Irreversible Electroporation (IRE) Combined with CD40 Agonism as In Situ Vaccine Therapy for Pancreatic Cancer

高达40%的胰腺癌患者存在局部晚期胰腺癌（LAPC），定义为 局部（非转移性）但不可切除。这一患者亚群的治疗是一个特别明显的未满足需求。 不可逆电穿孔（IRE）是一种越来越多地用于消融持续性LAPC的技术 全身治疗后。我们的小组已经证明，IRE可以作为一种“原位疫苗”，通过释放 在炎症环境中的肿瘤新抗原，从而促进肿瘤的先天免疫应答的识别。 免疫系统CD 40是位于抗原呈递细胞上的免疫受体，其充当桥梁 先天免疫系统和宿主对新抗原的特异性反应（适应性免疫）之间的关系 系统）。使用具有免疫活性的胰腺癌原位小鼠模型，我们已经表明， IRE与局部递送CD 40激动性抗体（CD 40 Ab）的组合可以改善局部效应 IRE和减少肝脏转移性疾病。ADC-1013（mitazalimab）是一种CD 40抗体，目前在 正在临床试验中作为转移性胰腺癌的全身治疗方法进行研究。它也已经交付 通过局部（瘤内）注射到各种浅表和深部肿瘤中。局部（瘤内）递送是 吸引人之处在于它具有更有效同时减少全身副作用的潜力。瘤内注射 在IRE时也是可行的，IRE通常通过开放手术方法进行。我们假设 LAPC患者IRE时局部给予CD 40激动剂可增强全身免疫功能， IRE的作用，增强局部疾病控制，并最终减少远处复发。我们建议 在手术IRE时进行瘤内注射mitazalimab的I期研究，以确定 推荐的2期剂量，并为未来的研究建立初步疗效。与此同时，我们将执行 相关的研究，以确定这种组合是否可以产生对新抗原的免疫应答， 使用肿瘤活检的无偏生物信息学分析管道。我们的多学科团队是独一无二的 有资格进行拟议的研究。白色是一个外科肿瘤学家在加州大学圣地亚哥分校的临床专业知识， IRE及其实验室生成了初步数据。Wainberg博士是加州大学洛杉矶分校的医学肿瘤学家， 在免疫肿瘤学临床试验方面的专业知识，特别是CD 40激动剂。将从所有受试者中招募受试者 五个加州大学胰腺癌联盟中心。Schoenberger医生，在拉霍亚 免疫学研究所将协助从人类肿瘤样本中识别新抗原并进行测量 治疗后血液样本中的免疫反应。我们假设这种新的治疗方法 LAPC将被证明是安全的，其无进展生存期上级优于既往接受过治疗的患者 只有IRE。有了这些数据，白色和温伯格博士将能够很好地设计一个更大的多功能 中心的疗效研究，这一大型亚组的研究不足的胰腺癌患者。

Up to 40% of patients with pancreatic cancer present with locally advanced pancreas cancer (LAPC), defined as localized (non-metastatic) but unresectable. Treatment of this patient subset is a particularly glaring unmet need. Irreversible electroporation (IRE) is a technique that is being used increasingly for ablation of persistent LAPC after systemic therapy. Our group has demonstrated that IRE can function as an "in situ vaccine" by releasing tumor neoantigens in the setting of inflammation and thereby promoting recognition of the tumor by the innate immune system. CD40 is an immune receptor located on antigen-presenting cells that serves as a bridge between the innate immune system and the host’s specific response to neoantigens (the adaptive immune system). Using immunocompetent orthotopic mouse models of pancreatic cancer, we have shown that the combination of IRE with local delivery of a CD40 agonistic antibody (CD40 Ab), can both improve the local effects of IRE and decrease metastatic disease in the liver. ADC-1013 (mitazalimab) is a CD40 antibody that is currently being studied in clinical trials as a systemic therapy for metastatic pancreatic cancer. It has also been delivered by local (intratumoral) injection into a variety of superficial and deep tumors. Local (intratumoral) delivery is appealing in that it has potential to be more effective while decreasing systemic side effects. Intratumoral injection is also feasible at the time of IRE, which is generally performed via an open surgical approach. We hypothesize that local delivery of a CD40 agonist at the time of IRE in patients with LAPC will augment the systemic immune effects of IRE, enhance local disease control, and ultimately decrease distant recurrence. We propose to conduct a phase I study of intratumoral mitazalimab injection at the time of surgical IRE to determine a recommended Phase 2 dose and establish preliminary efficacy for future studies. In parallel, we will perform correlative studies to determine if this combination can generate immune responses to neoantigens identified using an unbiased bioinformatic analysis pipeline of tumor biopsies. Our multi-disciplinary team is uniquely qualified to conduct the proposed studies. Dr. White is a surgical oncologist at UCSD with clinical expertise in IRE and whose laboratory generated the preliminary data. Dr. Wainberg is a medical oncologist at UCLA with expertise in immuno-oncology clinical trials and specifically CD40 agonists. Subjects will be recruited from all five of the University of California Pancreatic Cancer Consortium centers. Dr. Schoenberger, at the La Jolla Institute for Immunology, will assist with neoantigen identification from human tumor samples and measurement of immune responses in post-treatment blood samples. We hypothesize that this novel approach to the treatment of LAPC will prove to be safe, and result in progression-free survival superior to that of patients previously treated with IRE alone. With these data in hand, Drs. White and Wainberg will be well-positioned to design a larger multi- center efficacy study for this large subgroup of understudied pancreatic cancer patients.