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  • Review Article
  • Published:

Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines

Nature Reviews Cancer volume 8, pages 351–360 (2008)Cite this article

Key Points

  • Many attempts at cancer immunotherapy have been conducted; however, apart from melanoma, in which impressive clinical responses have been noted in a small minority of patients, the overall results have been disappointing.

  • Therapeutic vaccines require induction of robust cell-mediated immunity, capable of attacking and eliminating abnormal antigen-bearing cells. This calls for close collaboration between cells of the innate and adaptive immune systems.

  • A popular approach to therapeutic cancer vaccination has been vaccination with exact major histocompatibility complex (MHC)-binding peptides derived from the sequence of tumour-associated antigens. However, this approach is far from optimal because it can lead to immunological tolerance of the immunizing antigens.

  • Peptide vaccines have been improved by the inclusion of agonists of the Toll-like receptors, the expression of epitopes to induce by cytotoxic T cells (Tc) and T helper cells within the same peptide and an increase in the length of the peptide used.

  • Synthetic long peptide (SLP) vaccines have evolved as a simple solution for the many problems that have surfaced with minimal Tc peptide vaccines. SLP are not able to bind directly to MHC class I and their presentation to Tc therefore indicates that they have to be taken up and processed before they are presented. As a result SLP can induce a more effective immune response.

  • SLP have recently entered phase I/II clinical trials in patients with premalignant and malignant human papillomavirus-induced cancers with promising results.

Abstract

This Review deals with recent progress in the immunotherapy of established (pre)malignant disease of viral or non-viral origin by synthetic vaccines capable of inducing robust T-cell responses. The most attractive vaccine compounds are synthetic long peptides (SLP) corresponding to the sequence of tumour viral antigens or tumour-associated non-viral antigens. Crucial to induction of therapeutic T-cell immunity is the capacity of SLP to deliver specific cargo to professional antigen-presenting cells (dendritic cells (DC)). Proper DC activation then induces the therapeutic CD4+ and CD8+ T-cell responses that are associated with regression of established (pre)malignant lesions, including those induced by high-risk human papilloma virus.

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Figure 1: Different pharmacokinetics explains the superior immunogenicity of synthetic long peptides vaccines over minimal peptide vaccines.
Figure 2: Maximal use of immunogenic potential with synthetic long peptides but not with minimal peptides.

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Acknowledgements

The authors have received funding for their studies from the Dutch Cancer Society (UL 2003-2817), Integrated project FP 6 “CANCERIMMUNOTHERAPY”, Contract No. 518234, Network of Excellence DC-Thera, contract LSHB-CT-2004-512074, and ISA Pharmaceuticals B.V., Bilthoven, the Netherlands.

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Authors and Affiliations

  1. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333, ZA, the Netherlands

    Cornelis J.M. Melief

  2. Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333, ZA, the Netherlands

    Sjoerd H. van der Burg

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  1. Cornelis J.M. Melief
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Correspondence to Cornelis J.M. Melief or Sjoerd H. van der Burg.

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Competing interests

The LUMC, Leiden, the Netherlands hold a patent on long peptide vaccines (US 7202034) on which S.H.v.d.B. and C.J.M.M. are named as inventors, solely to indicate these facts. C.J.M.M. is partly employed as of 20 January 2008 as Chief Scientific Officer by ISA Pharmaceuticals, Bilthoven, the Netherlands, the company which exploits this long peptide vaccine patent and has co–funded the clinical trials with the HPV16 SLP vaccine in the Leiden University Medical Center.

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DATABASES

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non-small-cell lung cancer

ovarian cancer

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Glossary

Dendritic cells

Specialized antigen-presenting cells, the immunogenicity of which leads to the induction of antigen-specific immune responses. Dendritic cells have been used in numerous clinical trials to induce anti-tumour immune responses in cancer patients.

CD4+ T-helper cells

T cells that express the CD4 surface glycoprotein and produce cytokines, particularly IL-2, that are necessary for the expression of effector function by other cells in the immune system, especially CD8+ T cells.

CD8+ cytotoxic T cells

A T cell bearing the CD8 cell-surface glycoprotein, which recognizes MHC class I molecules on target cells and is involved in killing these cells.

Tolerance

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

Toll-like receptor

(TLR). A family of receptors that recognize conserved products unique to microorganisms (such as lipopolysaccharide), which are known as pathogen-associated molecular patterns (PAMPs). TLR-mediated events signal to the host that a microbial pathogen is present.

Antigen-presenting cells

(APC). These process antigen and present antigen fragments to other cells of the immune system (cross-presentation) to initiate an immune response. Dendritic cells are the most potent APC.

ELISPOT

An antibody-capture-based method for enumerating specific T cells (CD4+ and CD8+) that secrete a particular cytokine (often IFNγ).

Regulatory T cells

A subset of CD4+CD25+FOXP3+ T cells that control the responses of other T cells and tolerance to self antigens. They can suppress the activation of other T cells in a contact-dependent manner.

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Melief, C., van der Burg, S. Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nat Rev Cancer 8, 351–360 (2008). https://doi.org/10.1038/nrc2373

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