Comparison of naïve and central memory derived CD8 + effector cell engraftment fitness and function following adoptive transfer.

Human CD8 ⁺ effector T cells derived from CD45RO ⁺ CD62L ⁺ precursors enriched for central memory (T _CM ) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45RO ⁺ CD62L ^- precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8 ⁺ effector T cells derived from CD45RA ⁺ CD62L ⁺ precursors enriched for naïve and stem cell memory precursors (T _N/SCM ) with that of T _CM . We found that cytotoxic T cells (CTLs) derived from T _CM transcribed higher levels of CD28, FOS, INFγ, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of γ-chain cytokines compared to CTLs derived from T _N/SCM . Higher frequencies of CTLs derived from T _CM retained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/ Scid IL-2RγC ^null mice, CD8 ⁺ T _CM derived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8 ⁺ T _CM derived CD19CAR ⁺ CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8 ⁺ T _N/SCM derived counterparts. These studies support the use of T _CM enriched cell products for adoptive therapy of cancer.