Chimeric Antigen Receptor T Cells Targeting CD79b Show Efficacy in Lymphoma with or without Cotargeting CD19.

Abstract

PURPOSE:

T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA approved for the treatment of relapsed or refractory large B-cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging.

EXPERIMENTAL DESIGN:

We developed a novel CAR construct directed against CD79b, a critical receptor for successful B-cell development that remains highly expressed in several subtypes of B-cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models.

RESULTS:

We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19+, CD19-, and mixed CD19+/CD19-B-cell lymphoma.

CONCLUSIONS:

Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B-cell lymphomas.

• Authors: Maria Ormhøj, Irene Scarfò, Maria L Cabral, Stefanie R Bailey, Selena J Lorrey, Amanda A Bouffard, Ana P Castano, Rebecca C Larson, Lauren S Riley, Andrea Schmidts, Bryan D Choi, Rikke S Andersen, Oriane Cédile, Charlotte G Nyvold, Jacob H Christensen, Morten F Gjerstorff, Henrik J Ditzel, David M Weinstock, Torben Barington, Matthew J Frigault, Marcela V Maus
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 23 Pg. 7046-7057 (12 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 31439577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antigens, CD19
• CD19 molecule, human
• CD79 Antigens
• CD79B protein, human
• Receptors, Chimeric Antigen

Topics

• Animals
• Antigens, CD19 (immunology)
• Apoptosis
• CD79 Antigens (immunology)
• Cell Proliferation
• Humans
• Immunotherapy, Adoptive (methods)
• Lymphocyte Activation
• Lymphoma, Mantle-Cell (immunology, metabolism, therapy)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Prognosis
• Receptors, Chimeric Antigen (immunology)
• T-Lymphocytes (immunology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays