STRATEGIES TO ENHANCE ADOPTIVE TRANSFER OF T CELL CLONES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In principle, the adoptive transfer of cytotoxic T-lymphocyte (CTL) clones specific for antigens expressed by pathogens or malignant cells could be therapeutically effective and allow precise control of specificity, function, and magnitude of T-cell immunity. However, the infusion of cultured CTL clones in clinical trials has failed to eradicate tumors or provide long-term control of infection. Novel approaches including administration of homeostatic cytokines such as IL15 have been proposed to promote T-cell persistence and establishment of T-cell memory after transfer. To examine this possibility, we employed a nonhuman-primate model of adoptive T-cell transfer using culture conditions and cell doses identical to those in human studies. Initial experiments in two immunocompetent macaques were designed to evaluate the intrinsic survival properties of adoptively transferred autologous CMV-specific CD8+ CTL clones. The clones were isolated by limiting dilution, transduced to express a truncated CD19 gene to provide a unique surface marker for tracking infused CTL, and expanded in vitro. The infusion of 3-6x108 CD19+ CD8+CTL/kg was safe and resulted in high levels of transferred cells in the blood which remained present 5 months. These CTL were also found in lymph node and bone marrow samples obtained 14 days after transfer. Upon infusion, the CD19+CD8+ CTL exhibited an effector phenotype (CD62L'CD127'), but reacquired markers of central memory T cells (TCM) in vivo (CD62L+CD127+). A subset of the cells also reacquired functional attributes of TCM including diminished direct lytic activity and rapid proliferation in response to antigen. Thus, a portion of the CTL clone retained the capacity to persist and revert to TCM. Studies in 3 macaques have been initiated to identify an IL15-regimen which is safe and confers a biologic effect on endogenous CD8+ T cells. We are now examining whether administration of IL15 can further improve the efficiency of T-cell transfer.