AGR2-superantigen vaccine conjugate for the treatment of pancreaticductal adenocarcinoma

AGR2-超抗原疫苗缀合物用于治疗胰导管腺癌

基本信息

批准号：
10857460
负责人：
Reeder McNeil Robinson
金额：
$ 78.27万
依托单位：
LEUKOGENE THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-17 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10857460
关键词：
Adenocarcinoma Affinity Animals Anterior Antibody titer measurement Antigen-Presenting Cells Antigens B-Lymphocytes Binding Biochemistry Biological Markers Blood C57BL/6 Mouse CTLA4 gene Cancer Model Cancer Vaccines Carrier Proteins Cell Line Cells Clinic Color Conjugate Vaccines Dependence Detection Development Diagnosis Dose Drug Metabolic Detoxication Effector Cell Enzyme-Linked Immunosorbent Assay Exotoxins Family Firefly Luciferases Flow Cytometry Goals Haemophilus influenzae Head Head of pancreas Histocompatibility Antigens Class II Histopathology Human Immune Immune Targeting Immune checkpoint inhibitor Immune response Immunohistochemistry Immunologic Markers Immunologics Immunophenotyping Immunosuppression Immunotherapy Implant Interleukin-6 KPC model Malignant Neoplasms Malignant neoplasm of pancreas Maximum Tolerated Dose Measures Mediating Modeling Monitor Mus Operative Surgical Procedures Pancreas Pancreatic Ductal Adenocarcinoma Patient-Focused Outcomes Patients Peptide/MHC Complex Phase Pre-Clinical Model Protein Disulfide Isomerase Proteins Radiation therapy Recombinants Research Schedule Serum Streptococcus Streptococcus pyogenes Superantigens Surface Surrogate Markers Survival Rate T cell response T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissues Toxic effect Toxicology Treatment Protocols Tumor Antigens Tumor Markers Tumor-Infiltrating Lymphocytes Vaccinated Vaccination Vaccines Work anti-CTLA4 antibodies anti-PD-1 anti-cancer bioluminescence imaging body system cancer therapy checkpoint inhibition chemotherapy clinical candidate clinical development cytokine release syndrome drug candidate effective therapy immune cell infiltrate immunogenic immunogenicity in vivo innovation member mouse model mutant novel overexpression pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm phase 1 study phase 2 study pre-clinical programs receptor binding response subcutaneous success synergism targeted treatment theories therapeutic vaccine tumor tumor growth tumor microenvironment tumor progression tumorigenesis vaccine candidate vaccine development vaccine immunotherapy vaccine strategy

项目摘要

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.

项目摘要/摘要胰腺导管腺癌（PDAC）是最致命的癌症之一。生存率差在很大程度上是由于诊断出PDAC的后期且缺乏有效的靶向疗法。而田野免疫疗法在某些恶性肿瘤中的总体生存率显着提高，它们尚未转化为 PDAC。该研究计划的长期目标是开发一种新型的癌症疫苗来治疗 PDAC。我们小组和其他人的初步研究表明，前梯度-2（AGR2）蛋白A，A PDAC肿瘤发生和高度在> 90％的PDAC患者中表示。 AGR2具有细胞内氧化折叠功能，也从它位于PDAC细胞表面并脱落到肿瘤微环境中的细胞。我们假设AGR2是开发PDAC靶向疫苗的可行靶标，并将测试该目标理论使用新的免疫疗法候选药物。来自链球菌有丝分裂外毒素Z-2（SMEZ-2）链球菌为链球菌是一种细菌超抗原（SAG），与MHC II分子结合抗原呈现具有高亲和力的细胞（APC）。在初步研究中，我们产生了一个排毒的Agr2-Smez-2结合物我们假设将刺激强大的抗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。阶段的目标这项研究的1是：（1）证明Agr2-Smez-2在体内的抗PDAC疗效，以及（2）测量B和T 接种小鼠的抗AGR2反应的细胞生物标志物。在第1阶段成功时，阶段的目标本研究的2个是：（1）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）比较通过现有的MHC II特异性结合介导的SMEZ-2的上级免疫原性疫苗载体蛋白和（3）以确定体内AgR2-Smez-2的最佳剂量，时间表和毒理学特征。这项工作具有创新性，因为我们将研究我们专有的Agr2-的抗PDAC机制 SMEZ-2疫苗并表征了不同小鼠模型中诱导的免疫反应。这项工作将支持开发一流的疫苗来治疗PDAC，PDAC是一种癌症疗法。此外，我们希望这项研究将允许其他免疫疗法（即检查点抑制）有效地在患者中提供PDAC反应。