Page 242 - Haematologica Vol. 109 - July 2024

ARTICLE - Platelet Biology & its Disorders
GPIbα CAAR T cells function like a Trojan horse to eliminate autoreactive B cells to treat immune thrombocytopenia
Jie Zhou,1,2* Yanyan Xu,3* Jinhui Shu,1,2 Haojie Jiang,3 Linlin Huang,1,2 Min Xu,1,2 Junling Liu,3 Yu Hu1,2 and Heng Mei1,2
1Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei; 2Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, Hubei and 3Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
*JZ and YX contributed equally as first authors.
Abstract
Breakthrough treatment for refractory and relapsed immune thrombocytopenia (ITP) patients is urgently needed. Autoan- tibody-mediated platelet clearance and megakaryocyte dysfunction are important pathogenic mediators of ITP. Glycoprotein (GP) Ibα is a significant autoantigen found in ITP patients and is associated with poor response to standard immunosup- pressive treatments. Here, we engineered human T cells to express a chimeric autoantibody receptor (CAAR) with GPIbα constructed into the ligand-binding domain fused to the CD8 transmembrane domain and CD3ζ-4-1BB signaling domains. We performed cytotoxicity assays to assess GPIbα CAAR T-cell selective cytolysis of cells expressing anti-GPIbα B-cell re- ceptors in vitro. Furthermore, we demonstrated the potential of GPIbα CAAR T cells to persist and precisely eliminate GPIbα-specific B cells in vivo. In summary, we present a proof of concept for CAAR T-cell therapy to eradicate autoimmune B cells while sparing healthy B cells with GPIbα CAAR T cells that function like a Trojan horse. GPIbα CAAR T-cell therapy is a promising treatment for refractory and relapsed ITP patients.
Correspondence: H. Mei hmei@hust.edu.cn
Y. Hu
dr_huyu@126.com
Received: Accepted: Early view:
July 2, 2023. January 23, 2024. February 1, 2024.
https://doi.org/10.3324/haematol.2023.283874
©2024 Ferrata Storti Foundation Published under a CC BY-NC license
Introduction
Primary immune thrombocytopenia (ITP) is a bleeding dis- order mainly mediated by pathogenic anti-platelet autoan- tibodies secreted by autoreactive B cells and plasma cells, eventually leading to accelerated platelet destruction and megakaryocyte dysfunction.1-3 Platelet autoantibodies are predominantly directed against the platelet glycoproteins (GP) IIb/IIIa (CD41/CD61) and GPIb/IX (CD42b/CD42c/CD42a) in ITP.4,5 B-cell-targeted therapies in ITP patients appear to be well tolerated short term but lack long-term tolerance, and many patients relapse after drug withdrawal. Only 20% to 30% of patients treated with CD20-targeted B-cell deple- tion therapy (rituximab) can achieve a long-term response (5 years).6-8 A possible reason for this therapeutic failure is the presence of rituximab-resistant splenic memory B cells and long-lived plasma cells (LLPC) secreting high-affinity autoantibodies.9-12 Failure of splenectomy therapy may be due to the presence of peripheral memory B cells and bone marrow LLPC in ITP patients.9,13 Thus, novel therapeutic strategies that eradicate autoreactive B cells (including
memory B cells) while sparing healthy B cells would sig- nificantly advance ITP treatment.
Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable success in neoplastic hematologic disorders, especially B-cell malignancies, with the cost of eradicating normal B cells. Based on CAR T-cell therapy, the concept of chimeric autoantibody receptor T cells (CAAR T) was proposed and applied to the treatment of pemphigus14 and muscle-specific tyrosine kinase myasthenia gravis.15 The extracellular ligand-binding domain of the CAAR structure was designed to contain autoantigens, thus mediating the specific cytolysis of autoreactive B cells by T cells in the above studies.
GPIbα, a surface membrane protein of platelets, initiates signaling events within platelets by binding to the A1 domain of von Willebrand factor (VWF).16,17 In ITP, platelet-associ- ated anti-GPIb/IX antibodies are associated with a lower platelet count18,19 and inadequate responses to corticoste- roids, intravenous immunoglobulin (IVIg), rituximab, and recombinant human thrombopoietin (rhTPO) compared with anti-GPIIb/IIIa antibodies.20-24 Epitope mapping of ITP
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