AGR2-superantigen vaccine conjugate for the treatment of pancreaticductal adenocarcinoma

项目摘要/摘要 胰腺导管腺癌(PDAC)是最致命的癌症之一。低存活率在很大程度上是 由于诊断PDAC的时间较晚，缺乏有效的靶向治疗。而这一领域 免疫疗法显著提高了一些恶性肿瘤的总存活率，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来治疗癌症 PDAC。我们等人的初步研究表明，前梯度-2(AGR2)蛋白是一种 蛋白二硫键异构酶(PDI)是蛋白二硫键异构酶(PDI)家族中的一员，在PDAC的癌变过程中被诱导，并高度 在90%的PDAC患者中有表达。AGR2具有细胞内氧化折叠功能，也可从 定位于PDAC细胞表面并进入肿瘤微环境的细胞。我们 假设AGR2是开发PDAC靶向疫苗的一个可操作的目标，并将测试 理论上使用了一种新的免疫治疗候选药物。链球菌有丝分裂外毒素Z-2(SMEZ-2) 化脓性链球菌是一种细菌超抗原，在抗原呈递时与MHC II分子结合。 具有高亲和力的细胞(APC)。在初步研究中，我们产生了一种解毒的AGR2-SMEZ-2结合物 我们假设会刺激一种强大的抗PDAC免疫反应。我们在初步研究中发现AGR2- SMEZ-2在小鼠中产生强大的抗AGR2反应，并且没有明显的毒性。阶段性目标 本研究的第一项工作是：(1)验证AGR2-SMEZ-2的体内抗PDAC效果；(2)测定B和T 免疫小鼠中抗AGR2反应的细胞生物标记物。在第一阶段取得成功后，阶段的目标 本研究的两个方面是：(1)为了显示AGR2-SMEZ-2疫苗接种与体内检查点抑制之间的协同作用， (2)比较MHC II特异性结合介导的SMEZ-2的免疫原性。 疫苗载体蛋白，以及(3)确定AGR2-SMEZ的最佳剂量、程序和毒理学特征- 2活体内。这项工作具有创新性，因为我们将研究我们专有的AGR2的反PDAC机制- SMEZ-2疫苗，并研究其在不同小鼠模型中诱导的免疫应答。这项工作将 支持开发治疗PDAC的一流疫苗，PDAC是一种几乎不存在的癌症 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)，以便在患者中有效地提供PDAC反应。

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.