Anticancer virus – JX-594
It is possible to modify viruses so they can be used to kill cancer cells
It is possible to modify viruses so they can be used to kill cancer cells, targeting them to cells where genetic pathways are activated, or there has been a loss of tumour suppressor function. The virus selectively replicates within the tumour, where it multiplies and causes lysis of the infected cell, and then spreads to nearby cancer cells.
The viruses can also induce tumour specific cytotoxic T-lymphocytes that express therapeutic transgene products, thus leaving them armed and, potentially, capable of killing refractory tumour cells. The idea has not yet succeeded as there are delivery issues, and the spread of the virus within the tumour is not efficient enough.
Jennerex Biotherapeutics has been investigating the possibility of a vaccinia derived oncolytic virus in cancer therapy.1 It was derived from vaccinia by the insertion of two human genes – GMCSF and GLB1 – into thymidine kinase genes; inactivating this gene decreases the virus’s virulence, and increases its ability to replicate in a tumour specific way so that it destroys cancers with EGFR, ErbB-1 or Ras pathway activation.2 The idea is that this will work as a vaccine and immunotherapy, by directing immune response against the tumour.
In a pilot Phase I trial, the maximum tolerated dose was not reached,3 and so a Phase I dose escalation study was carried out in primary and metastatic liver cacer patients.4 A total of 14 patients were given doses of up to 3 x 109 PFU of the virus, and 1 x 109 was found to be the maximum tolerated dose as two patients given the higher dose experienced dose limiting toxicities. All patients experienced mild flu-like symptoms, and there was only one serious adverse event that was attributed to the vaccination, with other serious side-effects associated with tumour progression.
All of the patients developed antibodies to the vaccine within three to 15 days of dosing, and 10 could be assessed for CT responses. Three had an objective response, and a further six stable disease; the tenth progressed. All bar two of the patients had detectable JX-594 genomes between days 3 and 22. Phase II trials in liver cancer are under way, and Phase III trials are planned.
References
1. A. Merrick, Curr. Opin. Investig. Drugs. 2009, 10, 1372
2. S.H. Thorne et al. J. Clin. Invest. 2007, 117, 3350
3. M.J. Mastrangelo et al. Cancer Gene Ther. 1999, 6, 409
4. T.C. Liu et al. Mol. Ther. 2008, 16, 1637