IL23R-Specific CAR Tregs for the Treatment of Crohn’s Disease

Author:

Cui Yue1ORCID,David Marion1ORCID,Bouchareychas Laura1,Rouquier Sandrine1,Sajuthi Satria2,Ayrault Marion1,Navarin Candice1,Lara Gregory1,Lafon Audrey1,Saviane Gaëlle1,Boulakirba Sonia1,Menardi Alexandra1,Demory Alexandra1,Frikeche Jihane1,de la Forest Divonne Beghelli Stephanie1,Lu Hsiaomei Heidi2,Dumont Celine1,Abel Tobias1,Fenard David1,de la Rosa Maurus1,Gertner-Dardenne Julie1

Affiliation:

1. Research, Sangamo Therapeutics , Valbonne , France

2. Bioinformatics, Sangamo Therapeutics , Richmond, CA , USA

Abstract

Abstract Background and Aims Regulatory T cells (Tregs) are key regulators in maintaining tissue homeostasis. Disrupted immune homeostasis is associated with Crohn’s disease (CD) pathogenesis. Thus, Treg therapy represents a promising long-acting treatment to restore immune balance in the diseased intestine. Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment. This innovative approach also provides the opportunity to improve therapy for CD. By targeting a disease-relevant protein, interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-CAR for treating active CD. Methods Intestinal IL23R expression from active CD was verified by immunohistochemical analysis. Phenotypic and functional characteristics of IL23R-CAR Tregs were assessed using in vitro assays and their migration capacity was monitored in a xenograft tumor model. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR Treg activation against colon biopsy-derived cells from active CD patients. Results Our study showed that IL23R-CAR displayed negligible tonic signaling and a strong signal-to-noise ratio. IL23R-CAR Tregs maintained regulatory phenotype during in vitro expansion, even when chronically exposed to proinflammatory cytokines and target antigen. IL23R engagement on IL23R-CAR Tregs triggered CAR-specific activation and significantly enhanced their suppressive activity. Also, IL23R-CAR Tregs migrated to IL23R-expressing tissue in humanized mice. Finally, IL23R-CAR Tregs elicited a specific activation against colon biopsy-derived cells from active CD, suggesting an efficient CAR engagement in active CD. Molecular profiling of CD patient biopsies also revealed transcriptomic and proteomic patterns associated with IL23R-CAR activation. Conclusions Overall, our results demonstrate that IL23R-CAR Tregs represent a promising therapy for active CD.

Funder

Sangamo Therapeutics

Publisher

Oxford University Press (OUP)

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