Strategies to Enhance Adoptive Transfer T Cell Clones

描述（由申请人提供）：在癌症和感染性疾病的啮齿动物模型中进行的研究已经证明，具有确定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应答并提供治疗益处，并且越来越多的证据表明，使用T细胞的过继免疫疗法在人类恶性肿瘤和感染中具有治疗活性。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对感染的长期控制。这部分是由于目前的方法无法通过过继转移建立足够大小和持久性的免疫应答以获得持续的治疗功效。对调节淋巴细胞生长和存活的细胞因子如IL 15的研究，以及对维持淋巴细胞数量但允许抗原特异性T细胞响应于体内刺激而扩增的稳态机制的研究，提供了对可用于通过T细胞克隆的过继转移更好地建立T细胞免疫的策略的见解。该提案的目标是开发通过过继转移CD8+ T细胞克隆来改善体内持续高水平抗原特异性T细胞应答的建立的策略，并且可以应用于T细胞治疗癌症的临床试验。这些研究将在非人灵长类动物（Macacca nemestrina）中进行，并利用对恒河猴巨细胞病毒（rhCMV）具有特异性的CD8+ T细胞克隆作为模型靶抗原。将采用常规用于增殖用于临床过继性T细胞治疗的人T细胞的培养技术，以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）。确定体内给予白细胞介素（IL 2）和白细胞介素15（IL 15）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细胞应答的幅度和持久性是否可以通过体内抗原刺激来增强。

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.