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  • Review Article
  • Published:

T-cell-receptor gene therapy

Nature Reviews Immunology volume 2, pages 512–519 (2002)Cite this article

Key Points

  • The induction of T-cell immunity against foreign antigens in healthy individuals is best achieved by vaccination.

  • Adoptive-transfer-based approaches for the induction of T-cell immunity are favoured in situations in which individuals are unable to mount the desired T-cell response, such as in settings of immunodeficiency or self-tolerance.

  • The adoptive transfer of T cells is a clinical strategy of proven value, but its application is limited by the complicated nature of the process.

  • Experiments in mouse model systems indicate that the adoptive transfer of T-cell receptors (TCRs) might be an interesting alternative strategy that would have several advantages. However, TCR gene transfer has not been tested yet in clinical trials.

  • A main advantage of TCR gene transfer is that it would allow the use of in vitro-selected or -engineered TCRs. It remains unclear whether increasing the affinity of TCRs would enhance the in vivo function of redirected T cells.

  • Chimeric receptors might be an interesting alternative to full-length TCR genes. However, the relative merits of the two approaches have not been compared in in vivo models.

  • To make TCR gene transfer a realistic therapeutic option, it will be important to establish the possible side-effects of this procedure. Furthermore, a precondition for widespread application will be the development of rapid and simple gene-transfer strategies.

  • As for many other gene-therapy trials, minimization of the immunogenicity of introduced gene products remains an important issue.

Abstract

T cells are tightly controlled cellular machines that monitor changes in epitope presentation. Although T-cell function is regulated by means of numerous interactions with other cell types and soluble factors, the T-cell receptor (TCR) is the only structure on the T-cell surface that defines its antigen-recognition potential. Consequently, the transfer of T-cell receptors into recipient cells can be used as a strategy for the passive transfer of T-cell immunity. In this review, I discuss the pros and cons of TCR gene transfer as a strategy to induce defined virus- and tumour-specific T-cell immunity.

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Figure 1: Vector systems for stable gene transfer.
Figure 2: Mixed TCR dimers and ignorant self-specific cells.
Figure 3: Alloreactivity and TCR transfer.

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Acknowledgements

I wish to apologize to those colleagues whose work could not be discussed owing to space limitations. I thank my colleagues at the Department of Immunology, in particular H. Kessels and M. Wolkers for their useful comments and suggestions. Work in my laboratory is supported by grants from the Dutch Cancer Society and the Netherlands Organization for Scientific Research.

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  1. Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, CX, 1066, Amsterdam, The Netherlands

    Ton N. M. Schumacher

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Glossary

ACTIVE IMMUNIZATION

The induction of immunity by activation and expansion of the endogenous immune repertoire.

PASSIVE IMMUNIZATION

The induction of immunity by the transfer of immunoglobulins or T cells.

LYMPHOMA

A tumour derived from cells that are native to the lymphoid tissues, such as B cells and T cells.

HER2/NEU

Human epidermal growth factor receptor 2; a receptor tyrosine kinase that is overexpressed in a subset of human breast cancers.

SV40 LARGE T ANTIGEN

A transforming protein that is encoded by simian virus 40 and that is also a target of CTL attack.

ALLOGENEIC STEM-CELL TRANSPLANTATION

(allo-SCT). The transfer of haematopoietic stem cells from donor to recipient. To achieve antitumour effects, the transplant either contains donor T cells or transplantation is followed by donor lymphocyte infusions.

MINOR HISTOCOMPATIBILITY ANTIGENS

Polymorphic peptides derived from normal cellular proteins that can be recognized in the context of MHC molecules. Immune responses against these polymorphic antigens can result in graft-versus-host reactions, graft rejection or beneficial antitumour responses.

RETROVIRAL TRANSDUCTION

The introduction of genes through infection of cells with a retrovirus that carries the target gene.

EPISOMAL REPLICATION

The autonomous replication of plasmid DNA that resides in host cells without chromosomal integration.

IGNORANCE

Failure to initiate a T-cell response through lack of encounter with antigen — for example, owing to compartmentalization of antigen.

ALLELIC EXCLUSION

Inhibition of the rearrangement of the second TCR allele on function rearrangement of the first allele.

SUICIDE GENES

Genes that are used in gene-transfer protocols, such as the herpes-simplex virus thymidine kinase gene, that allow the regulated death of the gene-modified cell population.

MHC TETRAMERS

Fluorescently labelled tetravalent complexes of MHC class I or class II molecules with antigenic peptide. They can be used to identify antigen-specific T cells by flow cytometry.

SOMATIC HYPERMUTATION

The process by which antigen-activated B cells in germinal centres mutate their rearranged immunoglobulin genes.

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Schumacher, T. T-cell-receptor gene therapy. Nat Rev Immunol 2, 512–519 (2002). https://doi.org/10.1038/nri841

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