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

Abstract

CD62LC precursors enriched for na€ ıve 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, INFg, 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 g-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-2RgC null mice, CD8 C T CM derived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8C T CM derived CD19CAR C CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8 C T N/SCM derived counterparts. These studies support the use of T CM enriched cell products for adoptive therapy of cancer.

Ex vivo Akt inhibition promotes the generation of potent CD19CAR T cells for adoptive immunotherapy

“…Studies have shown that T cells with memory characteristics positively correlate with in vivo persistence and antitumor activity post adoptive transfer [32]. Despite no statistically significant differences as a result of variation among donors and a limited number of donors, our studies consistently demonstrated that Akti-treated CD19CAR T cells exhibited higher expression levels of CD62L and CD28 without expression of exhaustion phenotypes such as KLRG1, which are the traits required for efficient anti-tumor activity following adoptive transfer [33]. In further support, there did not appear to be a difference in telomere length between cultures with or without Akti.…”

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells

“…Evidence of the engagement of this subpopulation of T cells is critical as Tcm cells have been shown to be indispensable in developing a prolonged anti‐tumour defence in a number of studies of adoptive immunotherapy 16. Both memory and effector T cells secrete high levels of TNF‐ α , IL‐2, IL‐6 and IFN‐ γ .…”

“…In both mouse and non‐human primate studies, adoptively transferred CD8 + Tem cells rapidly developed into effector cells and efficiently killed tumour cells but only Tcm cells formed a persistent reservoir of functional T cells, occupied memory cell niches and provided a lasting anti‐cancer immune response 12, 13. Comparisons have also been made between the Tcm and naive CD8 + T cell repertoires and, although the findings are somewhat conflicting, both subpopulations bring a specific contribution to successful tumour elimination 14, 15, 16. Despite their crucial role in tumour clearance, CD8 + T cells on their own are not capable of delivering a sustained cancer remission.…”

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Additional factors can affect the functional level and differentiation states of effector and memory T cells including the genetic signature of key effector genes, epigenetic states [319] as well as distinct metabolic pathway [320]. Nevertheless, it seems that T CM could mediate increased persistence and growth leading to better anti-tumor activity compared to T EM in xenograft models [321,322]. Moreover, the use of central memory-derived CD19 1st gen.…”