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ONYX-015: Clinical data are encouraging

Nature Medicine volume 4, pages 1341–1342 (1998)Cite this article

To the editor—In the September issue of Nature Medicine, Hall et al. published an article1 challenging the utility of E1B, 55-kDa-deficient adenoviruses in tumor therapy, with particular emphasis on our ONYX-015 virus. They reached very different conclusions than our earlier work2,3, showing that this virus specifically targets p53-deficient cells. Indeed, the title of their paper, "p53-dependent cell death/ apoptosis is required for a productive adenovirus infection", is surprising, because adenovirus targets p53 for destruction (as do many other DNA viruses) through E1B, 55-kDa and E4orf6 binding, and because data from several groups (including the authors) show that adenovirus efficiently replicates in cells with mutant p53 (refs. 1,2,3). Furthermore, several groups have shown that adenovirus induces cytopathic effects (CPEs) in most, if not all, p53-mutant cell lines1,3,4. Therefore, functional p53 is clearly not required for adenovirus infection, replication or induction of CPEs in cells2,3,4,5. We have developed selectively-replicating adenoviruses, such as ONYX-015, with a view to using them to destroy p53-deficient tumors. Preliminary data from clinical trials in patients with head and neck cancer are encouraging (see below and ref. 6).

Hall et al. show that p53 can influence the timing of virus-induced CPE at a single multiplicity of infection in cancer cell lines. Is this conclusion at odds with data from other groups, or with the ONYX-015 approach to cancer therapy? Definitely not! If functional p53 shortens the time to cell death, the predicted result would be a reduction in virus production or 'burst'; therefore, p53 would slow the spread of adenovirus in a tissue (especially an adenovirus defective in p53 destruction such as ONYX-015). Unfortunately, the authors do not report data on viral replication over time in matched cell lines with or without p53. Data from other groups, however, do show that the timing of cell death is a chief determinant of viral replication. Delaying infected cell death (for example, through deletion of the gene for the protein) results in an increased viral 'burst' (W. Wold, personal communication). Accelerating infected cell death (for example, through deletion of the gene for the E1B, 19-kDa protein), in contrast, results in a decreased viral 'burst'7.

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References

  1. Hall, A.R. et al. p53-dependent cell/death apoptosis is required for a productive adenovirus infection. Nature Med. 4, 1068–1072 (1998).

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  2. Bischoff, J. et al. An adenovirus mutant that replicates selectively in p53 deficient tumor cells. Science 274, 373– 376 (1996).

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  7. Subramanian, T., Kuppuswamy, M., Gysbers, J., Mak, S. & Chinnadurai, G. The 19 kDa tumor antigen encoded by early region E1B of adenovirus 2 is required for efficient synthesis and for protection of viral DNA. J. Biol. Chem. 259, 11777–11783 (1984).

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Authors and Affiliations

  1. Vice President, Clinical Research,

    David Kirn

  2. Scientist, Virology Onyx Pharmaceuticals, 3031 Research Drive , Richmond, 94806, CA

    Terry Hermiston

  3. Director, Cancer Center University of California, 2340 Sutter Street, San Francisco, San Francisco, 94115, CA

    Frank McCormick

Authors
  1. David Kirn
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  2. Terry Hermiston
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  3. Frank McCormick
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Kirn, D., Hermiston, T. & McCormick, F. ONYX-015: Clinical data are encouraging. Nat Med 4, 1341–1342 (1998). https://doi.org/10.1038/3902

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