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CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates

2018; American Society for Clinical Investigation; Volume: 128; Issue: 9 Linguagem: Inglês

10.1172/jci98793

1558-8238

Benjamin Watkins, Victor Tkachev, Scott N. Furlan, Daniel J. Hunt, Kayla Betz, Alison Yu, Melanie Brown, Nicolas Poirier, Hengqi Zheng, Agne Taraseviciute, Lucrezia Colonna, Caroline Mary, Gilles Blancho, Jean-Paul Soulillou, Angela Panoskaltsis‐Mortari, Prachi Sharma, Anapatricia García, Elizabeth Strobert, Kelly Hamby, Aneesah Garrett, Taylor Deane, Bruce R. Blazar, Bernard Vanhove, Leslie S. Kean,

Immunotherapy and Immune Responses

Controlling graft-versus-host disease (GVHD) remains a major unmet need in stem cell transplantation, and new, targeted therapies are being actively developed. CD28-CD80/86 costimulation blockade represents a promising strategy, but targeting CD80/CD86 with CTLA4-Ig may be associated with undesired blockade of coinhibitory pathways. In contrast, targeted blockade of CD28 exclusively inhibits T cell costimulation and may more potently prevent GVHD. Here, we investigated FR104, an antagonistic CD28-specific pegylated-Fab′, in the nonhuman primate (NHP) GVHD model and completed a multiparameter interrogation comparing it with CTLA4-Ig, with and without sirolimus, including clinical, histopathologic, flow cytometric, and transcriptomic analyses. We document that FR104 monoprophylaxis and combined prophylaxis with FR104/sirolimus led to enhanced control of effector T cell proliferation and activation compared with the use of CTLA4-Ig or CTLA4-Ig/sirolimus. Importantly, FR104/sirolimus did not lead to a beneficial impact on Treg reconstitution or homeostasis, consistent with control of conventional T cell activation and IL-2 production needed to support Tregs. While FR104/sirolimus had a salutary effect on GVHD-free survival, overall survival was not improved, due to death in the absence of GVHD in several FR104/sirolimus recipients in the setting of sepsis and a paralyzed INF-γ response. These results therefore suggest that effectively deploying CD28 in the clinic will require close scrutiny of both the benefits and risks of extensively abrogating conventional T cell activation after transplant.