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

高达40%的胰腺癌患者患有局部晚期胰腺癌(LAPC)，定义为 局部性(非转移性)但不能切除。这一患者亚群的治疗是一个特别明显的未得到满足的需求。 不可逆电穿孔(Ire)是一种越来越多地用于永久性LAPC消融的技术。 经过系统治疗后。我们的团队已经证明了IRE可以作为一种“原位疫苗”通过释放 肿瘤新抗原在炎症环境中的作用，从而促进先天对肿瘤的识别 免疫系统。CD40是一种位于抗原提呈细胞上的免疫受体，起着桥梁的作用 在先天免疫系统和宿主对新抗原的特异性反应之间(获得性免疫 系统)。使用免疫活性的原位小鼠胰腺癌模型，我们已经证明 IRE联合局部注射CD40激动型抗体(CD40-Ab)均可改善局部疗效 减少肝脏转移性疾病。ADC1013(Mitazalimab)是一种CD40抗体，目前 正在进行临床试验，作为转移性胰腺癌的全身疗法。它也已经交付了 通过局部(瘤内)注射到各种浅表和深层肿瘤中。局部(肿瘤内)分娩是 吸引力在于，它有可能在降低系统性副作用的同时更有效。瘤内注射 在IRE时也是可行的，IRE通常通过开放的外科入路进行。我们假设 在LAPC患者IRE时局部应用CD40激动剂将增强系统免疫。 IRE的效果，加强了局部疾病控制，并最终减少了远处复发。我们建议 手术时进行瘤内注射米他利玛单抗的I期研究，以确定 推荐的第二阶段剂量，并为未来的研究建立初步疗效。同时，我们将表演 相关研究确定这种组合是否能对已识别的新抗原产生免疫反应 使用一种无偏见的肿瘤活检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。怀特博士是加州大学圣迭戈分校的外科肿瘤学家，在 IRE和谁的实验室产生了初步数据。温伯格博士是加州大学洛杉矶分校的内科肿瘤学家 擅长免疫肿瘤学临床试验，特别是CD40激动剂。受试者将从所有 加州大学胰腺癌联盟的五个中心。勋伯格博士，在La Jolla 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。我们推测这种新的治疗方法 LAPC的治疗将被证明是安全的，并导致比以前治疗的患者更好的无进展生存 只带着愤怒。有了这些数据，怀特博士和温伯格博士将很好地设计一个更大的多 针对这一大群研究不足的胰腺癌患者的中心疗效研究。

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.