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.
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