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

摘要 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“异物” 肿瘤。然而，胰腺癌的微环境具有丰富的 免疫抑制细胞和致密的基质，防止抗肿瘤免疫细胞的渗透。 电穿孔是一种在实验室中已经使用了几十年的技术；施加电压 到细胞上，为DNA和RNA的输送打洞。不可逆电穿孔(Ire)是现在的一种技术。 临床上用于消融不能通过手术切除的局部肿瘤(局部晚期 肿瘤)。我们的目标是使用IRE作为一种“原位疫苗”来帮助宿主识别外源肿瘤蛋白。 (新抗原)，并产生抗肿瘤免疫反应，从而降低复发率。我们有 利用小鼠胰腺癌模型显示，IRE产生抗肿瘤免疫细胞，防止 新肿瘤的生长(预防性免疫)。我们假设把IRE和那些能增强 免疫反应将导致对已建立的、远处肿瘤的抑制(治疗性免疫或 “非范围”效应)。在目标1中，我们将使用小鼠模型来比较IRE和放射治疗的效果 (XRT)，因为这是最相关的临床参照物。这两种方法都用于临床消融。 (杀死)局部晚期胰腺癌，但已被证明能刺激全身免疫反应 临床前模型。我们假设IRE会引起更强的免疫反应，因为XRT导致 纤维化(疤痕形成)会抑制免疫细胞的渗透。在目标2中，我们将局部消融与局部消融相结合。 在转移性胰腺癌小鼠模型中传递刺激先天免疫系统的药物。 在目标3中，我们将使用一种新的模型，在该模型中，人类肿瘤及其相关的免疫细胞被植入 转化为免疫功能受损的小鼠，以创造出一种“人性化”的免疫系统。我们将使用此模型来 研究IRE对人类肿瘤的影响。我们已经组建了一个多学科团队，包括 在IRE、小鼠肿瘤模型、间质生物学、免疫疗法、临床试验和临床护理方面具有广泛的专业知识 胰腺癌患者的比例。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，这种方法也可能 有益于转移性疾病患者。由于IRE技术已经在临床上使用，一种 临床试验：一种或多种待研究药物在IRE期间或之后作为佐剂给予的临床试验 在不久的将来，治疗很可能是可行的。我们将使用拟议研究的数据来设计 这样的研究。

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.