Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions

Marybeth S. Hughes, Yik Y L Yu, Mark E. Dudley, Zhili Zheng, Paul F. Robbins, Yong Li, John Wunderlich, Robert G. Hawley, Morvarid Moayeri, Steven A. Rosenberg, Richard A. Morgan

Research output: Contribution to journalArticle

Abstract

The genes for the α and β chains of a highly reactive anti-MART-1 T-cell receptor were isolated from T-lymphocytes that mediated in vivo regression of tumor in a patient with metastatic melanoma. These genes were cloned and inserted into MSCV-based retroviral vectors. After transduction, greater than 50% gene transfer efficiency was demonstrated in primary T-lymphocytes stimulated by an anti-CD3 antibody. The specificity and biologic activity of TCR gene-transduced T-cells was determined by cytokine production after coculture of T-cells with stimulator cells pulsed with MART-1 peptide. The production of interferon-γ and granulocyte macrophage-colony stimulating factor (GM-CSF) was comparable to highly active MART-1 specific peripheral blood lymphocytes (PBL) in the amount of cytokine produced and transduced cells recognized peptide pulsed cells at dilutions similar to cytotoxic T lymphocyte (CTL) clones. Human leukocyte antigen (HLA) class I restricted recognition was demonstrated by mobilization of degranulation marker CD107a, by cell lysis, by cytokine production, and by proliferation in the presence of HLA-A2-positive but not HLA-A2-negative melanoma cell lines. Similar data was obtained when tumor-infiltrating lymphocytes (TIL) were transduced with the TCR genes, converting previously nonreactive cells to tumor reactive cells. TCR-transduced T-cells are thus attractive candidates for evaluation in cell transfer therapies of patients with cancer.

Original languageEnglish (US)
Pages (from-to)457-472
Number of pages16
JournalHuman Gene Therapy
Volume16
Issue number4
DOIs
StatePublished - Apr 2005
Externally publishedYes

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T-Lymphocytes
HLA Antigens
Genes
Cytokines
varespladib methyl
Melanoma
Tumor-Infiltrating Lymphocytes
Patient Transfer
Neoplasms
Peptides
Cytotoxic T-Lymphocytes
Granulocyte-Macrophage Colony-Stimulating Factor
Cell- and Tissue-Based Therapy
Coculture Techniques
T-Cell Antigen Receptor
Interferons
Anti-Idiotypic Antibodies
Clone Cells
Lymphocytes
Cell Line

ASJC Scopus subject areas

  • Genetics

Cite this

Hughes, M. S., Yu, Y. Y. L., Dudley, M. E., Zheng, Z., Robbins, P. F., Li, Y., ... Morgan, R. A. (2005). Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions. Human Gene Therapy, 16(4), 457-472. https://doi.org/10.1089/hum.2005.16.457

Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions. / Hughes, Marybeth S.; Yu, Yik Y L; Dudley, Mark E.; Zheng, Zhili; Robbins, Paul F.; Li, Yong; Wunderlich, John; Hawley, Robert G.; Moayeri, Morvarid; Rosenberg, Steven A.; Morgan, Richard A.

In: Human Gene Therapy, Vol. 16, No. 4, 04.2005, p. 457-472.

Research output: Contribution to journalArticle

Hughes, MS, Yu, YYL, Dudley, ME, Zheng, Z, Robbins, PF, Li, Y, Wunderlich, J, Hawley, RG, Moayeri, M, Rosenberg, SA & Morgan, RA 2005, 'Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions', Human Gene Therapy, vol. 16, no. 4, pp. 457-472. https://doi.org/10.1089/hum.2005.16.457
Hughes, Marybeth S. ; Yu, Yik Y L ; Dudley, Mark E. ; Zheng, Zhili ; Robbins, Paul F. ; Li, Yong ; Wunderlich, John ; Hawley, Robert G. ; Moayeri, Morvarid ; Rosenberg, Steven A. ; Morgan, Richard A. / Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions. In: Human Gene Therapy. 2005 ; Vol. 16, No. 4. pp. 457-472.
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