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Can immunotherapy by gene transfer tip the balance against colorectal cancer?
  1. S M TODRYK,
  2. H CHONG,
  3. R G VILE
  1. H PANDHA,
  2. N R LEMOINE
  1. Laboratory of Molecular Therapy,
  2. Imperial Cancer Research Fund Molecular Oncology Unit,
  3. Imperial College School of Medicine,
  4. Hammersmith Hospital, London W12 0NN, UK
  5. Laboratory of Molecular Pathology,
  6. Imperial Cancer Research Fund Molecular Oncology Unit,
  7. Imperial College School of Medicine,
  8. Hammersmith Hospital, London W12 0NN, UK
  1. Dr Stephen Todryk (email:s.todryk{at}icrf.icnet.uk).

https://doi.org/10.1136/gut.43.4.445

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    Gene therapy, in particular the transfer of genes encoding immunostimulatory molecules (cytokines and costimulatory molecules) as well as selectively cytotoxic enzymes and DNA vaccination, has the potential of enhancing cell mediated immune responses against tumours including those of colorectal origin. Genes can be transferred using viral vectors either to cultured tumour cells in vitro that can be returned to the patient as a “cancer vaccine”, or directly to tumour cells in vivo. Vaccination with DNA constructs expressing specific tumour antigens characteristic of colorectal neoplasia can trigger immune recognition and destruction of tumour cells. The aim is to tip the balance from protumour to antitumour mechanisms by generating a local immune response and systemic antitumour immune memory to destroy metastases. Studies in murine models, combined with human studies, show that such approaches could become an adjunct to current treatments for human colorectal cancer in the near future.

    Introduction

    Colorectal cancer comprises 10–15% of deaths from cancer in industrial nations, second only to lung cancer.1 Survival rates (40% >5 years) have remained stable over the past 20 years and so a number of treatments to supplement surgical resection and chemotherapy are under investigation, including enhancement of the immune response. This article considers gene therapy, in particular the transfer of immunomodulatory genes and selectively cytotoxic enzymes to tumour cells as well as DNA vaccination, as a means of enhancing cell mediated immunity specifically for the treatment of colorectal cancer.

    The current model for colorectal tumorigenesis postulates a multi-stage progression involving an accumulation of gene mutations (APC, K-ras, p53, DNA mismatch repair genes), alterations in gene expression (c-myc, MHC) and chromosome losses, during which regulation of cell growth is disrupted.2Dietary and inherited genetic factors predispose to such changes. The majority of deaths from colorectal cancer follow tumour metastasis …

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    • Leading articles express the views of the author and not those of the editor and editorial board.