# Bischoff 1996: the adenovirus that was said to replicate only where p53 was lost

Source: https://onco.cc/key-papers/paper-bischoff-onyx-015-science-1996/  
OnCo record `paper-bischoff-onyx-015-science-1996` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

An adenovirus missing the gene that disables the cell's main tumour suppressor appeared to grow only in cancer cells that had already lost that suppressor, a claim that launched the field's first big clinical programme and was later shown to be the wrong explanation.

## Summary

Adenovirus E1B encodes a 55-kilodalton protein that inactivates p53. Bischoff and colleagues showed that a mutant adenovirus lacking it replicated in and lysed p53-deficient human tumour cells but not cells with functional p53, and that putting the 55-kilodalton protein back into the latter made them susceptible. Injection into p53-deficient human cervical carcinomas in nude mice significantly reduced tumour size and completely regressed 60 per cent of tumours.

The virus became ONYX-015, the most heavily studied oncolytic virus of the 1990s, and later, with a nearly identical design, the Chinese product H101. The tidy mechanism did not survive: O'Shea and colleagues showed in 2004 that selectivity tracks late viral RNA export rather than p53 status, which is why ONYX-015 activity in trials never sorted by p53.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Science
- Year: 1996
- DOI: 10.1126/science.274.5286.373
- Authors: Bischoff JR, Kirn DH, Williams A, et al.
- Findings: An adenovirus not expressing the E1B 55-kilodalton protein replicated in and lysed p53-deficient human tumour cells but not cells with functional p53.; Ectopic expression of the 55-kilodalton E1B protein in p53-functional cells made them susceptible to the mutant virus.; Injection into p53-deficient human cervical carcinomas in nude mice reduced tumour size significantly and caused complete regression of 60 per cent of tumours.
- What it means: This is the paper that made oncolytic viruses look like precision medicine: a named genetic lesion, a virus built to exploit it, a biomarker to select patients. None of that held. It is the field's most useful cautionary tale, because the drug went into large trials on a mechanism that turned out to be wrong, and the selectivity that does exist has never been reducible to one gene.
- Caveats: The p53 explanation was overturned. O'Shea and colleagues showed in Cancer Cell in 2004 that late viral RNA export, not p53 inactivation, determines the selectivity of this mutant.; Clinical response to ONYX-015 did not track p53 status in the trials that looked, so the biomarker never worked.; Nude-mouse xenografts of a cervical carcinoma line, with the virus injected directly into an accessible tumour.

## Sources

- Science 1996: https://doi.org/10.1126/science.274.5286.373
- PubMed: https://pubmed.ncbi.nlm.nih.gov/8832876/
- O'Shea 2004, the correction to the mechanism (Cancer Cell): https://doi.org/10.1016/j.ccr.2004.11.012

## Connected records

- fronts: [Immunotherapy](https://onco.cc/fronts/immunotherapy/)
- technologies: [Oncolytic viruses](https://onco.cc/technologies/oncolytic-virus/)
- targets: [TP53](https://onco.cc/targets/tp53/)
- people: [Frank McCormick](https://onco.cc/people/frank-mccormick/)
- journals: [Science](https://onco.cc/journals/science/)

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