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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.
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.
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.
Shares Science, Oncolytic viruses.
Shares Science, Oncolytic viruses.