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Small-molecule BCL6 inhibitor effectively treats mice with non-sclerodermatous chronic graft-versus-host disease

Katelyn Paz, Ryan Flynn, Jing Du, Jun Qi, Leo Luznik, Ivan Maillard, Kelli P. MacDonald, Geoffrey R. Hill, Jonathan S. Serody, William J. Murphy, Peter T. Sage, Arlene H. Sharpe, David Miklos, Corey S. Culter, John Koreth, Joseph H. Antin, Robert J. Soiffer, Jerome Ritz, James E. Bradner, Ari M. Melnick and Bruce Blazar

Key points

  • BCL6 expression is necessary in donor marrow B- and T-cells for a germinal center reaction in chronic GVHD mice.

  • A small-molecule inhibitor of BCL6 mediated transcriptional repression presents a novel therapeutic strategy for chronic GVHD.

Abstract

Patient outcomes for steroid-dependent or -refractory cGVHD are poor and only ibrutinib has been FDA approved for this indication. cGVHD is often driven by the germinal center (GC) reaction, in which T follicular helper cells interact with GC B-cells to produce antibodies that are associated with disease pathogenesis. The transcriptional co-repressor BCL6 is a member of the BTB/POZ transcription factor family and master regulator of the immune cells in the GC reaction. We demonstrate that BCL6 expression in both donor T-cells and B-cells is necessary for cGVHD development, pointing to BCL6 as a therapeutic cGVHD target. A small-molecule BCL6 inhibitor reversed active cGVHD in a mouse model of multi-organ system injury with bronchiolitis obliterans associated with a robust GC reaction but not in cGVHD mice with scleroderma as the prominent manifestation. For cGVHD patients with antibody-driven cGVHD, targeting of BCL6 represents a new approach with specificity for a master GC regulator that would extend the currently available second-line agents.

  • Submitted March 19, 2018.
  • Accepted September 17, 2018.