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CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates
Benjamin K. Watkins, … , Bernard Vanhove, Leslie S. Kean
Benjamin K. Watkins, … , Bernard Vanhove, Leslie S. Kean
Published August 13, 2018
Citation Information: J Clin Invest. 2018;128(9):3991-4007. https://doi.org/10.1172/JCI98793.
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Research Article Immunology Transplantation

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

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Abstract

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.

Authors

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

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Figure 10

Transplant-associated events in the FR104/sirolimus cohort.

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Transplant-associated events in the FR104/sirolimus cohort.
(A) Donor ch...
(A) Donor chimerism in the peripheral blood, bone marrow aspirate samples, and flow cytometrically sorted peripheral blood granulocytes and T and B lymphocytes, measured by microsatellite analysis (12, 62, 84) (plotted on the left y axes) and the ANC (plotted on the right y axes) in FR104/sirolimus recipients who survived more than 50 days after transplant. (B) Kaplan-Meier plot showing the relative number of hematologically engrafted recipients in FR104/sirolimus (n = 9) and CTLA4-Ig/sirolimus (n = 7) cohorts. (C) Overall survival curves of FR104/sirolimus (n = 9) and CTLA4-Ig/sirolimus (n = 7) cohorts. The Kaplan-Meier product-limit method was used to calculate survival. (D) The concentrations of IFN-γ, IL-1RA, IL-6, and IL-12 in serum samples from recipients from the No Rx, sirolimus, FR104, and FR104/sirolimus cohorts. Each line represents a single transplant recipient. Gray boxes above the graph provide the timing of infectious transplant-related events observed in the FR104/sirolimus cohort.
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