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Long-term phenotypic, functional and genetic stability of cancer-specific T-cell receptor (TCR) αβ genes transduced to CD8+ T cells

Gene Therapy volume 15, pages 695–699 (2008)Cite this article

Abstract

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-αβ genes from a human leukocyte antigen (HLA)-A*2402-restricted CTL clone specific for MAGE-A4143–151. The TCR-αβ 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-αβ gene-modified CD8+ T cells showed cytotoxic activity and interferon-γ 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-αβ 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-αβ genes were stably maintained phenotypically, functionally and genetically. Our results indicate that TCR-transduced αβ T cells by retroviral transduction represent an efficient and promising strategy for adoptive T-cell transfer for long term.

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Abbreviations

CTL:

cytotoxic T lymphocyte

EBV-B cells:

Epstein–Barr virus-transformed B cells

ELISA:

enzyme-linked immunosorbent assay

ELISPOT assay:

enzyme-linked immunospot assay

GM-CSF:

granulocyte macrophage colony-stimulating factor

HLA:

human leukocyte antigen

IFN:

interferon

IL:

interleukin

LTR:

long terminal repeat

MSCV:

murine stem cell virus

PBLs:

peripheral blood lymphocytes

PBMCs:

peripheral blood mononuclear cells

PGK:

phosphoglycerate kinase

TCR:

T-cell receptors

TNF:

tumor necrosis factor.

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Acknowledgements

We thank C Hyuga, S Hori and J Suzuki for their excellent technical support. This study was supported by a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Author notes

  1. A Hiasa and M Hirayama: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan

    A Hiasa, M Hirayama, S Kitano & H Shiku

  2. Department of Cancer Vaccine, Mie University Graduate School of Medicine, Mie, Japan

    M Hirayama, H Nishikawa & H Shiku

  3. Center for Cell and Gene Therapy, Takara Bio Inc., Shiga, Japan

    I Nukaya, S S Yu, J Mineno & I Kato

Authors
  1. A Hiasa
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  2. M Hirayama
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  3. H Nishikawa
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  4. S Kitano
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  5. I Nukaya
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  6. S S Yu
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  7. J Mineno
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  8. I Kato
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  9. H Shiku
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Corresponding author

Correspondence to H Shiku.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Hiasa, A., Hirayama, M., Nishikawa, H. et al. Long-term phenotypic, functional and genetic stability of cancer-specific T-cell receptor (TCR) αβ genes transduced to CD8+ T cells. Gene Ther 15, 695–699 (2008). https://doi.org/10.1038/sj.gt.3303099

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