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

评估联合系统化疗和多轮内镜超声引导射频消融治疗胰腺癌的安全性和有效性的单组 II 期研究

• 批准号: 10743356
• 负责人: Jennifer Bailey Lundberg
• 金额: $ 67.61万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743356
• 关键词: 5' -Nucleotidase; Ablation; Abscopal effect; Adenocarcinoma; Adenosine; Adoption; Animal Model; Antitumor Response; CXCR4 gene; Cells; Chemotherapy and/or radiation; Clinical; Clinical Trials; Clinical Trials Design; Coagulative necrosis; Collaborations; Collagen; Combination immunotherapy; Combined Modality Therapy; Contralateral; Data; Deposition; Desmoplastic; Development; Diagnosis; Disease; Drug Delivery Systems; Endoscopic Ultrasonography; Evaluation; Excision; Failure; Fibroblasts; Funding; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Granzyme; Health; Hypoxia; Image; Immune; Immune Targeting; Immune checkpoint inhibitor; Immunologic Stimulation; Immunosuppression; Immunotherapy; Incidence; Infrastructure; Institution; Knowledge; Life; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Mission; Modeling; Monitor; Mus; Outcome; Pancreatic Ductal Adenocarcinoma; Pancreatic duct; Patient-Focused Outcomes; Patients; Phase; Phase II Clinical Trials; Pre-Clinical Model; Publishing; Radiofrequency Interstitial Ablation; Research; Research Personnel; Resectable; Resected; Safety; Serum; Site; Stromal Cell-Derived Factor 1; Survival Rate; TNFRSF5 gene; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tumor Immunity; Tumor Tissue; United States National Institutes of Health; Unresectable; Vascularization; anti-PD-L1; anti-tumor immune response; arm; bench to bedside; cancer clinical trial; cancer diagnosis; cancer infiltrating T cells; cancer therapy; chemotherapy; clinical care; clinically relevant; early phase clinical trial; immune activation; immune checkpoint blockade; immunomodulatory therapies; immunoregulation; improved; improved outcome; in vivo; inhibitor; innovation; minimally invasive; neovascularization; novel; novel therapeutic intervention; participant enrollment; phase 2 study; pre-clinical; primary outcome; programmed cell death ligand 1; programs; public health relevance; response; response biomarker; safety and feasibility; secondary outcome; single-cell RNA sequencing; standard of care; subcutaneous; success; survival outcome; targeted treatment; therapy resistant; transcriptomics; treatment response; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

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.

项目概要/摘要 胰腺导管腺癌 (PDAC) 的特点是对治疗耐药，通常在以下时间诊断： 处于晚期，限制了治疗选择。治疗失败的一个因素是严重的结缔组织增生和 有据可查的缺氧和免疫抑制肿瘤微环境（TME）。在 PDAC 中，有几个 治疗方法，包括单独化疗和放疗或与免疫检查点相结合 抑制剂，已显示出最小的治疗成功。超声内镜引导射频消融 (EUS-RFA) 是一种很有前途的 PDAC 局部消融、基质和免疫调节剂疗法。我们已经建立了 一项综合研究计划，旨在评估 EUS-RFA 对可切除患者的治疗效果 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 消融部位或通过评估对侧肿瘤进行系统性消融（远隔效应）。成功的 我们的临床和小鼠数据的合并将揭示对 RFA 介导的免疫机制的理解 刺激、免疫抑制检查点和 RFA-免疫治疗联合策略以改善 PDAC 生存结果。我们最近确定了一种微创、可重复的安全性和可行性 可与全身化疗一起使用的技术：EUS-RFA。我们的 II 期临床试验（PANCARDINAL- 1) 通过 12 名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 EUS 后患者血清中的 CD40 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 抑制可增强 RFA 介导的肿瘤生长减少。鉴于这些发现，我们 假设针对免疫检查点阻断和免疫抑制的多管齐下的方法 与 RFA 结合将改善 EUS-RFA 的未来临床试验设计并提高 PDAC 生存率 结果。我们提出以下具体目标： 目标 1：评估重复化疗的效果 EUS-RFA 对可切除 PDAC 中肿瘤生长、长期结果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- 使用或不使用新型联合免疫疗法，可以提高肿瘤免疫力并改善药物输送。影响和 创新：该提案是第一个执行检查 EUS-RFA 改善化疗的临床试验的提案 - PDAC 的基础治疗。通过临床相关动物模型的补充整合，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 网络将作为持续的从实验室到临床方法的管道，以建立新的 PDAC 治疗的护理标准。