Generation and application of human induced-stem cell memory T cells for adoptive immunotherapy

Adoptive T-cell therapy is an effective strategy for cancer immunotherapy. However, infused T cells frequently become functionally exhausted, and consequently offer a poor prognosis after transplantation into patients. Adoptive transfer of tumor antigen-specific stem cell memory T (T_SCM) cells is expected to overcome this shortcoming as T_SCM cells are close to naïve T cells, but are also highly proliferative, long-lived, and produce a large number of effector T cells in response to antigen stimulation. We previously reported that activated effector T cells can be converted into T_SCM-like cells (iT_SCM) by coculturing with OP9 cells expressing Notch ligand, Delta-like 1 (OP9-hDLL1). Here we show the methodological parameters of human CD8⁺ iT_SCM cell generation and their application to adoptive cancer immunotherapy. Regardless of the stimulation by anti-CD3/CD28 antibodies or by antigen-presenting cells, human iT_SCM cells were more efficiently induced from central memory type T cells than from effector memory T cells. During the induction phase by coculture with OP9-hDLL1 cells, interleukin (IL)-7 and IL-15 (but not IL-2 or IL-21) could efficiently generate iT_SCM cells. Epstein–Barr virus-specific iT_SCM cells showed much stronger antitumor potentials than conventionally activated T cells in humanized Epstein–Barr virus transformed-tumor model mice. Thus, adoptive T-cell therapy with iT_SCM offers a promising therapeutic strategy for cancer immunotherapy.