Abstract
Adoptive cell transfer therapy using tumor-infiltrating lymphocytes for patients with metastatic melanoma has demonstrated significant objective response rates. One major limitation of these current therapies is the frequent inability to isolate tumor-reactive lymphocytes for treatment. Genetic engineering of peripheral blood lymphocytes with retroviral vectors encoding tumor antigen-specific T-cell receptors (TCRs) bypasses this restriction. To evaluate the efficacy of TCR gene therapy, a murine treatment model was developed. A retroviral vector was constructed encoding the pmel-1 TCR genes targeting the B16 melanoma antigen, gp100. Transduction of C57BL/6 lymphocytes resulted in efficient pmel-1 TCR expression. Lymphocytes transduced with this retrovirus specifically recognized gp100-pulsed target cells as measured by interferon-gamma secretion assays. Upon transfer into B16 tumor-bearing mice, the genetically engineered lymphocytes significantly slowed tumor development. The effectiveness of tumor treatment was directly correlated with the number of TCR-engineered T cells administered. These results demonstrated that TCR gene therapy targeting a native tumor antigen significantly delayed the growth of established tumors. When C57BL/6 lymphocytes were added to antigen-reactive pmel-1 T cells, a reduction in the ability of pmel-1 T cell to treat B16 melanomas was seen, suggesting that untransduced cells may be deleterious to TCR gene therapy. This model may be a powerful tool for evaluating future TCR gene transfer-based strategies.
Original language | English |
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Pages (from-to) | 1-6 |
Number of pages | 6 |
Journal | Human vaccines & immunotherapeutics |
Volume | 31 |
Issue number | 1 |
DOIs | |
Publication status | Published - Jan 2008 |
Keywords
- Animals
- CD8-Positive T-Lymphocytes
- Cell Line, Tumor
- Coculture Techniques
- Genetic Therapy
- Genetic Vectors
- Immunophenotyping
- Immunotherapy, Adoptive
- Interferon-gamma
- Lymphocyte Activation
- Lymphocytes
- Melanoma, Experimental
- Membrane Glycoproteins
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Receptors, Antigen, T-Cell
- Receptors, Antigen, T-Cell, alpha-beta
- Spleen
- Transfection
- gp100 Melanoma Antigen
- Journal Article
- Research Support, N.I.H., Intramural