The Ex Vivo Treatment of Donor T Cells with Cosalane, an HIV Therapeutic and Small-Molecule Antagonist of CC-Chemokine Receptor 7, Separates Acute Graft-versus-Host Disease from Graft-versus-Leukemia Responses in Murine Hematopoietic Stem Cell Transplantation Models

Despite recent advances in therapy, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for a range of high-risk hematologic malignancies. However, acute graft-versus-host disease (aGVHD) continues to limit the long-term success of HSCT, and new therapies are still needed. We previously demonstrated that aGVHD depends on the ability of donor conventional T cells (T_cons) to express the lymph node trafficking receptor, CC-Chemokine Receptor 7 (CCR7). Consequently, we examined the ability of cosalane, a recently identified CCR7 small-molecule antagonist, to attenuate aGVHD in mouse HSCT model systems. Here we show that the systemic administration of cosalane to transplant recipients after allogeneic HSCT did not prevent aGVHD. However, we were able to significantly reduce aGVHD by briefly incubating donor T_cons with cosalane ex vivo before transplantation. Cosalane did not result in T_con toxicity and did not affect their activation or expansion. Instead, cosalane prevented donor T_con trafficking into host secondary lymphoid tissues very early after transplantation and limited their subsequent accumulation within the liver and colon. Cosalane did not appear to impair the intrinsic ability of donor T_cons to produce inflammatory cytokines. Furthermore, cosalane-treated T_cons retained their graft-versus-leukemia (GVL) potential and rejected a murine P815 inoculum after transplantation. Collectively, our data indicate that a brief application of cosalane to donor T_cons before HSCT significantly reduces aGVHD in relevant preclinical models while generally sparing beneficial GVL effects, and that cosalane might represent a viable new approach for aGVHD prophylaxis.

Acute Graft-versus-Host Disease; CC-Chemokine Receptor 7; Cosalane; Graft-versus-Leukemia.