T cells redirected against Igβ for the immunotherapy of B cell lymphoma

• Published in: Leukemia 2020-03, Vol.34 (3), p.821-830
• Main Authors: Jiang, Dongpeng, Tian, Xiaopeng, Bian, Xiaosen, Zhu, Tingting, Qin, Huimin, Zhang, Ruixi, Xu, Yang, Pan, Zhansheng, Huang, Haiwen, Fu, Jianhong, Wu, Depei, Chu, Jianhong
• Format: Article
• Language: English
• Subjects: 13/31; 14/34; 14/5; 42/41; 64/60; 692/699/1541/1990/291/1621/1915; 692/699/67/1059/2325; 96/44; Animals; Antigens; B-cell lymphoma; B-cell receptor; Cancer Research; Caspase-9; CD19 antigen; CD28 antigen; CD28 Antigens - metabolism; CD79 Antigens - immunology; Cell Line, Tumor; Coculture Techniques; Critical Care Medicine; Hematology; Humans; Immunotherapy; Immunotherapy, Adoptive; Intensive; Interferon; Internal Medicine; K562 Cells; Lymphocytes; Lymphocytes T; Lymphoma; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - therapy; Lysosomal-Associated Membrane Protein 1 - metabolism; Medicine; Medicine & Public Health; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Neoplasm Transplantation; Oncology; Receptors, Chimeric Antigen - immunology; Signal transduction; Suicide; Suicide genes; T-Lymphocytes - immunology; Xenografts; Xenotransplantation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-019-0607-5

CD19-redirected CAR-T immunotherapy has emerged as a promising strategy for treatment of B cell lymphoma, however, many patients often relapsed due to antigen loss. Therefore, it is urgently needed to explore other suitable antigens targeted by CAR-T cells to cure B cell lymphoma. Igβ is a component of the B cell receptor (BCR) complex, which is highly expressed on the surface of lymphoma cells. In this study, we engineered T cells to express anti-Igβ CAR with CD28 costimulatory signaling moiety and observed that Igβ-CAR T cells could efficiently recognize and eliminate Igβ + lymphoma cells both in vitro and in two different lymphoma xenograft models. The specificity of Igβ-CAR T cells was further confirmed through wild type or mutated Igβ gene transduction together with Igβ-specific knockout in target cells. Of note, both the in vitro and in vivo effect of Igβ CAR-T cells was comparable with that of CD19 CAR-T cells. Importantly, Igβ CAR-T cells recognized and eradicated patient-derived lymphoma cells in the autologous setting. Lastly, the safety of anti-Igβ CAR-T cells could be further enhanced by introduction of the inducible caspase-9 suicide gene system. Collectively, Igβ-specific CAR-T cells may be a promising immunotherapeutic approach for B cell lymphoma.