Review Article | Published:

Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded

Nature Reviews Microbiology volume 6, pages 529540 (2008) | Download Citation

Abstract

Virotherapy is currently undergoing a renaissance, based on our improved understanding of virus biology and genetics and our better knowledge of many different types of cancer. Viruses can be reprogrammed into oncolytic vectors by combining three types of modification: targeting, arming and shielding. Targeting introduces multiple layers of cancer specificity and improves safety and efficacy; arming occurs through the expression of prodrug convertases and cytokines; and coating with polymers and the sequential usage of different envelopes or capsids provides shielding from the host immune response. Virus-based therapeutics are beginning to find their place in cancer clinical practice, in combination with chemotherapy and radiation.

Key points

  • Viruses are reprogrammed into vectors for cancer treatment based on three types of modification: targeting, arming and shielding. Viruses that are turned into therapeutics are beginning to find their place in cancer clinical practice, in combination with chemotherapy and radiation.

  • The principles of virus reprogramming are illustrated in this article using adenovirus, a DNA virus with a naked icosahedral capsid, and measles virus, an enveloped RNA virus with a helical capsid.

  • Targeting introduces multiple layers of cancer specificity, thereby improving safety and efficacy. The four basic layers of specificity are: particle activation through cancer-specific proteases; cell entry through cancer-specific cell-surface proteins; control of viral transcription and replication by tissue-specific promoters; and preferential spread of viruses that exploit cancer-specific molecular defects.

  • Arming occurs through genes that express prodrug convertases, pro-apoptotic proteins or immuno-activating proteins.

  • Coating with polymers and sequential usage of different envelopes or capsids provides shielding from the host immune response.

  • The window of therapeutic opportunity can be extended by temporary immunosuppression.

  • A five-step plan to turn a virus of choice into a potential oncolytic is discussed.

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Acknowledgements

R.C. has been supported by the National Institutes of Health (grant CA90636) and the Alliance of Cancer Gene Therapy. M.A.B. has been supported by the Department of Defense (grant W81XWH-05-1-0269) and the Susan G. Komen Foundation (grant BCTR0504036).

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  1. Department of Molecular Medicine, Rochester, 55905 Minnesota, USA.

    • Roberto Cattaneo
    •  & Tanner Miest
  2. Department of Internal Medicine, Rochester, 55905 Minnesota, USA.

    • Elena V. Shashkova
    •  & Michael A. Barry
  3. Department of Immunology, Division of Infectious Diseases, Translational Immunovirology and Biodefense Program, Mayo Clinic, Rochester, 55905 Minnesota, USA.

    • Michael A. Barry

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Correspondence to Roberto Cattaneo or Michael A. Barry.

Glossary

Glioblastoma

The most common and aggressive type of primary brain tumour. Treatment can involve chemotherapy, radiotherapy and surgery, none of which provide a cure.

Matrix metalloproteinase

A proteolytic enzyme that degrades the extracellular matrix and has important roles in tissue remodelling and tumour metastasis.

Fibre protein

In adenoviruses, a trimeric antennae-like protein that projects from the virion and mediates initial cell-binding events by different serotypes with CAR, CD46 and, perhaps, other receptors.

Penton base

The pentameric protein base of the fibre trimer. For some adenoviruses, this protein mediates interactions with cellular integrins for binding and cell entry.

Non-Hodgkin's lymphoma

A diverse group of cancers that arise from lymphocytes and have varying courses, treatments and prognoses.

Myeloma

A type of cancer of the plasma cells (immune-system cells in bone marrow that produce antibodies) that is often called multiple myeloma.

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https://doi.org/10.1038/nrmicro1927

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