Optimization of High Frequency Irreversible Electroporation (H-FIRE) for tumor ablation and immune system activation in pancreatic cancer applications

高频不可逆电穿孔 (H-FIRE) 的优化，用于胰腺癌应用中的肿瘤消融和免疫系统激活

• 批准号: 10659581
• 负责人: Irving C Allen
• 金额: $ 56.66万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-10 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659581
• 关键词: Ablation; Address; Aftercare; Anatomy; Animal Model; Apoptosis; Biophysics; Blood Vessels; Cancer cell line; Cell Death; Cell membrane; Cessation of life; Chemotherapy and/or radiation; Clinical; Clinical Research; Clinical Trials; Complication; Data; Defect; Development; Diagnosis; Diameter; Disease; Distal; Duct (organ) structure; Electrodes; Electroporation; Elements; Family suidae; Feedback; Fourier Analysis; Frequencies; Future; Geometry; Heterogeneity; Human; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Immunology; In Situ; Injury; Interphase; Location; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Methods; Modality; Mus; Necrosis; Neoplasm Metastasis; Nerve; Nodule; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic duct; Pancreatitis; Patients; Physiologic pulse; Physiological; Physiology; Play; Pre-Clinical Model; Prognosis; Protocols documentation; Recurrence; Risk; Role; Safety; Series; Site; Solid Neoplasm; Spectrum Analysis; Stenosis; Structural defect; Structure; Survival Rate; Techniques; Technology; Testing; Theoretical Studies; Therapeutic; Time; Tissues; Treatment Protocols; Tumor Burden; Tumor Immunity; Tumor Tissue; United States; Unresectable; Width; Work; anti-tumor immune response; biophysical properties; cancer cell; clinical translation; clinically relevant; effective therapy; electric field; electric impedance; fighting; in vivo; invention; ionization; mouse model; nanoscale; novel; novel therapeutic intervention; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; patient derived xenograft model; physical property; porcine model; pre-clinical; preclinical study; prevent; response; translation to humans; treatment strategy; tumor; tumor ablation; tumor heterogeneity; tumor microenvironment; tumor progression; tumor xenograft

PROJECT SUMMARY: Pancreatic cancer accounts for approximately 3% of all cancers in the United States and approximately 7% of all cancer related deaths. New treatment paradigms are direly needed. Emerging tumor ablation techniques have shown significant promise. This proposal will focus on High-Frequency Irreversible Electroporation (H-FIRE), which delivers a series of electric pulses through electrodes inserted directly into the tumor to produce structural defects in the target cell membrane resulting in cancer cell death. The objective of this proposal is to utilize our mouse and novel pig preclinical animal models to expand upon the preliminary data presented in this proposal and generate critical mechanistic, safety, and efficacy data necessary to support future H-FIRE clinical trials in pancreatic cancer patients. Our overarching hypothesis is that H-FIRE will effectively mitigate heterogeneity in physiologically and clinically relevant pancreatic tumors, with treatments leading to contiguous zones of ablation near critical tissue structures. We further postulate that the benefits of H-FIRE will ultimately extend beyond focal tumor ablation and generate a predictable, tunable systemic anti-tumor immune response reducing metastatic burden and preventing recurrence. Specific Aim 1 will characterize the biophysical response of pancreatic cancer cells and tissues to H-FIRE. This Aim will evaluate the hypothesis that H-FIRE pulse parameters can be tuned to achieve different cell death outcomes (apoptosis, pyroptosis, necroptosis, or necrosis) that are highly relevant to tumor ablation, the tumor microenvironment, and anti-tumor immune responses. In concert, we will assess ablation development with real time treatment feedback using Fourier Analysis Spectroscopy (FAST). We expect to determine which parameters (i.e. pulse width, energized time, interphase/interpulse delay) play significant roles in tuning cell death elicited within relevant cancer cell lines and ex vivo tissues. Specific Aim 2 will establish H-FIRE treatment strategies for pancreatic cancer that optimize tumor ablation and systemic anti-tumor immune responses. Using Pan02 mouse models, this Aim will test the hypothesis that H-FIRE is an effective treatment modality for precise and complete pancreatic tumor ablation in vivo. We also postulate that due to the unique features of H-FIRE mediated cell death and resultant changes in the tumor microenvironment, focal tumor ablation will result in predictable and tunable systemic anti-tumor host immune responses reducing metastatic burden and preventing recurrence. Specific Aim 3 will define H-FIRE treatment parameters and determine its safety profile utilizing physiologically and clinically relevant porcine models of pancreatic cancer. This Aim will test the hypothesis that H-FIRE can effectively ablate orthotopic pancreatic tumors under physiologically and clinically relevant in situ conditions. To test this hypothesis, we will utilize novel, orthotopic, porcine pancreatic cancer models featuring a diverse range of clinically relevant physical properties that are predicted to impact H-FIRE efficacy in human patients.

项目摘要：胰腺癌约占美国所有癌症的3％ 大约有7％的与癌症相关的死亡。需要新的治疗范例。新兴 肿瘤消融技术已显示出巨大的希望。该建议将重点放在高频上 不可逆的电穿孔（H火），它通过插入的电极传递一系列电脉冲 直接进入肿瘤，在靶细胞膜中产生结构缺陷，导致癌细胞死亡。 该建议的目的是利用我们的小鼠和新型猪临床前动物模型扩展 该提案中介绍的初步数据并产生关键的机械，安全性和功效数据 支持胰腺癌患者未来H火的临床试验所必需的。我们的总体假设 是H火将有效地减轻生理和临床相关的胰腺异质性 肿瘤，处理导致关键组织结构附近消融的连续区域。我们进一步 假设H火的益处最终将超出局灶性肿瘤消融并产生A 可预测的可调的全身性抗肿瘤免疫反应减轻转移负担并防止 复发。具体目标1将表征胰腺癌细胞和 组织到H火。此目的将评估可以将H火脉冲参数调谐到的假设 实现高度相关的不同细胞死亡结果（凋亡，凋亡，坏死或坏死） 肿瘤消融，肿瘤微环境和抗肿瘤免疫反应。在音乐会上，我们将评估 使用傅立叶分析光谱法（FAST）进行实时治疗反馈的消融发展。我们 期望确定哪些参数（即脉冲宽度，通电时间，间相/间隙延迟）播放 在相关的癌细胞系和离体组织中引起的调节细胞死亡的重要作用。具体目标 2将建立胰腺癌的H火治疗策略，以优化肿瘤消融和 全身性抗肿瘤免疫反应。使用PAN02鼠标模型，此目标将检验以下假设。 H火是体内精确和完整的胰腺肿瘤消融的有效治疗方式。我们也是 假设由于H火发生介导的细胞死亡的独特特征和肿瘤的导致变化 微环境，局灶性肿瘤消融将导致可预测且可调的全身性抗肿瘤宿主免疫 反应减轻了转移负担并防止复发。特定目标3将定义H火 治疗参数并确定其安全性利用生理和临床相关的安全性 胰腺癌的猪模型。这个目标将检验H火可以有效烧毁的假设 在生理和临床上相关的原位条件下的原位胰腺肿瘤。测试这个 假设，我们将利用新型的，原位的猪胰腺癌模型，具有多种多样的范围 预计会影响人类患者H火的功效的临床相关物理特性。