Strategies to Enhance Adoptive Transfer T Cell Clones

增强过继转移 T 细胞克隆的策略

• 批准号: 7217915
• 负责人: STANLEY R. RIDDELL
• 金额: $ 38.36万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217915
• 关键词: Adoptive Immunotherapy; Adoptive Transfer; Antigen Targeting; Antigen-Presenting Cells; Antigens; CD8 Antigens; CD8B1 gene; Cell Survival; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Culture Techniques; Cytomegalovirus; Cytotoxic T-Lymphocytes; Goals; Growth; Human; IL2 gene; Immune; Immune response; Immunity; In Vitro; Infection; Infection Control; Infusion procedures; Interleukin-15; Interleukin-2; Interleukins; Lymphocyte; Lymphocyte Count; Macaca mulatta; Macaca nemestrina; Maintenance; Malignant Neoplasms; Modeling; Molecular Immunology; Numbers; Rodent Model; Safety; Specificity; T memory cell; T-Lymphocyte; Therapeutic; Translating; Treatment Efficacy; base; cancer therapy; cytokine; human disease; improved; in vivo; insight; migration; nonhuman primate; research study; response; tumor

DESCRIPTION (provided by applicant): Studies in rodent models of cancer and infectious diseases have demonstrated that the adoptive transfer of T cells of defined antigen specificity and function can establish or augment an immune response in vivo and provide therapeutic benefit, and there is increasing evidence that adoptive immunotherapy with T cells has therapeutic activity in human malignancies and infection. However, in most clinical studies the infusion of large numbers of cultured T cells or T cell clones has failed to completely eradicate tumors or provide long-term control of infection. This is in part due to the inability with current approaches to establish an immune response of sufficient magnitude and persistence by adoptive transfer for sustained therapeutic efficacy. Studies of cytokines such as IL15 that regulate lymphocyte growth and survival, and of homeostatic mechanisms that operate to maintain lymphocyte numbers but permit expansion of antigen-specific T cells in response to in vivo stimulation have provided insights into strategies that might be employed to better establish T cell immunity by the adoptive transfer of T cell clones. The goals of this proposal are to develop strategies that improve the establishment of a persistent high-level antigen-specific T cell response in vivo by the adoptive transfer of CD8+ T cell clones, and can be applied to clinical trials of T cell therapy for cancer. The studies will be performed in non-human primates (Macacca nemestrina), and utilize CD8+ T cell clones specific for rhesus cytomegalovirus (rhCMV) as a model target antigen. Culture techniques that are routinely used to propagate human T cells for clinical adoptive T cell therapy will be employed to improve our ability to directly translate the results to studies of T cell therapy for human malignancy and infection. The specific aims are: 1). To determine the effect of the in vivo administration of interleukin (IL2) and interleukin 15 (IL15) on the persistence, function, and migration of adoptively transferred CD8+ antigen-specific T cell clones. 2). To determine the effects of lymphodepletion prior to T cell transfer on the persistence, function, and migration of adoptively transferred CD8+ antigen-specific T cell clones. 3). To determine whether the magnitude and persistence of a CD8+ cytotoxic T cell response established by adoptive transfer can be enhanced by antigen stimulation in vivo.

描述（由申请人提供）：对癌症和传染病的啮齿动物模型的研究表明，具有确定的抗原特异性和功能的T细胞的过继转移可以在体内建立或增强免疫反应并提供治疗益处，并且越来越多的证据表明T细胞的过继免疫疗法对人类恶性肿瘤和感染具有治疗活性。然而，在大多数临床研究中，输注大量培养的T细胞或T细胞克隆未能完全根除肿瘤或提供对感染的长期控制。这部分是由于当前的方法无法通过过继转移建立足够强度和持久性的免疫反应以实现持续的治疗效果。对调节淋巴细胞生长和存活的细胞因子（例如 IL15）以及维持淋巴细胞数量但允许抗原特异性 T 细胞响应体内刺激而扩增的稳态机制的研究，为通过 T 细胞克隆的过继转移更好地建立 T 细胞免疫的策略提供了见解。该提案的目标是制定策略，通过 CD8+ T 细胞克隆的过继转移，改善体内持久高水平抗原特异性 T 细胞应答的建立，并可应用于癌症 T 细胞治疗的临床试验。这些研究将在非人类灵长类动物 (Macacca nemestrina) 中进行，并利用恒河猴巨细胞病毒 (rhCMV) 特异性的 CD8+ T 细胞克隆作为模型靶抗原。常规用于繁殖用于临床过继性 T 细胞治疗的人类 T 细胞的培养技术将用于提高我们将结果直接转化为人类恶性肿瘤和感染的 T 细胞治疗研究的能力。具体目标是： 1）。确定体内施用白细胞介素 (IL2) 和白细胞介素 15 (IL15) 对过继转移的 CD8+ 抗原特异性 T 细胞克隆的持久性、功能和迁移的影响。 2）。确定 T 细胞转移前淋巴细胞清除对过继转移的 CD8+ 抗原特异性 T 细胞克隆的持久性、功能和迁移的影响。 3）。确定通过过继转移建立的 CD8+ 细胞毒性 T 细胞反应的强度和持久性是否可以通过体内抗原刺激得到增强。