CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates
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
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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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 5

FR104/sirolimus synergistically modulates T cell effector and proliferative transcriptional signals dysregulated during aGVHD.

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FR104/sirolimus synergistically modulates T cell effector and proliferat...
(A) Top panel: number of genes DE in the FR104 (n = 3; at day 14), sirolimus (n = 4; at terminal analysis), and FR104/sirolimus (n = 6; at day 14) cohorts compared with the No Rx cohort at terminal analysis. Each bar represents the number of DE genes that are unique for each comparison. Bottom panel: number of genes DE in the CTLA4-Ig (n = 3; at day 14), sirolimus (n = 4; at terminal analysis), and CTLA4-Ig/sirolimus (n = 6; at day 14) cohorts compared with the No Rx cohort at terminal analysis. Each bar represents the number of DE genes that are unique for each comparison. (B) Venn diagram showing the number of genes uniquely DE in either the FR104/sirolimus or the CTLA4-Ig/sirolimus cohorts compared with the No Rx cohort and the degree of overlap between these 2 DE gene lists. Red text depicts the number of overrepresented transcripts; blue text depicts the number of underrepresented transcripts. (C) Functional characterization of pathways enriched in both the overrepresented and underrepresented genes, defined as shown in B: underrepresented genes unique for FR014/sirolimus vs. No Rx comparison (left); overrepresented genes unique for FR014/sirolimus vs. No Rx comparison (middle); and underrepresented genes shared between FR104/sirolimus vs. NoRx and CTLA4-Ig/sirolimus vs. NoRx comparisons (right). A complete list of the individual pathways identified is found in Supplemental Table 5. Pathway identification used a Benjamini-Hochberg–corrected P value of less than 0.05. (D) Representative GSEA underrepresented plots of cell cycle– and immune response–related gene sets and an overrepresented naive T cell–related gene set in the FR104/sirolimus (n = 6) transcriptome in comparison with the CTLA4-Ig/sirolimus transcriptome (n = 6; transcriptomes derived from T cells isolated at day 28 from both cohorts) with FDR of q < 0.05.