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Clinical development of gene therapy for colorectal cancer

Key Points

  • Colorectal cancer (CRC) is the second most common type of cancer in the Western world. Despite improvements in treatment, CRC recurs in up to 50% of patients and ultimately proves to be fatal.

  • CRC lends itself to various gene-therapy approaches, which include gene correction, virus-directed enzyme–prodrug therapy, immunogenetic manipulation and virotherapy.

  • CRC can be confined to organs (liver) or compartments (peritoneal cavity) for most of its natural history, allowing regional administration of the gene vector.

  • Gene-replacement trials have been initiated combining adenoviral TP53, which can act as a cytotoxic sensitizer, and conventional chemotherapy.

  • Virus-directed enzyme–prodrug therapy involves viral delivery of a transgene encoding an enzyme that can convert a non-toxic prodrug to a cytotoxic species. Early-phase clinical trials have been initiated with cytosine deaminase/fluorocytosine, herpes simplex virus thymidine kinase/gancyclovir and nitroimidazole reductase/CB1954.

  • Adenoviral transduction of allogeneic CRC cells with the gene encoding interleukin-2, vaccinia and fowl-pox vaccines aimed at inducing T-cell responses to carcinoembryonic antigen, and manipulation of MHC expression have all produced clinical immune responses in trials of immunogenetic therapies.

  • Virotherapy, with replication-competent adenoviruses engineered to proliferate in CRC cells with mutant p53 or RB, has been used to treat patients with hepatic metastases, in combination with 5-fluorouracil.

  • Randomized clinical trials are required to show the added value of gene therapy in the management of CRC; it is probable that combination gene therapy will be required to complement conventional chemotherapy.

Abstract

Colorectal cancer (CRC) is the second most common type of malignancy in Western nations. Improvements in surgical and radiotherapeutic techniques and the increased availability of new cytotoxic drugs have improved outcome, but 50% of patients still die from recurrent or metastatic disease. Several features of its natural history render CRC a good candidate for gene therapy. Techniques include gene replacement, virus-directed enzyme–prodrug therapy, immune manipulation and virotherapy, all of which have entered clinical trials.

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Figure 1: Molecular events that characterize the transition to adenocarcinoma.
Figure 2: Virus-directed enzyme–prodrug therapy.
Figure 3: Trial scheme for direct intratumoral inoculation of an adenovirus encoding nitroimidazole reductase to patients with operable primary or secondary liver cancer.
Figure 4: Immunogenetic therapy for colorectal cancer.
Figure 5: Combination gene therapy as adjuvant treatment for CRC.

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Author information

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DATABASES

Cancer.gov

colorectal cancer

GenBank

HSV-TK

LocusLink

APC

CD86

FGF2

GM-CSF

ICAM1

IL-2

IFN-α

IFN-γ

KRAS

LFA3

p53

RB

FURTHER INFORMATION

National Translational Cancer Research Network

Glossary

ONCO-FETAL ANTIGENS

Cell-surface-associated antigens that are normally expressed during specific phases of embryogenesis but are not expressed at significant levels in adults. These can be dysregulated during carcinogenesis.

ASYMPTOMATIC TRANSAMINITIS

The increase of liver enzymes (such as aspartate and alanine aminotransferases) that are measurable in the blood in response to tissue damage.

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). A genetic region encoding proteins that are involved in antigen presentation to T cells. MHC class I molecules bound to peptide are recognized by the T-cell receptors of CD8+ T cells.

CAPILLARY LEAK SYNDROME

Involves damage to vascular endothelial cells, and the extravasation of fluids and proteins, resulting in weight gain and, in its most severe form, kidney damage and pulmonary oedema.

PHAGE DISPLAY

Technology for displaying a protein (or peptide) on the surface of a bacteriophage, which contains the gene(s) that encodes the displayed protein(s), thereby physically linking the genotype and phenotype.

PANNING

The process of separating target-binding clones from nonbinding clones for a phage display library.

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Kerr, D. Clinical development of gene therapy for colorectal cancer. Nat Rev Cancer 3, 615–622 (2003). https://doi.org/10.1038/nrc1147

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