的方法 与RFA的结合将改进EUS-RFA未来的临床试验设计，并提高PDAC存活率 结果。我们提出以下具体目标：目标1：评价重复化疗的效果 EUS-RFA对可切除PDAC肿瘤生长、远期疗效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治疗对持续抗-RFA的影响 肿瘤免疫和改善药物输送，使用和不使用新的联合免疫疗法。影响和 创新：这项提案是第一次进行临床试验，检查EUS-RFA改善化疗- PDAC的基础治疗。通过补充纳入临床相关的动物模型，我们将 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网络将作为正在进行的板凳到床边方法的管道，以建立新的 治疗PDAC的护理标准。

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.