Markey, Kate A., Kuns, Rachel D., Browne, Daniel J., Gartlan, Kate H., Robb, Renee J., Martins, J. Paulo, Henden, Andrea S., Minnie, Simone A., Cheong, Melody, Koyama, Motoko, Smyth, Mark J., Steptoe, Raymond J., Belz, Gabrielle T., Brocker, Thomas, Degli-Esposti, Mariapia A., Lane, Steven W., and Hill, Geoffrey R. (2018) Flt-3L expansion of recipient CD8α+ dendritic cells deletes alloreactive donor T cells and represents an alternative to posttransplant Cyclophosphamide for the prevention of GVHD. Clinical Cancer Research, 24 (7). pp. 1604-1616.

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Abstract

Purpose: Allogeneic bone marrow transplantation (BMT) provides curative therapy for leukemia via immunologic graft-versus-leukemia (GVL) effects. In practice, this must be balanced against life threatening pathology induced by graft-versus-host disease (GVHD). Recipient dendritic cells (DC) are thought to be important in the induction of GVL and GVHD.

Experimental Design: We have utilized preclinical models of allogeneic BMT to dissect the role and modulation of recipient DCs in controlling donor T-cell–mediated GVHD and GVL.

Results: We demonstrate that recipient CD8α+ DCs promote activation-induced clonal deletion of allospecific donor T cells after BMT. We compared pretransplant fms-like tyrosine kinase-3 ligand (Flt-3L) treatment to the current clinical strategy of posttransplant cyclophosphamide (PT-Cy) therapy. Our results demonstrate superior protection from GVHD with the immunomodulatory Flt-3L approach, and similar attenuation of GVL responses with both strategies. Strikingly, Flt-3L treatment permitted maintenance of the donor polyclonal T-cell pool, where PT-Cy did not.

Conclusions: These data highlight pre-transplant Flt-3L therapy as a potent new therapeutic strategy to delete alloreactive T cells and prevent GVHD, which appears particularly well suited to haploidentical BMT where the control of infection and the prevention of GVHD are paramount. Clin Cancer Res; 1–13. ©2018 AACR.

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