Targeting B cell–activating factor (BAFF) and B cell receptor (BCR) pathways may improve outcomes among patients with chronic graft-vs-host disease (cGVHD) risk, according to a model published in Blood.
Among patients undergoing allogeneic hematopoietic stem cell (allo-SCT) or bone marrow transplantation (allo-BMT) for the treatment of hematologic disease, including cancer, cGVHD represents a serious and potentially life-threatening treatment-related adverse event. Although T cell and B cell involvement are established factors in cGVHD, removing T cells also attenuates the treatment’s anti-cancer effects.
Targeting B cell activity, therefore, is an important avenue of investigation in this area, though previous study of this modality has shown mixed results. Ibrutinib, which targets BCR-activated B cells, is approved for GVHD treatment; this therapy does not, however, affect BAFF, which previous study shows determines B cell homeostasis.
For this mouse model, researchers attempted to determine the role BAFF has, if any, in cGVHD incidence, with the further aim of establishing whether targeting BAFF is likely to yield therapeutic benefit.
Analysis suggested that, post allo-SCT, mice that developed cGVHD showed increases in BAFF production. Higher BAFF levels also appeared to increase NOTCH2 expression on mouse B cells. Higher BAFF levels also maintained SYK protein levels on B cells even after targeting BCR.
A further finding indicating that, among mice with disease, BAFF transcripts in CD41 T cells were higher, suggested that donor cell–BAFF production may influence the incidence of GVHD.
BAFF increases were generally linked with GVHD manifestation, circulating GL71 B cell counts, and production of alloantibodies.
“On the basis of the previously reported association between excess BAFF and cGVHD, the anti-BAFF monoclonal antibody belimumab is already being examined for safety and efficacy in allogeneic transplantation,” the authors wrote. “Our data provide a novel mechanistic rationale for SYK or BAFF blockade in cGVHD and other diseases with aberrations in B-cell tolerance.”
Jia W, Poe JC, Su H, et al. BAFF promotes heightened BCR responsiveness and manifestations of chronic GVHD after allogeneic stem cell transplantation. Blood. 2021;137(18):2544-57. doi:10.1182/blood.2020008040