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

不可逆电穿孔 (IRE) 联合 CD40 激动作为胰腺癌原位疫苗治疗

• 批准号: 10718057
• 负责人: Stephen Philip Schoenberger
• 金额: $ 62.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718057
• 关键词: 3-Dimensional; Ablation; Adaptive Immune System; Adjuvant; Advanced Malignant Neoplasm; Aftercare; Agonist; Alligators; Antibodies; Antigen-Presenting Cells; Attention; Bioinformatics; Biological Sciences; Biopsy; Blood specimen; California; Clinical; Clinical Trials; Coculture Techniques; Correlative Study; Data; Disease; Distant; Dose; Electroporation; Future; Hand; Human; Immune; Immune response; Immunocompetent; Immunologic Adjuvants; Immunologic Markers; Immunologic Receptors; Immunology; Immunooncology; Implant; Inflammation; Inflammatory; Injections; Innate Immune System; KPC model; Laboratories; Laparotomy; Liver; Localized Disease; Malignant neoplasm of pancreas; Marketing; Measurement; Measures; Medical Oncologist; Metastatic Neoplasm to the Liver; Methods; Modeling; Mus; Nonmetastatic; Nucleic Acids; Operative Surgical Procedures; Organoids; Pancreas; Pancreatic Ductal Adenocarcinoma; Patient Recruitments; Patient Selection; Patients; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Phase; Plasma; Positioning Attribute; Progression-Free Survivals; Qualifying; Recommendation; Recurrence; Registries; Reporting; Research; Safety; Sampling; Subgroup; Surgical Oncologist; Systemic Therapy; T cell response; T-Lymphocyte; TNFRSF5 gene; Techniques; Technology; Time; Toxic effect; Tumor-Derived; Universities; Unresectable; Vaccine Therapy; adaptive immune response; advanced pancreatic cancer; analysis pipeline; anti-tumor immune response; antitumor effect; burden of illness; cancer clinical trial; cytokine; cytokine release syndrome; design; disorder control; efficacy study; enzyme linked immunospot assay; experience; first-in-human; human study; improved; in situ vaccine; mouse model; multidisciplinary; neoantigens; novel strategies; pancreatic cancer model; pancreatic cancer patients; patient subsets; phase 1 study; pre-clinical; preclinical study; primary endpoint; receptor; recruit; response; scale up; secondary endpoint; side effect; treatment response; tumor; tumor ablation; ultrasound

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.

多达40％的胰腺癌患者患有局部晚期胰腺癌（LAPC），定义为 局部（非转移性），但无法切除。该患者子群的治疗是一个特别明显的未满足需求。 不可逆的电穿孔（IRE）是一种越来越多地用于消融持续LAPC的技术 全身治疗后。我们的小组已经证明，IRE可以通过释放来充当“原位疫苗” 肿瘤新抗原在炎症的情况下，从而促进先天性的肿瘤识别 免疫系统。 CD40是位于抗原呈递细胞上的免疫接收器，用作桥梁 在先天免疫系统和宿主对新抗原的特定反应之间（适应性免疫） 系统）。使用胰腺癌的免疫能力的原位小鼠模型，我们表明 IRE与局部递送CD40激动剂抗体（CD40 AB）的结合都可以改善局部效应 生气和减少肝脏转移性疾病。 ADC-1013（Mitazalimab）是一种CD40抗体，目前是 在临床试验中研究了转移性胰腺癌的全身疗法。它也已交付 由局部（肿瘤内）注射到各种表面和深肿瘤中。局部（肿瘤内）分娩 有吸引力的情况下，它有可能在减少系统性副作用的同时更加有效。肿瘤内注射 在IRE时也是可行的，这通常是通过开放手术方法进行的。我们假设 在LAPC患者IRE时，在IRE时的局部交付CD40激动剂将增强全身免疫力 IRE的影响，增强局部疾病控制，并最终减少遥远的复发。我们建议 在手术IRE时进行肿瘤内Mitazalimab注射的I期研究以确定A 推荐的第2阶段剂量并建立了未来研究的初步效率。同时，我们将执行 相关研究以确定这种组合是否可以产生对新抗原的免疫反应 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特的 有资格进行拟议的研究。怀特博士是UCSD的外科肿瘤学家，拥有临床专业知识 IRE，其实验室产生了初步数据。 Wainberg博士是加州大学洛杉矶分校的医学肿瘤学家 免疫肿瘤临床试验，特别是CD40激动剂方面的专业知识。主题将从所有人中招募 加利福尼亚大学胰腺癌财团中心的五个。 Schoenberger博士，在La Jolla 免疫学研究所将帮助从人类肿瘤样品中鉴定新抗原和测量 治疗后血液样本中的免疫反应。我们假设这种新颖的治疗方法 LAPC的证明将是安全的，并且导致无进度的生存率优于先前治疗的患者 掌握这些数据，Drs。白色和温伯格将有充分的位置，以设计较大的多种多样 对这一大量理解的胰腺癌患者的大型亚组的中心效率研究。