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.

在我们的最初研究中，我们首先描述了通过通过 用MHC I类限制的TCR基因逆转录了正常T细胞。随后，我们表明，如果TCR具有足够的亲和力，则由此产生的MHC 1类限制的CD4+ T细胞可以识别由肿瘤细胞表达的抗原的生理水平。因此，这些小说T细胞可以通过在肿瘤病变中帮助宿主免疫反应来增强抗肿瘤免疫反应。它们还可以促进采用转移的CD8+ T细胞的持久性和功能。 然而，关于体内TCR转导的CD4+ T细胞的生物学及其对CD8+ T细胞在体外或体内的影响一无所知。我们有初步数据显示，这种新的人群实际上抑制了CD8+ T细胞启动，这与其所需的功能相反。该项目的目的是更好地了解MHC 1类限制CD4+ T细胞在抗肿瘤免疫中的作用。我们的中心假设是，MHC I类限制了TCR转导的CD4+ T细胞以增强CD8+ T细胞的抗肿瘤免疫反应。我们预测，通过诱导它们成为能够在体外将DC许可获得Prime CD8+ T细胞的有效的TH细胞来实现这一目标。我们进一步预测，可以使TCR转导的CD4+ T细胞限制了MHC I类，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/预测将使用小鼠和人CD4+ T细胞的组合进行测试，以表达TIL 13831 TCR。这些TCR转导的CD4+ T细胞识别HLA-A2提出的酪氨酸酶：368-376表位，将其与其正常的小鼠或人类对应物进行比较，因为它们的能力分泌细胞因子，许可证DC可以启用/激活prime/激活幼稚和TCR转导的CD8+ T细胞，并介导Vivo中的肿瘤肿瘤回归。