Chimeric Antigen Receptor T Cells to Target cd79B in B-Ceall Lymphomas

Authors

Fuliang Chu
Jingjing Cao
Jingwei Liu
Haopeng Yang
Timothy J Davis
Shao-Qing Kuang
Xiaoyun Cheng
Zheng Zhang
Swathi Karri
Long T Vien
Laura Bover
Ryan Sun
Francisco Vega
Michael Green
Richard Eric Davis
Sattva S Neelapu

Publication Date

11-24-2023

Journal

The Journal for ImmunoTherapy of Cancer

Abstract

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, produced cytokines, degranulated, and exhibited robust cytotoxic activity in vitro against CD19

CONCLUSION: Our results indicated that this novel CD79b CAR T-cell therapy product has robust antitumor activity against B-cell lymphomas. These results supported initiation of a phase 1 clinical trial to evaluate this product in patients with relapsed or refractory B-cell lymphomas.

Keywords

Humans, Receptors, Chimeric Antigen, Neoplasm Recurrence, Local, Lymphoma, B-Cell, T-Lymphocytes, Antibodies, Monoclonal

Comments

Supplementary Materials

PMID: 38007239