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: 10154535
• 负责人: Rebekah White
• 金额: $ 41.97万
• 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/10154535
• 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; 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-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; checkpoint inhibition; clinical care; clinically relevant; design; immunotherapy clinical trials; 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.

抽象的 癌症免疫疗法的目的是利用患者的免疫系统拒绝入侵的“外国” 瘤。但是，胰腺癌微环境的特征是丰富 免疫抑制细胞和致密的基质，可防止抗肿瘤免疫细胞的浸润。 电穿孔是一种在实验室数十年来使用的技术。应用电子电压 到细胞制作孔以递送DNA和RNA。不可逆的电穿孔（IRE）现在是一种技术 在临床上用于消融无法通过外科手术去除的局部肿瘤（局部先进 肿瘤）。我们的目的是将IRE用作“原位疫苗”来帮助宿主识别外国肿瘤蛋白 （新抗原）并产生抗肿瘤免疫反应，以降低复发率。我们有 利用胰腺癌的小鼠模型表明IRE会产生抗肿瘤免疫细胞，以防止 新肿瘤的生长（预防性免疫学）。我们假设将IRE与增加的代理结合在一起 免疫响应将导致抑制已建立的远处肿瘤（治疗性免疫学或 “脱离”效果）。在AIM 1中，我们将使用鼠标模型比较IRE与放射治疗的影响 （XRT），因为这是最相关的临床比较器。两种方法在临床上用于消融 （杀死）局部晚期胰腺癌，但已显示出刺激全身免疫反应 临床前模型。我们假设IRE会引起更强的免疫反应，因为XRT会导致 纤维化（疤痕）将抑制免疫球浸润。在AIM 2中，我们将将本地消融与当地结合 在转移性胰腺癌小鼠模型中刺激先天免疫系统的药物的递送。 在AIM 3中，我们将使用一种新型模型，其中人类肿瘤及其相关的免疫细胞被植入 进入免疫功能低下的小鼠，以创建“人性化”免疫系统。我们将使用此模型 研究愤怒对人肿瘤的影响。我们组建了一个涵盖的多学科团队 IRE，小鼠肿瘤模型，基质生物学，免疫疗法，临床试验和临床护理方面的广泛专业知识 患有胰腺癌的患者。我们设想愤怒与免疫疗法的结合将首先 对局部晚期胰腺癌患者有益。但是，如果有效，这种方法也可能 对转移性疾病患者有益。由于IRE技术已经在临床上使用了 临床试验，其中一个或多个要研究的代理在IRE期间或之后进行调整。 在不久的将来，治疗可能是可行的。我们将使用拟议研究的数据进行设计 这样的研究。