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

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 2

Clinical aGVHD scoring and aGVHD-free survival.

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Clinical aGVHD scoring and aGVHD-free survival. (A and B) Longitudinal c...
(A and B) Longitudinal clinical aGVHD scoring (A) and GVHD-free survival curves (B) of untreated (No Rx, n = 11; red), CTLA4-Ig (n = 4; pink), sirolimus (n = 6; orange), FR104 (n = 3; blue), FR104/sirolimus (n = 9; navy), and CTLA4-Ig/sirolimus (n = 7; purple) cohorts. Scoring was based on our previously described NHP aGVHD clinical scoring system (12). GI aGVHD scores from FR104/sirolimus recipients with documented enteric infections were censored. Data are shown as mean ± SEM. For GVHD-free survival analysis, FR104/sirolimus recipients with documented graft rejection were excluded from this analysis. The Kaplan-Meier product-limit method was used to calculate survival. (C) Clinical aGVHD scoring in untreated (No Rx, n = 11), CTLA4-Ig (n = 4), sirolimus (n = 6), and FR104 (n = 3) cohorts on day 7. GI aGVHD scores from FR104/sirolimus recipients with documented enteric infections were censored. Data are shown as mean ± SEM. Statistical analysis was performed using 1-way ANOVA with Holm-Šidák multiple-comparison post test. (D) Clinical aGVHD scoring in the following cohorts, each at terminal analysis: untreated (No Rx, n = 11), CTLA4-Ig (n = 4), sirolimus (n = 6), FR104 (n = 3), FR104/sirolimus recipients undergoing terminal analysis before day 66 (n = 6), FR104/sirolimus recipients undergoing terminal analysis after day 66 (n = 3), CTLA4-Ig/sirolimus (n = 7), and autologous controls (n = 3). Data are shown as mean ± SEM. Statistical analysis was performed using 1-way ANOVA with Holm-Šidák multiple comparison post test. (E) Terminal aGVHD histopathologic scores. The scores shown represent the total score for the skin, liver, and GI tract (83). GI aGVHD scores from FR104/sirolimus recipients with documented enteric infections were censored. Data are shown as mean ± SEM. Statistical analysis was performed using 1-way ANOVA with Holm-Šidák multiple-comparison post test. *P < 0.05; **P < 0.01; ***P < 0.001.