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

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

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 1

The NHP model of aGVHD, FR104 PK, and pharmacodynamics analysis.

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The NHP model of aGVHD, FR104 PK, and pharmacodynamics analysis. (A) Exp...
(A) Experimental schematic. (B) PK analysis. PK was performed by ELISA on samples collected prior to and 30 minutes after each FR104 dosing and then on days 64, 71, 78, and 85 and at terminal analysis. Data combine FR104 (n = 3) and FR104/sirolimus (n = 9) cohorts. Data are shown as mean ± SEM. The vertical dashed line is drawn at day 66 to indicate the time period after which effective FR104 concentrations were no longer present in the peripheral blood. (C) The relative occupancy of CD28 receptors (number of CD28+ cells detectable with clone CD28.2 antibodies) within CD3+CD14–CD20–CD4+CD8– (top panel) and CD3+CD14–CD20–CD4–CD8+ (bottom panel) T cell populations measured longitudinally by flow cytometric analysis in FR104 (n = 3) and FR104/sirolimus (n = 9) cohorts. Data are shown as mean ± SEM. Shaded areas represent the time period of FR104 dosing. (D and E) The percentage of CD28+ cells within CD3+CD20–CD4+CD8– (top panels) and CD3+CD20–CD4–CD8+ (bottom panels) T cell populations in blood and tissue from FR104 (n = 3; D) and FR104/sirolimus, euthanized before day 66 after transplant (n = 6) or after day 66 (n = 3). (E) Treated recipients before transplantation and at the time of necropsy measured by flow cytometric analysis.