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.

项目摘要/摘要 胰腺导管腺癌（PDAC）的特征是耐药性，经常被诊断为 后期，限制治疗选择。造成治疗衰竭的一个促成因素是深刻的脱木质和 有据可查的缺氧和免疫抑制性肿瘤微环境（TME）。在PDAC中，有几个 治疗方法，包括单独的化疗和放射疗法或与免疫检查点结合 抑制剂显示出最小的治疗成功。内窥镜超声引导射频消融 （EUS-RFA）是PDAC的一种有前途的局部消融，基质和免疫调节剂治疗。我们已经建立了 一项全面的研究计划，以评估EUS-RFA的治疗益处 PDAC。同时，我们发布了一个临床前模型，以测试RFA处理如何改变本地的TME 通过评估对侧肿瘤（潜在的效应）进行消融部位或系统地消融。成功的 我们的临床和鼠数据的合并将揭示对RFA介导的免疫的机械理解 刺激，免疫抑制检查点和RFA免疫疗法组合策略，以改善PDAC 生存结果。我们最近确定了微创，可重复的安全性和可行性 可以与全身化学疗法一起使用的技术：EUS-RFA。我们的II期临床试验（胰腺 - 1）有12名注册患者，证明了重复EUS-RFA的耐受性，安全性和可行性 可切除PDAC的标准化学疗法。我们进一步发现患者血清中的CD40升高EUS- RFA，表明免疫激活和抗肿瘤免疫。使用我们的临床前模型，我们还显示了 CD73或PD-L1抑制增加了RFA介导的肿瘤生长减少。有了这些发现，我们 假设一种靶向免疫检查点阻断和免疫抑制的多收益方法 与RFA相结合将通过EUS-RFA改善未来的临床试验设计，并改善PDAC生存 结果。我们提出以下具体目的：目标1：评估化学疗法的影响 EUS-RFA对可切除PDAC中肿瘤生长，长期结局和抗肿瘤免疫机制 患者（Pancardinal-1试验）和目标2：确定重复的RFA治疗对维持抗抗衡的影响 肿瘤免疫力和具有和不具有新型免疫疗法的药物递送。影响和 创新：该提案是第一个执行临床试验，检查EUS-RFA以改善化学疗法 - 基于PDAC的治疗。通过补充临床相关的动物模型，我们将 确定未来研究的新型治疗策略。这笔资金将巩固建立 胸膜网络是作为持续的基准与床层方法建立新的新方法的管道 PDAC治疗的护理标准。