DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma.

Abstract

Chimeric antigen receptor (CAR) T cell therapies hold great potential for treating cancers, and new CARs that can target multiple tumor types and have the potential to target non-hematological malignancies are needed. In this study, the tumor recognition ability of a natural killer cell-activating receptor, DNAM-1 was harnessed to design CARs that target multiple tumor types. DNAM-1 ligands, PVR and nectin-2, are expressed on primary human leukemia, myeloma, ovarian cancer, melanoma, neuroblastoma, and Ewing sarcoma. DNAM-1 CARs exhibit high tumor cell cytotoxicity but low IFN-γ secretion in vitro. In contrast to other CAR designs, co-stimulatory domains did not improve the expression and function of DNAM-1 CARs. A DNAM-1/CD3zeta CAR reduced tumor burden in a murine melanoma model in vivo. In conclusion, DNAM-1-based CARs may have the potential to treat PVR and nectin-2 expressing hematological and solid tumors.

• Authors: Ming-Ru Wu, Tong Zhang, Andre Alcon, Charles L Sentman
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 64 Issue 4 Pg. 409-18 (Apr 2015) ISSN: 1432-0851 [Electronic] Germany
• PMID: 25549845 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, Differentiation, T-Lymphocyte
• CD226 antigen
• CD3 Complex
• CD3 antigen, zeta chain
• RNA, Messenger
• Receptors, Antigen, T-Cell

Topics

• Animals
• Antigens, Differentiation, T-Lymphocyte (genetics, immunology, metabolism)
• Blotting, Western
• CD3 Complex (genetics, immunology, metabolism)
• Cytotoxicity, Immunologic (immunology)
• Humans
• Melanoma (immunology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, Antigen, T-Cell (immunology)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes (immunology)
• Tumor Cells, Cultured