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

Cancer Sci. 2018 Jul;109(7):2130-2140. doi: 10.1111/cas.13648. Epub 2018 Jun 28.

Abstract

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 (TSCM ) cells is expected to overcome this shortcoming as TSCM 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 TSCM -like cells (iTSCM ) by coculturing with OP9 cells expressing Notch ligand, Delta-like 1 (OP9-hDLL1). Here we show the methodological parameters of human CD8+ iTSCM cell generation and their application to adoptive cancer immunotherapy. Regardless of the stimulation by anti-CD3/CD28 antibodies or by antigen-presenting cells, human iTSCM 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 iTSCM cells. Epstein-Barr virus-specific iTSCM 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 iTSCM offers a promising therapeutic strategy for cancer immunotherapy.

Keywords: Epstein-Barr virus; adoptive immunotherapy; cytokine; immunological memory; methodological study.

MeSH terms

  • Animals
  • Cell Line
  • Humans
  • Immunologic Memory
  • Immunotherapy, Adoptive / methods*
  • Lymphocyte Activation / immunology
  • Mice
  • Neoplasms* / immunology
  • Stem Cells / immunology*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes / immunology*