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  • Review Article
  • Published:

Supernatural T cells: genetic modification of T cells for cancer therapy

Nature Reviews Immunology volume 5, pages 928–940 (2005)Cite this article

Key Points

  • Despite having the power to protect us against infectious diseases, the immune system that Mother Nature provides ultimately fails when it comes to cancer. The same immune-system checks and balances that guard against autoimmunity lead to fundamental shortfalls and deficiencies in the antitumour capabilities of the endogenous immune system.

  • Our understanding of the molecular events that are important in the recognition of microorganisms by immune cells, and the downstream signalling processes that are important in mediating a response to these microbial threats, has led to the design of genes that can enable us to correct deficiencies in the anticancer immune response.

  • The endogenous immune system often lacks effective tumour-specific T cells, but specificity can be provided by genetic modification of 'ordinary' T cells with genes that encode cell-surface receptors that allow recognition of tumour cells. Examples of such receptors are T-cell receptors from rare responding patients or chimeric receptors that incorporate tumour-specific monoclonal antibodies.

  • It is possible to combine, within a single chimeric-receptor gene, molecular domains from several signal-transducing molecules to produce a 'super receptor' that endows T cells with increased antitumour activity.

  • When engaged in the struggle with tumour cells, natural T cells quickly 'tire', leading to their exhaustion or death. Various genetic strategies can be used to extend the lifespan of tumour-reactive T cells, with the possibility of producing the ultimate 'immortal' tumour-fighting cellular warriors.

  • Tumours might lack appropriate molecular signals that are important for attracting endogenous tumour-specific T cells. Genetic modification can be used to guide these T cells and enable them to home to, and penetrate, tumour tissue.

  • Tumours can produce inhibitory factors that can dampen the immune response, but T cells can be transduced with genes that endow them with resistance to such factors, thereby allowing them to realize their full antitumour potential.

  • With further improvements in the technology and the safety of genetic-modification strategies, it might soon be possible to transduce ordinary T cells with multiple genes to endow them with a coordinated genetic programme that gives them extraordinary activity against cancer.

Abstract

Immunotherapy is receiving much attention as a means of treating cancer, but complete, durable responses remain rare for most malignancies. The natural immune system seems to have limitations and deficiencies that might affect its ability to control malignant disease. An alternative to relying on endogenous components in the immune repertoire is to generate lymphocytes with abilities that are greater than those of natural T cells, through genetic modification to produce 'supernatural' T cells. This Review describes how such T cells can circumvent many of the barriers that are inherent in the tumour microenvironment while optimizing T-cell specificity, activation, homing and antitumour function.

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Figure 1: Schematic representation of a typical chimeric receptor.
Figure 2: Schematic representation of a supernatural T cell.

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Acknowledgements

We acknowledge support from the National Health and Medical Research Council (Australia), The Cancer Council Victoria (Australia) and the Susan G. Komen Breast Cancer Foundation (United States). We apologize to colleagues whose work might have been cited only indirectly through reviews, owing to space constraints.

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Authors and Affiliations

  1. Peter MacCallum Cancer Centre, Saint Andrews Place, East Melbourne, 3002, Victoria, Australia

    Michael H. Kershaw, Michele W. L. Teng, Mark J. Smyth & Phillip K. Darcy

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  1. Michael H. Kershaw
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  2. Michele W. L. Teng
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  3. Mark J. Smyth
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Correspondence to Michael H. Kershaw.

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DATABASES

Entrez Gene

4-1BB

BCL-2

BCL-XL

CD3ζ

CD4

CD28

CD95

CD95 ligand

CTLA4

CXCR2

DAP12

GATA3

ICOS

LCK

NKG2A

OX40

PD1

SYK

TGF-β

TNF

Glossary

TUMOUR-ASSOCIATED ANTIGEN

(TAA). An antigen that is expressed by tumour cells. These antigens belong to four main categories: overexpressed antigens that are also expressed in small amounts in some normal tissues; tissue-differentiation antigens, which are also expressed by non-malignant cells; mutated or aberrantly expressed molecules; and cancer-testis antigens, which are normally expressed in the testes and occasionally in the placenta.

CENTRAL TOLERANCE

Self-tolerance that is created at the level of the central lymphoid organs. Developing T cells, in the thymus, and B cells, in the bone marrow, that strongly recognize self-antigen face deletion or marked suppression.

PERIPHERAL TOLERANCE

The lack of self-responsiveness of mature lymphocytes in the periphery to specific antigens. These mechanisms control potentially self-reactive lymphocytes that have escaped central tolerance. Peripheral tolerance is associated with suppression of production of self-reactive antibodies by B cells and inhibition of self-reactive effector cells, such as cytotoxic T lymphocytes.

HUMANIZATION

A process by which parts of molecules originating from other species are replaced by the homologous domains of human molecules, using recombinant DNA techniques.

SINGLE-CHAIN VARIABLE FRAGMENT

A recombinant molecule that is composed of the variable regions of the heavy and light chains of immunoglobulin joined by a flexible oligopeptide linker.

HAPTEN

A molecule that can bind antibody but cannot by itself elicit an immune response. Antibodies that are specific for a hapten can be generated when the hapten is chemically linked to a protein carrier that can elicit a T-cell response.

IMMUNOEDITING

The process by which interaction of a heterogeneous population of tumour cells with the immune system generates tumour variants with reduced immunogenicity, which might therefore escape from immune responses.

SIGNAL-MOTIF LIBRARY

A collection of cDNA clones that encodes various intracellular-signalling domains joined together randomly and ligated to an extracellular antigen-recognition domain. Individual cells displaying different signalling constructs are screened for optimal function.

TELOMERES

Regions of highly repetitive DNA at the ends of linear eukaryotic chromosomes. They protect the ends of chromosomes from shortening on replication. Telomerase reverse transcriptase is a ribonucleoprotein enzyme that maintains the ends of chromosomes by adding a characteristic series of nucleotides to telomeres.

SMALL INTERFERING RNA

(siRNA). Synthetic RNA molecules of 19–23 nucleotides that are used to 'knockdown' (that is, silence the expression of) a specific gene. This is known as RNA interference (RNAi) and is mediated by the sequence-specific degradation of mRNA.

PATTERN-RECOGNITION RECEPTOR

(PRR). A host receptor (such as Toll-like receptors) that can sense pathogen-associated molecular patterns and initiate signalling cascades (which involve activation of nuclear factor-κB) that lead to an innate immune response.

CD4+CD25+ REGULATORY T CELL

A specialized type of CD4+ T cell that can suppress the responses of other T cells. These cells provide a crucial mechanism for the maintenance of peripheral self-tolerance and are characterized by expression of CD25 (also known as the α-chain of the interleukin-2 receptor) and the transcription factor forkhead box P3 (FOXP3).

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Kershaw, M., Teng, M., Smyth, M. et al. Supernatural T cells: genetic modification of T cells for cancer therapy. Nat Rev Immunol 5, 928–940 (2005). https://doi.org/10.1038/nri1729

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