TCR Transduced CD4+ T Cells for Adoptive Immunotherapy

TCR 转导的 CD4 T 细胞用于过继免疫治疗

• 批准号: 8555358
• 负责人: MICHAEL I. NISHIMURA
• 金额: $ 26.95万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555358
• 关键词: Adoptive Immunotherapy; Adoptive Transfer; Affinity; Antigens; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cells; Clinical; Clinical Trials; Cytolysis; Data; Effectiveness; Engineering; Epitopes; Gene Transfer; Gene-Modified; Goals; HLA-A2 Antigen; Histocompatibility Antigens Class I; Human; Human Engineering; Immune response; In Vitro; Infusion procedures; Lead; Learning; Lesion; Licensing; MHC Class I Genes; Mediating; Modeling; Monophenol Monooxygenase; Mus; Peptides; Physiological; Population; Property; Publishing; Regimen; Relative (related person); Reporting; Role; Source; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; Testing; Tumor Antigens; Tumor Immunity; Tumor-Infiltrating Lymphocytes; base; cellular engineering; cellular transduction; cytokine; improved; in vivo; melanoma; neoplastic cell; novel; preconditioning; response; tumor

In our original studies, we first described the ability to generate MHC class I restricted CD4+ T cells by retrovirally transduced normal T cells with MHC class I restricted TCR genes. We subsequently showed that if the TCR had sufficient affinity, the resulting MHC class 1 restricted CD4+ T cells could recognize physiologic levels of antigen expressed by tumor cells. Therefore, these novels T cells could augment the anti-tumor immune response by helping to prime the host immune response in tumor lesions. They could also promote the persistence and function of adoptively transferred CD8+ T cells. However, nothing is known about the biology of TCR transduced CD4+ T cells in vivo and their impact on the CD8+ T cells in vitro or in vivo. We have preliminary data that shows this novel population actually inhibits CD8+ T cell priming which would be contrary to their desired function. The goal of this project is to acquire a better understanding of the role of MHC class 1 restricted CD4+ T cells in anti-tumor immunity. Our central hypothesis is that MHC class I restricted, TCR transduced CD4+ T cells can be made to augment the antitumor immune response by CD8+ T cells. We predict this will occur by inducing them to become potent Th cells capable of licensing DC to prime CD8+ T cells in vitro. We further predict that MHC class I restricted, TCR transduced CD4+ T cells can be made promote the persistence and function of TCR transduced CD8+ T cells in vivo. These hypotheses/predictions will be tested using a combination of mouse and human CD4+ T cells transduced to express the TIL 13831 TCR. These TCR transduced CD4+ T cells, which recognize the tyrosinase: 368-376 epitope presented by HLA-A2, will be compared to their normal mouse or human counterparts for their ability secrete cytokines, license DC to prime/activate naive and TCR transduced CD8+ T cells, and mediate tumor regression in vivo.

在我们最初的研究中，我们首先描述了通过以下方式产生 MHC I 类限制性 CD4+ T 细胞的能力： 逆转录病毒转导带有 MHC I 类限制性 TCR 基因的正常 T 细胞。我们随后证明，如果 TCR 具有足够的亲和力，所得的 MHC 1 类限制性 CD4+ T 细胞可以识别肿瘤细胞表达的抗原的生理水平。因此，这些新型 T 细胞可以通过帮助启动肿瘤病变中的宿主免疫反应来增强抗肿瘤免疫反应。它们还可以促进过继转移的 CD8+ T 细胞的持久性和功能。 然而，对于 TCR 转导的 CD4+ T 细胞在体内的生物学及其对体外或体内 CD8+ T 细胞的影响一无所知。我们的初步数据表明，这个新群体实际上抑制了 CD8+ T 细胞的启动，这与其预期的功能相反。该项目的目标是更好地了解 MHC 1 类限制性 CD4+ T 细胞在抗肿瘤免疫中的作用。我们的中心假设是，MHC I 类限制性、TCR 转导的 CD4+ T 细胞可以增强 CD8+ T 细胞的抗肿瘤免疫反应。我们预测这将通过诱导它们成为能够在体外授权 DC 启动 CD8+ T 细胞的强效 Th 细胞来实现。我们进一步预测，MHC I 类限制性 TCR 转导的 CD4+ T 细胞可以促进 TCR 转导的 CD8+ T 细胞在体内的持久性和功能。这些假设/预测将使用转导表达 TIL 13831 TCR 的小鼠和人类 CD4+ T 细胞的组合进行测试。这些 TCR 转导的 CD4+ T 细胞可识别 HLA-A2 呈递的酪氨酸酶：368-376 表位，将与正常小鼠或人类对应细胞分泌细胞因子、许可 DC 启动/激活初始和 TCR 转导的 CD8+ T 细胞以及介导体内肿瘤消退的能力进行比较。