Optimized ex vivo expansion of anti-tumor Th1 and Tc1 for adoptive immunotherapy

用于过继免疫治疗的抗肿瘤 Th1 和 Tc1 的优化离体扩增

基本信息

批准号：
8720513
负责人：
PETER A COHEN
金额：
$ 57.01万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720513
关键词：
Adoptive Immunotherapy Agonist Animals Antigen-Presenting Cells Antigens Autologous Autologous Dendritic Cells Autologous Tumor-Infiltrating Lymphocyte Avidity Back Binding Blood Breast CD3 Antigens CD4 Positive T Lymphocytes CD8B1 gene Cancer Patient Cell Culture Techniques Cell Line Cell Survival Cells Clinical Clinical Trials Cytolysis Cytotoxic T-Lymphocytes Data Dendritic Cells Dose ERBB2 gene Epitopes Exposure to Figs - dietary Funding Goals Granulocyte-Macrophage Colony-Stimulating Factor Home environment Human Immune Targeting Immune response Immunity Immunization Immunotherapy In Vitro Inflammatory Infusion procedures Interferons Interleukin-12 Interleukin-2 Interleukin-7 Investigation Left Life Lymphocyte MHC Class II Genes Malignant Neoplasms Methods Modeling Mononuclear Mus Outcome Patients Peptide Vaccines Peptides Performance Peripheral Blood Mononuclear Cell Physiologic pulse Process Proteins Reporting Research Personnel Serum Solid Source Staging T cell response T-Cell Proliferation T-Lymphocyte T-Lymphocyte Epitopes TLR4 gene TLR8 gene Testing Th1 Cells Therapeutic Time Transfection Tumor Antigens Tumor Escape Tumor Expansion Tumor-Infiltrating Lymphocytes Vaccinated Vaccination Vaccines Variant cancer type cell type chemotherapy clinically relevant cytokine improved innovation malignant breast neoplasm melanoma neoplastic cell novel overexpression peripheral blood programs response success tumor

项目摘要

DESCRIPTION (provided by applicant): Recent clinical trials have demonstrated that advanced melanoma can be treated with a combination of nonmyeloablative chemotherapy and autologous adoptive T cell immunotherapy (AIT) to achieve a 50% clinical response rate. Such clinical responses are not, however, consistently durable. Cytotoxic T cells (CTL) are shortlived in the absence of T cell help (Th), with limited persistence after infusion. Furthermore, antigen (Ag) negative variants develop after infusion of CD8+ predominant tumor specific T cell lines, suggesting tumors readily escape from focused therapy. Our goal is to optimize and extend AIT to advanced breast cancer by providing functionally characterized tumor Ag-specific CD4+ Th1 cells as a central component of the infused product. Tumor Ag-specific CD4+ Th1 cells can home to tumor and secrete inflammatory cytokines, modulating the microenvironment to enhance the function of local antigen presenting cells (APC). The resultant increased processing of endogenous tumor cells results in epitope spreading. By providing a robust CD4+ Th1 immune response, tumor Ag-specific CD8+ T cells will be elicited, and the response generated will be long lived. We aim to promote tumor-specific, epitope spreading, Th1-type CD4+ responses as an essential component of effective AIT. This strategy has been validated by our own vaccine trials for Stage III/IV patients with HER-2/neu (HER2)-overexpressing breast cancer. Patients vaccinated with MHC Class II-binding HER2-derived peptides evidenced a significant survival advantage if they achieved not only enhanced CD4+ T cell responses to vaccine peptides, but also T cell responses to additional HER2 epitopes expressed by their tumors but absent from the vaccine. In animal studies we observe that the inclusion of autologous dendritic cells (DCs) during T cell culture can markedly improve T cell therapeutic performance at the time of re-infusion. Moreover, appropriately activated DCs can promote the expansion of T cells with higher functional avidity, including CD8+ cytolytic T cells that can directly lyse MHC-restricted tumors. We propose to develop a clinically relevant method to expand HER2 specific T cells ex vivo, using optimally activated autologous DC generated simultaneously in the same cultures as the T cells to be activated. We will also assess whether these culture methods increase epitope spreading.

描述（由申请人提供）：最近的临床试验表明，晚期黑色素瘤可以通过非甲状腺素化学疗法和自体产卵T细胞免疫疗法（AIT）的结合来治疗，以达到50％的临床反应率。但是，这种临床反应并非一致地持久。在缺乏T细胞帮助的情况下，细胞毒性T细胞（CTL）短暂存在，输注后持久性有限。此外，在输注CD8+主要的肿瘤特异性T细胞系后会出现抗原（Ag）阴性变异，这表明肿瘤很容易从聚焦治疗中逸出。我们的目标是通过提供功能表征的肿瘤AG特异性CD4+ Th1细胞作为注入产品的核心组成部分，优化并扩展到晚期乳腺癌。肿瘤AG特异性CD4+ TH1细胞可以回家肿瘤并分泌炎症细胞因子，调节微环境以增强局部抗原呈递细胞（APC）的功能。由此增加的内源性肿瘤细胞的加工导致表位扩散。通过提供鲁棒的CD4+ TH1免疫反应，将引起肿瘤Ag特异性CD8+ T细胞，并将长期存在。我们旨在促进肿瘤特异性，表位扩散，Th1型CD4+反应是有效AIT的重要组成部分。通过我们自己的疫苗试验对HER-2/NEU（HER2）过表达乳腺癌的III/IV患者的疫苗试验已经验证了该策略。如果他们不仅获得了对疫苗肽的CD4+ T细胞反应增强，还可以增强对肿瘤表达的其他HER2表位的反应，而是疫苗不存在的其他HER2表位，则用MHC II类结合的HER2衍生肽接种的患者证明了显着的生存优势。在动物研究中，我们观察到在T细胞培养过程中纳入自体树突状细胞（DC）可以显着改善T细胞的治疗性能。此外，适当活化的DC可以促进具有较高功能性感的T细胞的扩展，包括可以直接裂解MHC限制性肿瘤的CD8+细胞溶解T细胞。我们建议使用与要激活的T细胞同时生成的最佳激活自体DC，开发一种临床相关的方法，以在体内扩展HER2特异性T细胞。我们还将评估这些培养方法是否会增加表位扩展。