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Targeting of T lymphocytes to melanoma cells through chimeric anti-GD3 immunoglobulin T-cell receptors

Authors
 C.O Yun  ;  K. F. Nolan  ;  E.J. Beecham  ;  R.A. Reisfeld  ;  P. Junghans 
Citation
 Neoplasia, Vol.2(5) : 449-459, 2000 
Journal Title
NEOPLASIA
ISSN
 1522-8002 
Issue Date
2000
MeSH
Animals ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/immunology* ; Antigens, Neoplasm/immunology* ; Binding Sites ; Cell Line ; Chemotaxis, Leukocyte/physiology* ; Cytotoxicity, Immunologic ; Gangliosides/immunology* ; Genes, Immunoglobulin ; Humans ; Immunoglobulin Fab Fragments/genetics ; Immunoglobulin Fab Fragments/immunology ; Immunoglobulin Fragments/genetics ; Immunoglobulin Fragments/immunology ; Immunoglobulin Variable Region/genetics ; Immunoglobulin Variable Region/immunology ; Immunotherapy, Adoptive ; Interleukin-2/biosynthesis ; Jurkat Cells ; Kidney ; Melanoma/immunology* ; Membrane Proteins/genetics ; Mice ; Rats ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/immunology* ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/immunology ; T-Lymphocytes, Cytotoxic/cytology* ; T-Lymphocytes, Cytotoxic/immunology ; Transfection
Keywords
T-Cell ; Gene Therapy ; Immunotherapy ; Signalling
Abstract
Immunoglobulin T-cell receptors (IgTCRs) combine the specificity of antibodies with the potency of cellular killing by grafting antibody recognition domains onto TCR signaling chains. IgTCR-modified T cells are thus redirected to kill tumor cells based on their expression of intact antigen on cell surfaces, bypassing the normal mechanism of activation through TCR-peptide-major histocompatibility complex (MHC) recognition. Melanoma is one of the most immunoresponsive of human cancers and has served as a prototype for the development of a number of immunotherapies. The target antigen for this study is the ganglioside GD3, which is highly expressed on metastatic melanoma with only minor immunologic cross-reaction with normal tissues. To determine an optimal configuration for therapy, four combinations of IgTCRs were prepared and studied: sFv-epsilon, sFv-zeta, Fab-epsilon, Fab-zeta. These were expressed on the surface of human T cells by retroviral transduction. IgTCR successfully redirected T-cell effectors in an MHC-unrestricted manner, in this case against a non-T-dependent antigen, with specific binding, activation, and cytotoxicity against GD3+ melanoma cells. Soluble GD3 in concentrations up to 100 microg/ml did not interfere with recognition and binding of membrane-bound antigen. Based on the outcomes of these structural and functional tests, the sFv-zeta construct was selected for clinical development. These results demonstrate key features that emphasize the potential of anti-GD3 IgTCR-modified autologous T cells for melanoma therapies.
Files in This Item:
T200002551.pdf Download
DOI
10.1038/sj.neo.7900108
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
Yonsei Authors
Yun, Chae Ok(윤채옥)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/171812
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