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. The adoptive transfer of antigen-specific CD8+ effector T cells (TE) is being used to treat human viral and malignant disease with some success. However, the inconsistent or short in vivo persistence of transferred TE has been identified as a limitation of this approach. T cell growth factors such as interleukin (IL)-2 have been used to support the survival of transferred T cells. However, high-dose IL-2 can cause systemic toxicity, induces the expansion of CD4+FoxP3+ regulatory T cells (Treg), which can inhibit antitumor immunity, and may promote activationinduced cell death of transferred TE. IL-15 is a novel cytokine that has a critical role in the maintenance of T-cell memory and may be an alternative to IL-2 for supporting transferred T-cell survival. We administered IL-15 (2.515 ¿g/kg s.c.) to 8 macaques, either daily (n=3) or every 3 days (n= 5), and assessed toxicity and immunological effects. Daily IL-15 increased circulating NK and CD8+ T cells and expanded CD8+CD95+CCR7- effector memory (TEM) and CD95+CCR7+ central memory T cells (TCM). However, daily IL-15 (515 ¿g/kg) accumulated in vivo, causing reversible toxicities. Intermittent IL-15 treatment was safe, increased NK cells and CD8+ TEM or TCM, without boosting the CD4+ Treg. We are currently evaluating the administration of IL-15 to support adoptively transferred CD8+ TE in macaques. As previously reported, TCM-derived CD8+ TE transferred without cytokines persisted in vivo at low levels of 0.20.8% of CD8+ cells. By contrast, TE given with IL-15 persisted for up to 2 years at high levels (up to 10 % of CD8+ lymphocytes) after treatment in 2 animals. The transferred TE reverted to the memory pool and migrated to memory niches. Thus, IL-15 may provide an alternative to IL-2 to support the persistence of transferred TE in human immunotherapy.