Long-term phenotypic, functional and genetic stability of cancer-specific T-cell receptor (TCR) alphabeta genes transduced to CD8+ T cells.
In adoptive T-cell transfer as an intervention for malignant diseases, retroviral transfer of T-cell receptor (TCR) genes derived from CD8(+) cytotoxic T-lymphocyte (CTL) clones provides an opportunity to generate a large number of T cells with the same antigen specificity. We cloned the TCR-alphabeta genes from a human leukocyte antigen (HLA)-A(*)2402-restricted CTL clone specific for MAGE-A4(143-151). The TCR-alphabeta genes were transduced to 99.2% of non-TCR expressing SupT1, a human T-cell line, and to 12.7-32.6% of polyclonally activated CD8(+) T cells by retroviral transduction. As expected, TCR-alphabeta gene-modified CD8(+) T cells showed cytotoxic activity and interferon-gamma production in response to peptide-loaded T2-A(*)2402 and tumor cell lines expressing both MAGE-A4 and HLA-A(*)2402. A total of 24 clones were established from TCR-alphabeta gene-transduced peripheral blood mononuclear cells and all clones were functional on a transduced TCR-dependent manner. Four clones were kept in culture over 6 months for analyses in detail. The transduced TCR-alphabeta genes were stably maintained phenotypically, functionally and genetically. Our results indicate that TCR-transduced alphabeta T cells by retroviral transduction represent an efficient and promising strategy for adoptive T-cell transfer for long term.
Hiasa
A
A
Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
Hirayama
M
M
Nishikawa
H
H
Kitano
S
S
Nukaya
I
I
Yu
S S
SS
Mineno
J
J
Kato
I
I
Shiku
H
H
D019264:Adoptive Transfer / Q000379:methods*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003601:Cytotoxicity Tests, Immunologic; D019673:Genes, T-Cell Receptor alpha; D019674:Genes, T-Cell Receptor beta; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D012190:Retroviridae / Q000235:genetics; D037182:T-Cell Antigen Receptor Specificity; D013995:Time; D014161:Transduction, Genetic / Q000379:methods*
D007371:Interferon-gamma