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+ T cells is a promising treatment for human malignancies and infections. However, this approach is often limited by the poor persistence of transferred effector T cells (TE). Interleukin (IL)2 is frequently administered to support the survival of transferred T cells. High-dose IL2 can cause systemic toxicity, promotes the expansion of CD4+FoxP3+ regulatory T cells (Treg), which can inhibit antitumor immunity, and may promote activationinduced cell death of the transferred TE, if exposure is prolonged. IL15 is a novel cytokine that has a critical role in the maintenance of T-cell memory and may be an alternative to IL2 for supporting transferred T-cell survival. We first treated 5 macaques with IL15 (2.515 ¿g/kg s.c.) alone, either daily or every 3 days, and assessed toxicity and immunological effects. Daily IL15 increased the circulating NK and CD8+ T cells and expanded CD8+CD95+CCR7- effector memory (TEM) and CD95+CCR7+ central memory T cells (TCM). However, daily IL15 (515 ¿g/kg) accumulated in vivo, causing reversible toxicities. Intermittent IL15 treatment was safe, increased NK cells and CD8+ TEM or TCM, without boosting the CD4+ Treg. We then evaluated the ability of IL15 to support transferred CD8+ TE marked with CD19 in 2 macaques. As previously reported,1 TCM-derived CD8+ TE transferred without cytokines persisted in vivo at low levels of 0.20.8% of CD8+ cells. By contrast, T cells given with IL15 persisted at high levels (up to 10 % of CD8+ T cells) during and after treatment. The cells retained the ability to re-acquire a TCM phenotype and migrated to memory niches. Thus, IL15 can be safely administered and exerts a biologic effect on endogenous and transferred T cells. IL15 may be an alternative to IL2 or lymphodepletion to support the persistence of transferred T cells in human immunotherapy.