Targeting of T Lymphocytes to Melanoma Cells Through Chimeric Anti-GD3 Immunoglobulin T-Cell Receptors
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 s...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2000-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558600800159 |
| _version_ | 1830213056741769216 |
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| author | C.O. Yun K.F. Nolan E.J. Beecham R.A. Reisfeld P. Junghans |
| author_facet | C.O. Yun K.F. Nolan E.J. Beecham R.A. Reisfeld P. Junghans |
| author_sort | C.O. Yun |
| collection | DOAJ |
| description | 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-ɛ, sFv-ζ, Fab-ɛ, Fab-ζ. 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 μg/ml did not interfere with recognition and binding of membrane-bound antigen. Based on the outcomes of these structural and functional tests, the sFv-ζ 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. |
| first_indexed | 2024-12-18T06:15:18Z |
| format | Article |
| id | doaj.art-841534d181234fdf9a4702df30dc9c0e |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-18T06:15:18Z |
| publishDate | 2000-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-841534d181234fdf9a4702df30dc9c0e2022-12-21T21:18:17ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022000-09-012544945910.1038/sj.neo.7900108Targeting of T Lymphocytes to Melanoma Cells Through Chimeric Anti-GD3 Immunoglobulin T-Cell ReceptorsC.O. Yun0K.F. Nolan1E.J. Beecham2R.A. Reisfeld3P. Junghans4Biotherapeutics Development Lab, Harvard Institute of Human Genetics, Harvard Medical School, Boston, MA 02215Biotherapeutics Development Lab, Harvard Institute of Human Genetics, Harvard Medical School, Boston, MA 02215Biotherapeutics Development Lab, Harvard Institute of Human Genetics, Harvard Medical School, Boston, MA 02215Department of Immunology, Scripps Research Institute, La Jolla, CA 92037Biotherapeutics Development Lab, Harvard Institute of Human Genetics, Harvard Medical School, Boston, MA 02215Immunoglobulin 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-ɛ, sFv-ζ, Fab-ɛ, Fab-ζ. 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 μg/ml did not interfere with recognition and binding of membrane-bound antigen. Based on the outcomes of these structural and functional tests, the sFv-ζ 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.http://www.sciencedirect.com/science/article/pii/S1476558600800159T cellgene therapyimmunotherapysignalling |
| spellingShingle | C.O. Yun K.F. Nolan E.J. Beecham R.A. Reisfeld P. Junghans Targeting of T Lymphocytes to Melanoma Cells Through Chimeric Anti-GD3 Immunoglobulin T-Cell Receptors Neoplasia: An International Journal for Oncology Research T cell gene therapy immunotherapy signalling |
| title | Targeting of T Lymphocytes to Melanoma Cells Through Chimeric Anti-GD3 Immunoglobulin T-Cell Receptors |
| title_full | Targeting of T Lymphocytes to Melanoma Cells Through Chimeric Anti-GD3 Immunoglobulin T-Cell Receptors |
| title_fullStr | Targeting of T Lymphocytes to Melanoma Cells Through Chimeric Anti-GD3 Immunoglobulin T-Cell Receptors |
| title_full_unstemmed | Targeting of T Lymphocytes to Melanoma Cells Through Chimeric Anti-GD3 Immunoglobulin T-Cell Receptors |
| title_short | Targeting of T Lymphocytes to Melanoma Cells Through Chimeric Anti-GD3 Immunoglobulin T-Cell Receptors |
| title_sort | targeting of t lymphocytes to melanoma cells through chimeric anti gd3 immunoglobulin t cell receptors |
| topic | T cell gene therapy immunotherapy signalling |
| url | http://www.sciencedirect.com/science/article/pii/S1476558600800159 |
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