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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.

Author information

1
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
2
Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
3
Department of Immunology, International University of Health and Welfare School of Medicine, Narita, Japan.

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

PMID:
29790621
PMCID:
PMC6029822
DOI:
10.1111/cas.13648
[Indexed for MEDLINE]
Free PMC Article

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