T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells.

Abstract

The adoptive transfer of T cells expressing anti-CD19 chimeric antigen receptors (CARs) has shown remarkable curative potential against advanced B-cell malignancies, but multiple trials have also reported patient relapses due to the emergence of CD19-negative leukemic cells. Here, we report the design and optimization of single-chain, bispecific CARs that trigger robust cytotoxicity against target cells expressing either CD19 or CD20, two clinically validated targets for B-cell malignancies. We determined the structural parameters required for efficient dual-antigen recognition, and we demonstrate that optimized bispecific CARs can control both wild-type B-cell lymphoma and CD19(-) mutants with equal efficiency in vivo To our knowledge, this is the first bispecific CAR capable of preventing antigen escape by performing true OR-gate signal computation on a clinically relevant pair of tumor-associated antigens. The CD19-OR-CD20 CAR is fully compatible with existing T-cell manufacturing procedures and implementable by current clinical protocols. These results present an effective solution to the challenge of antigen escape in CD19 CAR T-cell therapy, and they highlight the utility of structure-based rational design in the development of receptors with higher-level complexity. Cancer Immunol Res; 4(6); 498-508. ©2016 AACR

• Authors: Eugenia Zah, Meng-Yin Lin, Anne Silva-Benedict, Michael C Jensen, Yvonne Y Chen
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 4 Issue 6 Pg. 498-508 (06 2016) ISSN: 2326-6074 [Electronic] United States
• PMID: 27059623 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antibodies, Bispecific
• Antigens, CD19
• Antigens, CD20
• CD19 molecule, human
• Cytokines
• Receptors, Antigen, T-Cell
• Recombinant Fusion Proteins

Topics

• Animals
• Antibodies, Bispecific (immunology)
• Antigens, CD19 (immunology)
• Antigens, CD20 (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Differentiation (immunology)
• Cytokines (biosynthesis)
• Cytotoxicity, Immunologic (immunology)
• Humans
• Immunotherapy, Adoptive (methods)
• K562 Cells
• Lymphoma, B-Cell (immunology, therapy)
• Mice, Inbred NOD
• Mice, SCID
• Receptors, Antigen, T-Cell (immunology)
• Recombinant Fusion Proteins (immunology)
• Tumor Cells, Cultured
• Tumor Escape (immunology)
• Xenograft Model Antitumor Assays