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

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

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Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
Department of Immunology, International University of Health and Welfare School of Medicine, Narita, Japan.


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.


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

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