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  • Review Article
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DNA vaccines: precision tools for activating effective immunity against cancer

Nature Reviews Cancer volume 8, pages 108–120 (2008)Cite this article

Key Points

  • Preventative vaccination against infectious organisms has had a dramatic effect on public health. Therapeutic vaccination against cancer is more challenging but, armed with new immunological insight and genetic technology, aims similarly to harness the power of the immune system, in this case to destroy or suppress tumour cells.

  • Passively transferred antibodies and T cells are clearly able to attack human cancer cells in vivo and are included in treatment protocols for some cancers. Active vaccination would generate these effector pathways, together with immunological memory that is able to continuously detect and remove any emergent cancer cells.

  • Tumour antigens are being rapidly revealed, and can be expressed on cell surfaces or, more commonly, as peptides in association with the major histocompatibility complex class I (or II) molecules. DNA vaccines can be designed to activate antibody and/or T-cell responses, providing focused immune attack on selected antigens.

  • DNA vaccines offer a precise but flexible strategy for delivering antigens to the immune system, and additional sequences encoding molecules to manipulate outcome can be included. The problem of translating success in preclinical models to patients seems to be overcome by using electroporation, which dramatically improves performance and is now in clinical trials for prostate cancer.

  • The key to bypassing immune tolerance and activating high levels of anti-tumour antibody or cytotoxic T cells lies in inducing CD4+ T-cell help. Sequences derived from microbial antigens can be incorporated into anti-tumour DNA vaccines, a strategy which mobilizes help for anti-tumour responses from the large non-tolerized anti-microbial repertoire.

  • Clinical trials are the real test, but the current question is largely of efficacy rather than toxicity. New thinking is informing pilot trial design within a highly regulated environment, and immunological assays that can be predictors of clinical outcome are developing rapidly.

Abstract

DNA vaccination has suddenly become a favoured strategy for inducing immunity. The molecular precision offered by gene-based vaccines, together with the facility to include additional genes to direct and amplify immunity, has always been attractive. However, the apparent failure to translate operational success in preclinical models to the clinic, for reasons that are now rather obvious, reduced initial enthusiasm. Recently, novel delivery systems, especially electroporation, have overcome this translational block. Here, we assess the development, current performance and potential of DNA vaccines for the treatment of cancer.

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Figure 1: Routes of antigen presentation.
Figure 2: A DNA fusion vaccine designed to activate immunity against B-cell lymphoma.
Figure 3: Pathway of provision of T-cell help for B cells.
Figure 4: DNA fusion vaccine designs based on help from fragment C.
Figure 5: T-cell help for induction of anti-tumour T-cell responses.
Figure 6: pDUO: a novel vaccine design that induces CD8+ T-cell responses by direct presentation.

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Acknowledgements

We thank the Leukaemia Research Fund, Tenovus and Cancer Research UK for support.

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Authors and Affiliations

  1. Cancer Sciences Division, Genetic Vaccine Group, University of Southampton School of Medicine, Southampton General Hospital, Southampton, SO16 6YD, UK

    Jason Rice, Christian H. Ottensmeier & Freda K. Stevenson

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  1. Jason Rice
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  2. Christian H. Ottensmeier
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  3. Freda K. Stevenson
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Correspondence to Freda K. Stevenson.

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Competing interests

Jason Rice, Christian H. Ottensmeier and Freda K. Stevenson hold stock in a small company (Genvax), of which Freda K. Stevenson is also a director. Jason Rice and Freda K. Stevenson also hold patents on their DNA fusion gene vaccine designs.

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DATABASES

National Cancer Institute

melanoma

prostate cancer

FURTHER INFORMATION

Freda K. Stevenson's homepage

Cancer Immunotherapy Consortium

Gene Therapy Clinical Trials Worldwide

Glossary

Graft versus leukaemia

Following allotransplantation of bone marrow or blood stem cells from a healthy donor into an MHC-matched patient, donor T cells may recognize peptides on patient leukaemia cells that result from polymorphic differences between the two individuals, resulting in beneficial immune attack.

