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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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 4

Impact of FR104 and FR104/sirolimus on T cell proliferation and effector differentiation.

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Impact of FR104 and FR104/sirolimus on T cell proliferation and effector...
(A) The percentage of Ki-67hi and GZMBveryhi within CD4+ and CD8+ T cell populations in the No Rx (n = 11), CTLA4-Ig (n = 4), sirolimus (n = 6), FR104 (n = 3), FR104/sirolimus (n = 9), and CTLA4-Ig/sirolimus (n = 7) cohorts. Data are shown as mean ± SEM. *P < 0.05 between the indicated groups and the FR104/sirolimus cohort using the Holm-Šidák–corrected t test. (B) The percentage of Ki-67hi and GZMBveryhi CD8+ T cells in tissues at terminal analysis in the HC (n = 3), No Rx (n = 10), sirolimus (n = 4), FR104 (n = 3), and FR104/sirolimus (sacrificed before day 66, n = 6; or after day 66, n = 3) cohorts. Data are shown as mean ± SEM. Bars represent statistically significant differences between groups, with *P < 0.05 using the Holm-Šidák–corrected t test. (C) The relative number of CD45RA+CCR7+CD95– naive CD4+ or CD8+ T cells, normalized to the corresponding pretransplant level in No Rx (n = 11), CTLA4-Ig (n = 4), sirolimus (n = 6), FR104 (n = 3), FR104/sirolimus (n = 9), and CTLA4-Ig/sirolimus (n = 7) cohorts. Data are shown as mean ± SEM. TN, naive T cells. (D) The relative number of CD45RA+CCR7+CD95– naive CD4+ or CD8+ T cells before and after discontinuation of FR104 in FR104/sirolimus cohort recipients who survived for more than 66 days (R.249, R.250, and R.251). Each line represents a single experiment. Statistical analysis was performed using the paired Student’s t test. (E) Representative GSEA plots. The top and middle panels represent proliferation-related and antigen-dependent immune activation gene sets, respectively. These transcripts are underrepresented in the FR104/sirolimus cohort on day 14 (n = 7) compared with FR104 (n = 3) and sirolimus monoprophylaxis (n = 4) cohorts at terminal analysis (FDR q < 0.05). Bottom panel represents naive T cell–related gene sets which are overrepresented in the FR104/sirolimus cohort on day 14 (n = 7) compared with FR104 (n = 3) and sirolimus monoprophylaxis (n = 4) cohorts at terminal analysis (FDR q < 0.05). (F) The relative expression of LAG3, PDCD1 (encoding PD-1), CTLA4, HAVCR2 (Tim3), and CD244 (2B4) transcripts. Horizontal significance bars denote comparisons with a moderated t statistic of *P < 0.05, corrected for multiple testing using the Benjamini-Hochberg method.