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：在美国，胰腺癌约占所有癌症的 3% 约占所有癌症相关死亡的 7%。迫切需要新的治疗范例。新兴 肿瘤消融技术已显示出巨大的前景。该提案将重点关注高频 不可逆电穿孔 (H-FIRE)，通过插入的电极传递一系列电脉冲 直接进入肿瘤，在靶细胞膜上产生结构缺陷，导致癌细胞死亡。 该提案的目的是利用我们的小鼠和新型猪临床前动物模型来扩展 本提案中提供的初步数据并生成关键的机械、安全性和有效性数据 对于支持未来在胰腺癌患者中进行 H-FIRE 临床试验是必要的。我们的总体假设 H-FIRE 将有效减轻生理和临床相关胰腺的异质性 肿瘤，通过治疗导致关键组织结构附近的连续消融区域。我们进一步 假设 H-FIRE 的好处最终将超越局部肿瘤消融并产生 可预测、可调节的全身抗肿瘤免疫反应，减少转移负担并预防 复发。具体目标 1 将表征胰腺癌细胞的生物物理反应和 组织 H-FIRE。该目标将评估 H-FIRE 脉冲参数可以调整为 实现高度相关的不同细胞死亡结果（细胞凋亡、焦亡、坏死性凋亡或坏死） 肿瘤消融、肿瘤微环境和抗肿瘤免疫反应。我们将一致评估 使用傅立叶分析光谱 (FAST) 进行实时治疗反馈的消融开发。我们 期望确定哪些参数（即脉冲宽度、通电时间、相间/脉冲间延迟）发挥作用 在调节相关癌细胞系和离体组织内引起的细胞死亡方面发挥着重要作用。具体目标 2 将建立 H-FIRE 胰腺癌治疗策略，优化肿瘤消融和 全身抗肿瘤免疫反应。使用 Pan02 小鼠模型，该目标将检验以下假设： H-FIRE 是一种在体内精确、彻底消融胰腺肿瘤的有效治疗方式。我们也 假设由于 H-FIRE 介导的细胞死亡和由此产生的肿瘤变化的独特特征 微环境中，局灶性肿瘤消融将产生可预测和可调节的全身抗肿瘤宿主免疫 缓解转移负担并预防复发。具体目标 3 将定义 H-FIRE 治疗参数并利用生理和临床相关性确定其安全性 猪胰腺癌模型。该目标将检验 H-FIRE 可以有效消融的假设 生理学和临床相关的原位条件下的原位胰腺肿瘤。为了测试这个 假设，我们将利用具有多种特征的新型原位猪胰腺癌模型 预计会影响 H-FIRE 对人类患者疗效的临床相关物理特性。