Early administration of calcineurin inhibitors limits the tolerogenic effect of PTCy in allogeneic hematopoietic transplant.

Early cyclosporine or tacrolimus administration before posttransplant cyclophosphamide preserves incompletely exhausted, clonally expanded donor T cells, and in patients predicts higher cGVHD risk.

• Why it matters: Calcineurin inhibitors are used clinically, but their effect on donor T-cell exhaustion in PTCy-based allogeneic transplant is unclear, as is how cGVHD can still be reduced by PTCy.
• What they did: In mice, cyclosporine given before PTCy preserved Ly6C+ donor T cells with less exhausted features; in PTCy-haploidentical PBSCT patients, tacrolimus before PTCy expanded Tex-int and CD4+ CTLs, which remained responsive to TCR stimulation and PD-1 blockade.
• The result: Tex-int and CD4+ CTLs expanded by day 28 predicted subsequent cGVHD, while delaying tacrolimus until day 5 after PTCy-haplo-PBSCT significantly reduced these effector-like T-cell expansions.

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