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EnglishT-cell receptor (TCR) gene transfer for cancer immunotherapy is limited by the availability of large numbers of tumorspecific T cells. TCR α and β chains were isolated from a highly lytic HLA-A2-restricted cytotoxic T lymphocyte (CTL) clone recognizing the melanoma-associated Melan-A/MART-1 antigen and inserted into a lentiviral vector carrying a bidirectional promoter capable of robust and coordinated expression of the two transgenes. Lentiviral vector-based gene delivery systems have shown increased transfer efficiency and transgene expression compared with the widely used γ-retroviral vectors. This vector performed more efficiently than a γ-retrovirus-based vector containing the same expression cassette, resulting in a T-cell population with 60% to 80% of transgenic TCR expression with mainly CD8+ intermediate effector phenotype. Transgenic T cells specifically produced cytokine in response to and killed antigen-expressing melanoma cells, retained an overlapping functional avidity in comparison with the TCR donor CTL clone, and exerted significant therapeutic effects in vivo upon adoptive transfer in melanoma-bearing severe combined immunodeficient mice. Optical imaging showed their accumulation in the tumor site. Overall, our results indicate that lentiviral vectors represent a valid tool for stable and high-intensity expression of transgenic TCR and support clinical exploitation of this approach for therapeutic application. ©2009 American Association for Cancer Research.
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| Data di pubblicazione: | 2009 | |
| Titolo: | Reprogramming T lymphocytes for melanoma adoptive immunotherapy by T-cell receptor gene transfer with lentiviral vectors | |
| Autori: | Bobisse, Sara; Rondina, Maria; Merlo, Anna; Tisato, Veronica; Mandruzzato, Susanna; Amendola, Mario; Naldini, Luigi; Willemsen, Ralph A.; Debets, Reno; Zanovello, Paola; Rosato, Antonio | |
| Rivista: | CANCER RESEARCH | |
| Parole Chiave: | Animals; Antigens, Neoplasm; Epitopes; Female; Genetic Vectors; HLA-A2 Antigen; Humans; Immunologic Memory; Immunotherapy, Adoptive; Jurkat Cells; Lentivirus; Leukocytes, Mononuclear; MART-1 Antigen; Melanoma; Mice; Mice, SCID; Neoplasm Proteins; Receptors, Antigen, T-Cell, alpha-beta; T-Lymphocytes; Transduction, Genetic; Genes, T-Cell Receptor alpha; Genes, T-Cell Receptor beta; Cancer Research; Oncology | |
| Abstract in inglese: | T-cell receptor (TCR) gene transfer for cancer immunotherapy is limited by the availability of large numbers of tumorspecific T cells. TCR α and β chains were isolated from a highly lytic HLA-A2-restricted cytotoxic T lymphocyte (CTL) clone recognizing the melanoma-associated Melan-A/MART-1 antigen and inserted into a lentiviral vector carrying a bidirectional promoter capable of robust and coordinated expression of the two transgenes. Lentiviral vector-based gene delivery systems have shown increased transfer efficiency and transgene expression compared with the widely used γ-retroviral vectors. This vector performed more efficiently than a γ-retrovirus-based vector containing the same expression cassette, resulting in a T-cell population with 60% to 80% of transgenic TCR expression with mainly CD8+ intermediate effector phenotype. Transgenic T cells specifically produced cytokine in response to and killed antigen-expressing melanoma cells, retained an overlapping functional avidity in comparison with the TCR donor CTL clone, and exerted significant therapeutic effects in vivo upon adoptive transfer in melanoma-bearing severe combined immunodeficient mice. Optical imaging showed their accumulation in the tumor site. Overall, our results indicate that lentiviral vectors represent a valid tool for stable and high-intensity expression of transgenic TCR and support clinical exploitation of this approach for therapeutic application. ©2009 American Association for Cancer Research. | |
| Digital Object Identifier (DOI): | 10.1158/0008-5472.CAN-09-0494 | |
| Handle: | http://hdl.handle.net/11392/2350771 | |
| Appare nelle tipologie: | 03.1 Articolo su rivista |
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