Onyx-15

Onyx 015 is an experimental intratumoral adenovirus, genetically modified from its original cold virus form. [ [http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=43035 Definition of ONYX-015 - National Cancer Institute Drug Dictionary ] ]

ONYX-015 is the commercial name for the adenovirus mutant "dl"1520 derived by Barker and Berk in 1987 [Barker DD, Berk AJ. Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection. Virology 1987; 156: 107-121.] . The name ONYX-015 was coined by ONYX Pharmaceuticals founder Frank McCormick, where a patent was put forward regarding the mechanism of action by which this virus might be used as a oncolytic agent.

A little virus background first - when an adenovirus enters a given host cell it has three main goals: to induce the cell cycle (to allow for the replication of virus genomes), to avoid premature death of the host cell (through cell suicide mechanisms or through the host immune system), and to exit the cell through lysis. The tumour suppressor protein p53 (TP53) is central to both the control of the cell cycle and the control of programmed cell suicide (apoptosis), and thus represents a key target for adenovirus. A normal (wild-type) adenovirus encodes (at least) two products that can bind to p53 and prevent its function. The best studied of these virus proteins is E1B55kDa, which is thought to bind and inactivate p53 with another viral counterpart, E4ORF6. Thus, when an adenovirus infects its host cell, the virus actively shunts the cell into the DNA synthesis (S) phase, this unscheduled cell cycle advance triggers (through p53) the cell to either arrest the cell cycle or directs the cell to apoptosis. Binding of p53 by E1B55kDa (and E4ORF6) neutralises p53, and allows the virus to replicate, package its genome and lyse the cell. In the instance that an adenovirus has no functional E1B55kDa protein, as is the case in "dl"1520 (ONYX-015), the virus can still infect a host cell and induce S phase, however, as it cannot neutralise p53, the cell either arrests or dies, both alternatives halt the virus life cycle and cut short the infection process.

Importantly, in around 50% of all cancers p53 is mutated. Thus, if ONYX-015 was to infect these tumour cells, the virus would be able to infect, shunt the cell into S-phase, and replicate uninhibited (due to the lack of p53) to complete a successful infectious cycle. Meanwhile, if ONYX-015 was to infect a neighbouring cell (with a wild type p53), it would be an abortive infection. Thus, the virus would represent a selective agent that could seek out and destroy all p53 mutant cancer cells while leaving normal cells largely unharmed... the perfect anti-cancer therapy!

This hypothesis formed the basis for ONYX Pharmaceutical's patent and, with an early paper in Science [Bischoff, J.R. et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274: 373−376.] , became the basis upon which clinical trials were started in end-stage head and neck tumour sufferers. Unfortunately, the trials were not as successful as one might have hoped, however, therapeutic efficacy was improved on combination with chemotherapeutic regimens. During these trials an array of data came out of many labs around the world showing that ONYX-015, while showing some promise in the chemo group, did not kill cells based on p53 status as initially proposed (and patented). Rather, it was shown that other functions of E1B55kDa were more important for this apparent tumour-selectivity. Progression to clinic for ONYX-015 ground to a halt, before being quickly picked up and licensed in China as H101.

The mechanism behind the partial response in the chemo arm is still unknown, however many scientists speculate this effect was not specific to the lack of E1B55kDa in ONYX-015, but was a general adenovirus effect - an effect that could quite likely be improved upon by using wild type strains fo the virus.

Chemotherapeutic Use

Onyx 015 has been used experimentally for combatting head and neck tumours, in combination with the standard chemotherapeutic agents cisplatin and 5-fluorouracil [ [http://www.nature.com/nm/journal/v6/n8/abs/nm0800_879.html A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer - Nature Medicine ] ]

References

*National Cancer Institute definition [http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=43035]

*Fadlo R. Khuri, 2000. "A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer" [http://www.nature.com/nm/journal/v6/n8/abs/nm0800_879.html]