Strategies to Enhance Adoptive Transfer T Cell Clones

描述(申请人提供)：在癌症和传染病的啮齿动物模型中的研究表明，过继转移具有特定抗原特异性和功能的T细胞可以建立或增强体内的免疫反应并提供治疗益处，而且越来越多的证据表明，以T细胞进行过继免疫治疗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，大量培养的T细胞或T细胞克隆的输注未能完全根除肿瘤或提供长期的感染控制。这在一定程度上是由于目前的方法不能通过过继转移建立足够大小和持久性的免疫反应，以实现持续的治疗效果。对IL15等调节淋巴细胞生长和存活的细胞因子的研究，以及对维持淋巴细胞数量但允许抗原特异性T细胞在体内刺激下扩张的动态平衡机制的研究，为通过过继转移T细胞克隆更好地建立T细胞免疫提供了洞察力。这项建议的目标是开发策略，通过过继转移CD8 T细胞克隆，在体内建立持久的高水平抗原特异性T细胞反应，并可应用于T细胞治疗癌症的临床试验。这项研究将在非人类灵长类动物(Macacca Nemstrina)中进行，并利用针对恒河猴巨细胞病毒(RhCMV)的CD8T细胞克隆作为模型靶抗原。常规用于临床过继T细胞治疗的人类T细胞培养技术将被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)。目的：研究体内注射白介素2(IL2)和白介素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)。目的：确定T细胞转移前淋巴滤除对过继转移的CD8抗原特异性T细胞克隆的持久性、功能和迁移的影响。 3)。目的：确定体内抗原刺激能否增强过继转移产生的CD8细胞毒T细胞反应的大小和持久性。

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.