Treating metastatic disease with a modified herpesvirus

March 27, 2002

Using bacteria or viruses to control tumors is an old idea, and many such biotherapeutic agents have been designed and tested in cell and animal models. Safety concerns are paramount in this work, and most candidates with oncolytic properties have remained sidelined at the preclinical stage because, despite a general tropism towards cancer cells, they retain some ability to infect normal host cells or to cause systemic disease. Here, Nakamura and colleagues describe a second-generation derivative of the herpes simplex virus (HSV-1) that, they suggest, may be ready to clear this hurdle. A previously engineered form of HSV-1, deficient in the viral gene for the enzyme ribonucleotide reductase, replicated preferentially in liver tumor cells, which divide rapidly and possess sufficient pools of deoxynucleotides to support efficient viral replication. The newer recombinant virus, Myb34.5, has this same defect but also carries an engineered form of the g134.5 gene. The product of this gene allows the virus to circumvent a host cell defense mechanism that would otherwise shut down protein synthesis in infected cells. In Myb34.5, g134.5 is expressed under control of the Myb promoter, which is active in cycling cells, leaving the virus with extremely limited ability to proliferate in healthy host tissues. Nakamura et al. show that injection of Myb34.5 into mice carrying a high load of metastatic liver cells affords these animals considerable protection and significantly extends their survival. Even when provided at doses 10-fold higher than a rapidly fatal dose of wild-type HSV-1, Myb34.5 did not kill or paralyze treated mice. The authors caution, however, that neither mice nor other experimental animals provide fully adequate models for HSV-1 infection. Hence, viral toxicity in humans remains a possibility.
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