Idiotypic antigen

Individual antigenic determinants from the variable regions of the Ig heavy and light chains are referred to as idiotopes; the sum of the individual idiotopes is referred to as the idiotype.

Cancer-testis antigens

(CTA). Cancer testis antigens are encoded by germline genes but are expressed only in tumours and in male germline cells. As the latter express no MHC molecules, the CTA are effectively tumour-specific.

Tolerance

The process that ensures that B- and T-cell repertoires are biased against self-reactivity, reducing the likelihood of autoimmunity.

Regulatory T cells

(TReg). Regulatory CD4+ T cells serve to limit immune responses, thereby protecting against autoimmunity. There are two main types, termed natural for those developing in the thymus and adaptive for those arising in the periphery following infection and possibly cancer.

Innate immunity

The first line of host defence against invading pathogenic organisms until an adaptive pathogen-specific immune response is able to develop. This is a multi-component system that includes various barriers to infection, such as physical barriers (for example, skin), physiological barriers (for example, stomach pH) and inflammatory barriers (for example, release of anti-bacterial serum proteins).

Leader (signal) sequence

Leader (or signal) sequences are hydrophobic domains which are cleaved from synthesized membrane-bound or secreted proteins during transfer into the endoplasmic reticulum through the Sec61 channel. For DNA vaccines, the leader sequence is placed at the 5′ end of the encoded antigen.

Cross-presentation

The uptake, processing and presentation by professional APCs of antigen that has been acquired from an exogenous source into the MHC class I pathway for induction of CD8+ T-cell responses.

Direct presentation

The conventional pathway of processing and presentation of antigen into the MHC class I pathway from an endogenous intracellular source.

Anti-CD40 antibodies

Agonistic anti-CD40 antibodies mimic the natural ligand (CD154) and stimulate DC to activate T-cell immunity.

Tetanus toxin

This is produced by the bacterium Clostridium tetani. Treatment with formaldehyde inactivates the toxin to produce tetanus toxoid, a non-toxic but extremely immunogenic derivative that is used as a vaccine in both adults and children.

T-cell help

Activated antigen-specific CD4+ T helper cells (TH) have a major role in linking and coordinating innate and adaptive immune responses. TH cells help B cells to produce antibodies and maintain circulating memory B cells; they also help stimulate and maintain both CD4+ and CD8+ T cell responses.

Single chain Fv

(scFv). A recombinant polypeptide sequence consisting of the variable regions from the immunoglobulin light and heavy chains. These are usually separated by a short linker sequence to allow the variable regions to fold and assume the native conformation of the antigen binding site of the immunoglobulin from which they are derived.

Fragment C

(FrC). A non-toxic yet highly immunogenic polypeptide corresponding to the ∼50 kDa carboxy-terminal portion of the heavy chain of tetanus toxin. It has a two-domain structure and the amino-terminal domain (DOM) contains a 'helper' peptide (p30) that has been shown to bind to a wide range of both murine and human MHC class II haplotypes, leading to CD4+ T-cell activation.

'Licensing' of dendritic cells

Licensing of dendritic cells by activated CD4+ T cells is essential for the generation of effective CD8+ T cell responses and possibly also for CD4+ T cell responses. Multiple interacting molecular pairs are likely to be involved, including CD40–CD40 ligand, CD28–CD80/86 and OX40–OX40 ligand.

Immunodominant peptides

The natural human CTL response to an antigen tends to focus on only a few immunodominant peptides. The precise mechanisms that establish this hierarchy remain unclear but the presentation of epitopes to naive CTL is controlled at several points, including processing efficiency, capacity to bind to MHC class I molecules and the stability of the bound complex on the cell surface.

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Rice, J., Ottensmeier, C. & Stevenson, F. DNA vaccines: precision tools for activating effective immunity against cancer. Nat Rev Cancer 8, 108–120 (2008). https://doi.org/10.1038/nrc2326

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