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Orio J.,HOpital Maisonneuve Rosemont Research CentreQC | Carli C.,HOpital Maisonneuve Rosemont Research CentreQC | Janelle V.,HOpital Maisonneuve Rosemont Research CentreQC | Giroux M.,HOpital Maisonneuve Rosemont Research CentreQC | And 7 more authors.
Cytotherapy | Year: 2015

Background aims: The adoptive transfer of exvivo-expanded Epstein-Barr virus (EBV)-specific T-cell lines is an attractive strategy to treat EBV-related neoplasms. Current evidence suggests that for adoptive immunotherapy in general, clinical responses are superior if the transferred cells have not reached a late or terminal effector differentiation phenotype before infusion. The cytokine interleukin (IL)-21 has shown great promise at limiting late T-cell differentiation invitro, but this remains to be demonstrated in anti-viral T-cell lines. Methods: We adapted a clinically validated protocol to rapidly generate EBV-specific T-cell lines in 12 to 14 days and tested whether the addition of IL-21 at the initiation of the culture would affect T-cell expansion and differentiation. Results: We generated clinical-scale EBV-restricted T-cell line expansion with balanced T-cell subset ratios. The addition of IL-21 at the beginning of the culture decreased both T-cell expansion and effector memory T-cell accumulation, with a relative increase in less-differentiated T cells. Within CD4 T-cell subsets, exogenous IL-21 was notably associated with the cell surface expression of CD27 and high KLF2 transcript levels, further arguing for a role of IL-21 in the control of late T-cell differentiation. Conclusions: Our results show that IL-21 has profound effects on T-cell differentiation in a rapid T-cell line generation protocol and as such should be further explored as a novel approach to program anti-viral T cells with features associated with early differentiation and optimal therapeutic efficacy. © 2015 International Society for Cellular Therapy.

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