Chimeric antigen receptor T cells to target CD79b in B-cell lymphomas

作者：Fuliang Chu, Jingjing Cao, Jingwei Liu, Haopeng Yang, Timothy J. Davis, Shao-Qing Kuang, Xiaoyun Cheng, Zheng Zhang, Swathi Karri, Long Vien, Laura Bover, Ryan Sun, Francisco Vega, Michael R. Green, R. Eric Davis, Sattva S. Neelapu · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2023 · DOI：10.1136/jitc-2023-007515 · 被引用次数：17 · 研究领域：CAR-T cell therapy research、Lymphoma Diagnosis and Treatment、Cutaneous lymphoproliferative disorders research

Background Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent and durable effects in B-cell malignancies. However, antigen loss or downregulation is a frequent cause of resistance. Here, we report development of a novel CAR T-cell therapy product to target CD79b, a pan B-cell antigen, widely expressed in most B-cell lymphomas. Methods We generated a novel anti-CD79b monoclonal antibody by hybridoma method. The specificity of the antibody was determined by testing against isogenic cell lines with human CD79b knock-in or knock-out. A single-chain variable fragment derived from the monoclonal antibody was used to make a panel of CD79b-targeting CAR molecules containing various hinge, transmembrane, and co-stimulatory domains. These were lentivirally transduced into primary T cells and tested for antitumor activity in in vitro and in vivo B-cell lymphoma models. Results We found that the novel anti-CD79b monoclonal antibody was highly specific and bound only to human CD79b and no other cell surface protein. In testing the various CD79b-targeting CAR molecules, superior antitumor efficacy in vitro and in vivo was found for a CAR consisting CD8α hinge and transmembrane domains, an OX40 co-stimulatory domain, and a CD3ζ signaling domain. This CD79b CAR specifically recognized human CD79b-expressing lymphoma cell lines but not CD79b knock-out cell lines. CD79b CAR T cells, generated from T cells from either healthy donors or patients with lymphoma, proliferated, pr...