Combining Irreversible Electroporation with Immunotherapy for the Systemic Treatment of Pancreatic Cancer

不可逆电穿孔与免疫疗法相结合用于胰腺癌的全身治疗

• 批准号: 10737800
• 负责人: Rebekah White
• 金额: $ 14.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-20 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737800
• 关键词: Ablation; Abscopal effect; Adjuvant; Adjuvant Therapy; Agonist; Antibodies; Biology; CD8-Positive T-Lymphocytes; Cells; Cellular Assay; Cicatrix; Clinical; Clinical Trials; Combined Modality Therapy; Contralateral; Country; DNA delivery; Data; Dendritic Cells; Diagnosis; Disease; Distant; Effector Cell; Electroporation; Fibrosis; Future; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunocompromised Host; Immunodeficient Mouse; Immunologic Adjuvants; Immunotherapeutic agent; Immunotherapy; Implant; Infiltration; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Invaded; Laboratories; Localized Disease; Malignant neoplasm of pancreas; Metastatic Neoplasm to the Liver; Methods; Modeling; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Organoids; Patient-Focused Outcomes; Patients; Pre-Clinical Model; Proteins; RNA; Radiation therapy; Recurrence; Research; Specimen; T cell response; T-Cell Activation; T-Lymphocyte; TLR7 gene; TNFRSF5 gene; Techniques; Therapeutic; Toll-like receptors; Tumor Immunity; Tumor-infiltrating immune cells; adaptive immune response; advanced pancreatic cancer; anti-tumor immune response; antigen-specific T cells; cancer immunotherapy; candidate identification; checkpoint inhibition; clinical care; clinically relevant; design; immune cell infiltrate; improved; in situ vaccine; irradiation; mouse model; multidisciplinary; neoantigens; new growth; novel; pancreatic cancer model; pancreatic cancer patients; patient derived xenograft model; pre-clinical; prevent; prophylactic; reconstitution; response; subcutaneous; treatment response; tumor; tumor ablation; tumor growth; tumor microenvironment; voltage

Abstract The goal of cancer immunotherapy is to utilize the patient’s immune system to reject the invading “foreign” tumor. However, the pancreatic cancer microenvironment is characterized by an abundance of immunosuppressive cells and a dense stroma that prevents infiltration of anti-tumor immune cells. Electroporation is a technique that has been utilized for decades in the laboratory; electrical voltage is applied to cells to make holes for delivery of DNA and RNA. Irreversible electroporation (IRE) is a technique now being used clinically for ablation of localized tumors that cannot be removed surgically (locally advanced tumors). Our objective is to use IRE as an "in situ vaccine" to help the host recognize foreign tumor proteins (neoantigens) and generate anti-tumor immune responses that will decrease recurrence rates. We have utilized mouse models of pancreatic cancer to show that IRE generates anti-tumor immune cells that prevent growth of new tumors (prophylactic immunity). We hypothesize that combining IRE with agents that augment the immune response will result in inhibition of established, distant tumors (therapeutic immunity or “abscopal” effects). In Aim 1, we will use mouse models to compare the effects of IRE to radiation therapy (XRT), as this is the most relevant clinical comparator. Both methods are used clinically for the ablation (killing) of locally advanced pancreatic cancer but have been shown stimulate systemic immune responses in preclinical models. We hypothesize that IRE will induce stronger immune responses because XRT causes fibrosis (scarring) that will inhibit immune cell infiltration. In Aim 2, we will combine local ablation with local delivery of agents that stimulate the innate immune system in mouse models of metastatic pancreatic cancer. In Aim 3, we will use a novel model in which human tumors and their associated immune cells are implanted into immunocompromised mice in order to create a “humanized” immune system. We will use this model to study the effects of IRE on human tumors. We have assembled a multi-disciplinary team that encompasses broad expertise in IRE, mouse tumor models, stromal biology, immunotherapy, clinical trials, and clinical care of patients with pancreatic cancer. We envision that the combination of IRE with immunotherapy will be first beneficial to patients with locally advanced pancreatic cancer. However, if effective, this approach may also be beneficial to patients with metastatic disease. Since the IRE technique is already in use clinically, a clinical trial in which one or more of the agents to be studied is delivered during or after IRE as adjuvant therapy would likely be feasible in the near future. We will use data from the proposed research to design such a study.

摘要 癌症免疫治疗的目标是利用患者的免疫系统来拒绝入侵的“外来” 肿瘤然而，胰腺癌微环境的特征是大量的 免疫抑制细胞和致密的基质，防止抗肿瘤免疫细胞的浸润。 电穿孔是一种已经在实验室中使用了几十年的技术;施加电压， 让细胞产生孔洞来输送DNA和RNA。不可逆电穿孔（IRE）是目前研究较多的一种技术 临床上用于消融不能手术切除的局部肿瘤（局部晚期 肿瘤）。我们的目标是将IRE作为一种“原位疫苗”，帮助宿主识别外源肿瘤蛋白 （新抗原）并产生抗肿瘤免疫应答，这将降低复发率。我们有 利用胰腺癌小鼠模型显示，IRE产生抗肿瘤免疫细胞， 新肿瘤的生长（预防性免疫）。我们假设IRE与能够增强 免疫应答将导致对已建立的远处肿瘤的抑制（治疗性免疫或 “远位”效应）。在目标1中，我们将使用小鼠模型来比较IRE与放射治疗的效果 (XRT)，因为这是最相关的临床对照药物。这两种方法在临床上都用于消融 （杀死）局部晚期胰腺癌，但已显示刺激全身免疫反应， 临床前模型。我们假设IRE将诱导更强的免疫应答，因为XRT会引起 纤维化（疤痕），这将抑制免疫细胞浸润。在目标2中，我们将联合收割机局部消融与 在转移性胰腺癌的小鼠模型中递送刺激先天免疫系统的药剂。 在目标3中，我们将使用一种新的模型，其中植入了人类肿瘤及其相关的免疫细胞 植入免疫缺陷小鼠体内，以创造一个“人源化”的免疫系统。我们将利用这一模式， 研究IRE对人类肿瘤的影响。我们组建了一个多学科团队， 在IRE、小鼠肿瘤模型、基质生物学、免疫治疗、临床试验和临床护理方面的广泛专业知识 胰腺癌的患者。我们设想IRE与免疫疗法的结合将是第一个 对局部晚期胰腺癌患者有益。然而，如果有效，这种方法还可以 对转移性疾病患者有益。由于IRE技术已经在临床上使用， 在IRE期间或之后给予一种或多种待研究药物作为辅助治疗的临床试验 在不久的将来，这种疗法可能是可行的。我们将使用拟议研究中的数据来设计 这样的研究。