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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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的癌症免疫治疗的目标是利用患者的免疫系统来排斥入侵的“外来物” 瘤。然而，胰腺癌微环境的特点是存在丰富的免疫抑制细胞和防止抗肿瘤免疫细胞浸润的致密基质。电穿孔技术已在实验室中使用了数十年。施加电压为细胞打孔以输送 DNA 和 RNA。不可逆电穿孔（IRE）现在是一种技术临床上用于消融无法手术切除的局部肿瘤（局部晚期肿瘤）。我们的目标是利用IRE作为“原位疫苗”来帮助宿主识别外来肿瘤蛋白（新抗原）并产生抗肿瘤免疫反应，从而降低复发率。我们有利用胰腺癌小鼠模型表明 IRE 产生抗肿瘤免疫细胞，可预防新肿瘤的生长（预防性免疫）。我们假设将 IRE 与增强剂相结合免疫反应将抑制已建立的远处肿瘤（治疗性免疫或 “远隔”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比较器。这两种方法在临床上均用于消融（杀死）局部晚期胰腺癌，但已被证明可以刺激全身免疫反应临床前模型。我们假设 IRE 会诱导更强的免疫反应，因为 XRT 会导致纤维化（疤痕）会抑制免疫细胞浸润。在目标 2 中，我们将局部消融与局部消融结合起来。在转移性胰腺癌小鼠模型中递送刺激先天免疫系统的药物。在目标 3 中，我们将使用一种新模型，其中植入人类肿瘤及其相关免疫细胞注入免疫功能低下的小鼠体内，以创建“人性化”的免疫系统。我们将使用这个模型来研究 IRE 对人类肿瘤的影响。我们组建了一支多学科团队，其中包括在 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拥有广泛的专业知识胰腺癌患者。我们预计 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，如果有效的话，这种方法也可能对患有转移性疾病的患者有益。由于IRE技术已经在临床上使用，在 IRE 期间或之后递送一种或多种待研究药物作为佐剂的临床试验治疗在不久的将来可能是可行的。我们将使用拟议研究的数据来设计这样的研究。