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  • Review Article
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Gene-engineered T cells for cancer therapy

Nature Reviews Cancer volume 13, pages 525–541 (2013)Cite this article

Subjects

Key Points

  • The abilities of T cells to coordinate immunity and to deliver lethal hits against diseased cells can be directed towards tumours by genetically modifying T cells.

  • Genes encoding specific antigen receptors can be inserted into T cells to enable them to recognize and respond to cancer cells.

  • Migration of T cells towards tumours can be facilitated by the expression of specific chemokine receptors in T cells.

  • Genetic modification of T cells can enhance their proliferation and survival, leading to a sustained attack on tumours.

  • Resistance to tumour-derived immunosuppressive factors can be provided genetically to T cells so that they can maintain their activity in a hostile environment.

  • Genes that confer sensitivity to drugs can be used to enable the elimination of T cells if they exert toxicity against vital normal tissues.

Abstract

T cells have the capacity to eradicate diseased cells, but tumours present considerable challenges that render T cells ineffectual. Cancer cells often make themselves almost 'invisible' to the immune system, and they sculpt a microenvironment that suppresses T cell activity, survival and migration. Genetic engineering of T cells can be used therapeutically to overcome these challenges. T cells can be taken from the blood of cancer patients and then modified with genes encoding receptors that recognize cancer-specific antigens. Additional genes can be used to enable resistance to immunosuppression, to extend survival and to facilitate the penetration of engineered T cells into tumours. Using genetic modification, highly active, self-propagating 'slayers' of cancer cells can be generated.

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Figure 1: Derivation of TCRs and CARs for the genetic modification of T cells.
Figure 2: The design of successive generations of CARs.
Figure 3: Genetic engineering strategies.
Figure 4: Examples of gene-engineered T cells attacking cancer cells.

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Acknowledgements

The authors wish to acknowledge funding from the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Sir Peter MacCallum Department of Oncology, Cancer Immunology Research Program, University of Melbourne, Parkville, 3010, Victoria, Australia

    Michael H. Kershaw, Jennifer A. Westwood & Phillip K. Darcy

  2. Department of Immunology, Monash University, Prahran, Victoria, 3181, Australia

    Michael H. Kershaw & Phillip K. Darcy

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  1. Michael H. Kershaw
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  2. Jennifer A. Westwood
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Correspondence to Michael H. Kershaw.

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PowerPoint slides

Glossary

Major histocompatibility complex

(MHC). A family of polymorphic molecules that are expressed on the surface of cells that associate with peptide antigens. T cells are activated by interaction between their T cell receptor and MHC peptide.

Tumour-infiltrating lymphocytes

(TILs). Various lymphocytes exist, including T cells, B cells and natural killer (NK) cells. These types of cells can be found within tumours.

Macrophages

A type of white blood cell that is able to engulf particulate matter or even whole cells.

Granulocytes

A type of white blood cell with a lobular nucleus. There are three main types of granulocyte: neutrophil, basophil and eosinophil.

Immune tolerance

A state in which autoreactive T cells and B cells are rendered non-responsive by the deletion or withdrawal of growth factors and survival signals. Tolerance can be induced at an early stage of cell development in a process termed central tolerance, or at later stages of cell development in a process termed peripheral tolerance.

Allogeneic

From another individual of the same species.

HLA type

The array of major histocompatibility complex genes in an individual.

Humanized

Much of the molecular framework of mouse T cell receptors and antibodies is replaced with similar regions from their human molecular counterparts, while retaining the antigen-binding regions of the mouse molecules.

CD4+ T helper cells

T cells that express CD4 and that normally interact with antigen in the context of major histocompatibility complex class II. On engagement with antigen, CD4+ T cells secrete cytokines that can stimulate ('help') CD8+ cytotoxic T lymphocytes to enable their optimal activation and proliferation.

Co-stimulatory molecules

Molecules that are expressed on the surface of T cells and that transmit signals on engagement with their ligands expressed by tumour cells or antigen-presenting cells. These signals are transmitted, in addition to the primary activation signal mediated by the T cell receptor (TCR), to amplify the TCR signal, leading to the full activation of T cells.

Cytotoxic T lymphocytes

(CTLs). A type of T cell that usually expresses CD8 and that recognizes antigen in the context of major histocompatibility complex class I. Following interaction between the T cell receptor and antigen, CD8+ T cells deliver cytotoxic hits against target cells through the secretion of lytic molecules.

Central memory

T cells that express CCR7 and CD62L and that recirculate among lymphoid tissue. They have a greater capacity to secrete cytokines than stem cell memory T cells but a relatively lower ability to self-renew.

Effector memory

T cells that lack expression of CD62L and CCR7 and that are predominantly found in peripheral tissues. Their ability to respond to antigen by secreting cytokines and carrying out cytolysis is increased above that of central memory T cells, but their capacity to self-renew is relatively low.

Stem cell memory T cells

Derived from naive T cells and express CCR7 and CD62L, which enable homing to the lymphoid compartment. They have a low capacity to engage in cytolysis and secretion of cytokines in response to antigen, but have the greatest capacity to self-renew and are able to generate the other subsets of memory and effector T cells.

Myeloid-derived suppressor cells

(MDSCs). A granulocyte-like cell, expressing CD11b and GR1, that can inhibit T cells through the production of TGFβ and the amino acid-depleting enzyme arginase.

T regulatory cells

(TReg cells). A type of T cell, usually expressing CD4, CD25 and FOXP3, which can inhibit the function of other T cells through a number of mechanisms including consumption of IL-2, production of TGFβ and inhibition of antigen-presenting cells.

Immune checkpoint receptors

Cell-surface molecules that are expressed by T cells and the normal function of which is to maintain self-tolerance and regulate the magnitude and duration of immune responses. Checkpoint receptors, including PD1 and TIM3, can be co-opted by tumours to inhibit antitumour immune responses.

Objective responses

A reduction in tumour burden that satisfies the criteria for a complete or partial response.

Partial responses

Usually refers to at least a 30% decrease in the sum of the longest diameters of all target lesions.

Complete response

The disappearance of all target lesions.

Colitis

Inflammation of the large intestine (colon) that can lead to bleeding, ulceration and loss of bowel function.

Universal CARs

Have extracellular antibody domains specific for a fluorochrome or biotin. T cells bearing these CARs could be used in combination with a fluoresceinated or biotin-coupled antibody specific for an antigen on any type of tumour.

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Kershaw, M., Westwood, J. & Darcy, P. Gene-engineered T cells for cancer therapy. Nat Rev Cancer 13, 525–541 (2013). https://doi.org/10.1038/nrc3565

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