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

• 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
• 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

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清髓性化疗和自体过继T细胞免疫治疗（AIT）的组合治疗，达到50%的临床反应率。然而，这种临床反应并不总是持久的。在没有T细胞帮助（Th）的情况下，细胞毒性T细胞（CTL）寿命很短，输注后持久性有限。此外，抗原（Ag）阴性变异在输注CD8+优势肿瘤特异性T细胞系后发生，表明肿瘤很容易逃避集中治疗。我们的目标是通过提供功能特征的肿瘤ag特异性CD4+ Th1细胞作为输注产品的核心成分，将AIT优化并扩展到晚期乳腺癌。肿瘤ag特异性CD4+ Th1细胞可归巢肿瘤并分泌炎性细胞因子，通过调节微环境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加工导致表位扩散。通过提供强大的CD4+ Th1免疫应答，肿瘤ag特异性CD8+ T细胞将被激发，并且产生的应答将长期存在。我们的目标是促进肿瘤特异性，表位扩散，th1型CD4+反应作为有效AIT的重要组成部分。我们自己针对HER2 /neu （HER2）过表达乳腺癌的III/IV期患者的疫苗试验证实了这一策略。如果接种MHC ii类结合HER2衍生肽的患者不仅获得增强的CD4+ T细胞对疫苗肽的反应，而且T细胞对肿瘤表达但疫苗中不存在的其他HER2表位的反应，则证明了显著的生存优势。在动物实验中，我们观察到在T细胞培养过程中加入自体树突状细胞（dc）可以显著提高T细胞再输注时的治疗性能。此外，适当激活的dc可以促进T细胞的扩增，具有更高的功能亲和性，包括CD8+细胞溶解T细胞，可以直接裂解mhc限制性肿瘤。我们建议开发一种临床相关的方法来体外扩增HER2特异性T细胞，使用与待激活T细胞在相同培养中同时产生的最佳活化的自体DC。我们还将评估这些培养方法是否会增加表位扩散。