CD28-targeting synergizes with mTOR inhibition to prevent graft-versus-host disease but increases infection-related fatality in nonhuman primates. T cells are the driving force that mediates graft-versus-host disease (GVHD) after transplantation. Thus, T cell suppression is key for GVHD treatment. Optimal T cell activation requires interaction between CD28, expressed on T cells, and CD80/CD86, expressed on antigen-presenting cells. Furthermore, activation of the metabolic regulator, mammalian target of rapamycin (mTOR) pathway, is critical for T cell function. Currently, there are FDA-approved medicines that inhibit CD80/CD86 (abatacept and belatacept) and mTOR (sirolimus). However, belatacept treatment unexpectedly led to increased acute organ rejection in a renal transplantation clinical trial, possibly by disrupting the checkpoint receptor cytotoxic T lymphocyte antigen 4, which also binds CD80/CD86. Whether blocking CD28 receptor specically is a viable option for GVHD is not clear. Watkins and colleagues evaluated the ecacy of a CD28-blocking antibody fragment (FR104) in a rhesus macaque GVHD model with hematopoietic stem cell transplantation. They compared the effects of single treatment using belatacept, sirolimus, or FR104, and combination treatment using belatacept/sirolimus or FR014/sirolimus. Their results showed that although belatacept and sirolimus treatment alone failed to prevent GVHD, FR104 single therapy was able to slow GVHD progression. The belatacept/sirolimus combination modestly increased GVHD-free survival, but FR104/sirolimus showed a signicantly stronger protection compared with belatacept/sirolimus. The authors compared the gene expression proles of T cells puried from recipients of the different treatment cohorts. They found that FR104 and sirolimus synergized to suppress multiple biological processes, including DNA repair, cell cycle, signal transduction, cell metabolism, and senescence, whereas belatacept/sirolimus primarily suppressed cell cycle alone. Surprisingly, despite the superior control of GVHD, FR104/sirolimus did not improve overall posttransplant survival because of increased infection-related death, which was attributed to disabled antimicrobial T cell function. This comprehensive preclinical study on nonhuman primates provides a new strategy for effective control of GVHD by inhibition of CD28. Moreover, it illustrates the delicate balance that we must maintain in any CD28-targeting immunotherapy. Previous efforts to boost T cell function by stimulating CD28 has led to near-fatal autoimmune reactions in a clinical trial. Conversely, although blocking CD28 eciently suppresses GVHD, it may result in lethal infection. Thus, the benet and risk of blocking CD28 for GVHD must be closely scrutinized in future clinical applications.
ASJC Scopus subject areas
- General Medicine