Cytotoxic T lymphocytes with a grafted recognition specificity for ERBB2-expressing tumor cells.
Experimental approaches which exploit the targeted cytolytic activity of lymphocytes are being developed for cancer therapy. We generated cytotoxic T lymphocytes (CTLs) with specificity for ERBB2 receptor-expressing tumor cells. A binding function was conferred directly on the zeta chain of the T-cell receptor (TCR) complex to circumvent major histocompatibility complex-restricted antigen recognition through the alpha and beta chains of the TCR. A chimeric gene was constructed which encoded a single-chain Fv antibody (scFv, consisting of the joined heavy- and light-chain variable domains of a monoclonal antibody against the extracellular domain of the ERBB2 receptor), a hinge region as a spacer, and the zeta chain of the TCR. This gene was introduced into CTLs by retroviral gene transfer. The signaling potential of the scFv/hinge/zeta receptors was demonstrated by secretion of interferon gamma upon coincubation with ERBB2-expressing cells. Target cells expressing the ERBB2 gene were lysed in vitro with high specificity by the scFv/hinge/zeta-expressing T cells. The growth of ERBB2-transformed cells in athymic nude mice was retarded by adoptively transferred scFv/hinge/zeta-expressing CTLs. Transduced CTLs labeled with a fluorescent dye were specifically detected in tumor sections. Our results suggest that tumor cell lysis by CTLs grafted in vitro with a major histocompatibility complex-independent recognition could become a gene-therapy approach to cancer treatment.
Moritz
D
D
Friedrich Miescher-Institute, Basel, Switzerland.
Wels
W
W
Mattern
J
J
Groner
B
B
D016475:3T3 Cells; D000818:Animals; D014408:Biomarkers, Tumor; D002460:Cell Line; D003001:Cloning, Molecular; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000096:biosynthesis / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000276:immunology* / Q000302:isolation & purification; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000276:immunology / Q000302:isolation & purification; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000276:immunology / Q000302:isolation & purification; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*; D014162:Transfection
D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D007371:Interferon-gamma; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins