AGR2-superantigen vaccine conjugate for the treatment of pancreaticductal adenocarcinoma

项目概要/摘要 胰腺导管腺癌（PDAC）是最致命的癌症之一。存活率低主要是因为 由于PDAC诊断的晚期和缺乏有效的靶向治疗。虽然该领域的 免疫疗法显著增加了某些恶性肿瘤的总生存率，但它们并没有转化为 PDAC。这项研究计划的长期目标是开发一种新的癌症疫苗，用于治疗 PDAC。我们小组和其他人的初步研究表明，前梯度-2（AGR 2）蛋白，一种 蛋白质二硫键异构酶（PDI）家族成员，在PDAC肿瘤发生过程中被诱导， >90%的PDAC患者表达。AGR 2具有细胞内氧化折叠功能，也可从 细胞定位于PDAC细胞的表面并脱落到肿瘤微环境中。我们 假设AGR 2是PDAC靶向疫苗开发的可操作靶点，并将测试 使用新的免疫治疗候选药物的理论。链球菌促有丝分裂外毒素Z-2（SMEZ-2）， 化脓性链球菌是一种细菌超抗原（SAg），在抗原呈递上与MHC II分子结合 细胞（APC）的高亲和力。在初步研究中，我们产生了解毒的AGR 2-SMEZ-2缀合物， 我们假设这将刺激强有力的抗PDAC免疫应答。我们在初步研究中发现AGR 2- SMEZ-2在小鼠中产生强烈的抗AGR 2应答，并且没有显示出明显的毒性。阶段的目标 本研究的主要目的是：（1）证明AGR 2-SMEZ-2的体内抗PDAC功效，和（2）测量B和T 免疫小鼠中抗AGR 2应答的细胞生物标志物。在第一阶段取得成功后， 本研究的2个目的是：（1）显示AGR 2-SMEZ-2疫苗接种和体内检查点抑制之间的协同作用， (2)为了比较通过MHC II特异性结合介导的SMEZ-2与现有的免疫原性相比的上级免疫原性， 疫苗载体蛋白，和（3）确定AGR 2-SMEZ-2在体内的最佳剂量、时间表和毒理学特征。这项工作是创新的，因为我们将研究我们专有的AGR 2的抗PDAC机制， SMEZ-2疫苗，并表征不同小鼠模型中诱导的免疫应答。这项工作将 支持开发用于治疗PDAC的一流疫苗，PDAC是一种几乎没有存在的癌症。 治疗此外，我们预计这项研究将允许其他免疫疗法（即检查点）。 抑制）以在患者中有效提供PDAC应答。

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Poor survival rates are largely due to the late stage at which PDAC is diagnosed and a lack of effective targeted therapies. While the field of immunotherapy has significantly increased overall survival in some malignancies, they have not translated to PDAC. The long-term goal of this research program is to develop a novel cancer vaccine for the treatment of PDAC. Preliminary studies by our group and others have shown that the Anterior Gradient-2 (AGR2) protein, a member of the protein disulfide isomerase (PDI) family, is induced during PDAC oncogenesis and highly expressed in >90% of PDAC patients. AGR2 has intracellular oxidative folding function and is also released from the cell where it localizes to the surface of PDAC cells and is shed into the tumor microenvironment. We hypothesize that AGR2 is an actionable target for the development of a PDAC targeted vaccine and will test that theory using a new immunotherapy drug candidate. Streptococcal Mitogenic Exotoxin Z-2 (SMEZ-2) from Streptococcus pyogenes is a bacterial superantigen (SAg) that binds to MHC II molecules on antigen presenting cells (APCs) with high affinity. In preliminary studies we generated a detoxified AGR2-SMEZ-2 conjugate that we hypothesize will stimulate a robust anti-PDAC immune response. We found in preliminary studies that AGR2- SMEZ-2 generates a robust anti-AGR2 response in mice and displays no overt toxicity. The objectives of Phase 1 of this study are: (1) to demonstrate anti-PDAC efficacy of AGR2-SMEZ-2 in vivo, and (2) to measure B and T cell biomarkers of an anti-AGR2 response in vaccinated mice. Upon success in Phase 1, the objectives of Phase 2 of this study are: (1) to show synergy between AGR2-SMEZ-2 vaccination and checkpoint inhibition in vivo, (2) to compare the superior immunogenicity of SMEZ-2 mediated through MHC II-specific binding over existing vaccine carrier proteins, and (3) to determine the optimal dose, schedule, and toxicology profile of AGR2-SMEZ-2 in vivo. This work is innovative because we will investigate the anti-PDAC mechanism of our proprietary AGR2- SMEZ-2 vaccine and characterize the induced immune response in different mouse models. This work will support the development of a first-in-class vaccine for the treatment of PDAC, a cancer with few existing therapies. In addition, we expect that this study will allow for other immunotherapies (namely checkpoint inhibition) to become effective in providing a PDAC response in patients.