Daratumumab Prevents Experimental Xenogeneic Graft-versus-host Disease by Skewing the T Cell Repertoire and Inhibiting T cell Activation and Migration

Graft-versus-host disease remains the major cause of mortality andmorbidity in non-relapse patients after allogeneic hematopoietic cell transplantation. As the number of patients undergoing allo-HCT increases, it will become imperative to determine safe and effective treatment options for patients with GVHD, especially those who become refractory to systemic steroid therapy. Daratumumab, a humanized IgG1 monoclonal antibody targeting the CD38epitope, is used for the treatment of multiple myeloma. CD38 is a multifunctionalectoenzyme that behaves either as an enzyme, a cell adhesion molecule or a cellsurface receptor involved in cell signaling. CD38 is also expressed on variousimmune effector and suppressor cells. However, the role of CD38 in the immuneresponse remains elusive. We questioned whether CD38 is a potential therapeutictarget against alloreactive T cells in the GVHD pathological process. Here, weinvestigated the impact of Dara on xenogeneic GVHD and graft-versus-leukemia effects in a humanized murine model of transplantation, where human peripheral blood mononuclear cells were adoptively transplanted into NSG mice. Mice receiving Dara treatment experienced less weight loss, longer survival and lower GVHD scores compared with those in the control group. Histological evaluations, flow cytometry, RNA-sequencing and RT-qPCR analysis revealed that Dara efficaciously mitigated GVHD through multiple mechanisms including inhibition of the proliferation, activation and differentiation of CD8+ cytotoxic T cells, reduced expression of 4 cytotoxic effector molecules, pro-inflammatory cytokines, chemokines and chemoattractant receptors by T cells and promotion of immunosuppressive T cells. More importantly, Dara preserved the GVL effect in a humanized mouse model of leukemia by metabolic reprograming of T cells to promote the induction of Th17, Th1/17, Tc17 and Tc1/17 cells. Our findings indicate that Dara may be an attractive therapeutic option to separate GVHD from GVL effects in patients with hematopoietic malignancies receiving allo-HCT.