From The Laboratory To The Clinic Oncolytic Herpes Simplex Viruses Appear Safe In Trials But Just How Effective Will They Be

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Within the past few years, two independent dose escalation phase I clinical trials using two different 7134.5 mutant derivatives, G207 (21 patients) and 1716 (9 patients), were completed in patients with recurrent glioblastoma who have failed to respond to conventional therapies (16,17). The oncolytic viruses were generally well tolerated. No adverse events, such as acute toxicity, viral shedding, clinically evident reactivation or encephalitis attributable to virus inoculation or replication were observed in either study at any of the doses, which escalated from 103-105 pfu with 1716 and 1 x 1063 x 109 with G207 (16,17). Patient deaths were primarily the reuslt of progressive cancer, with one report of radiation necrosis. Two of the G207 treated patients were alive as of December, 2003 (77). In addition, both studies were unable to establish a maximum tolerated dose (16,17). More recently, evidence has been obtained that is reportedly consistent with replication of 1716 within tumor samples over time, supporting the concept of tumor destruction by viral oncolysis (78). Finally, multiple injections of 1716 directly into skin lesions of a limited number of melanoma patients have proceeded without any harmful effects (79). A phase Ib/II study involving G207 is currently underway open to patients with recurrent glioblastoma that has been refractory to prior chemotherapy (NLM identifier NCT00028158; In the phase Ib segment, doses will escalate from 109-1010, and provided no safety issues arise, the phase II component aimed at evaluating efficacy will begin using the highest dose tolerated in the phase Ib study. Studies to determine the efficacy of 1716 treatment are set to proceed as well.

Clinical trials have also commenced using NV1020 to treat colon cancer that has spread to the liver and has not responded to prior chemotherapy (NLM identifier NCT00012155; This study, which is no longer recruiting patients, is a dose escalating protocol designed to evaluate the safety, tolerability, and antitumor activity of a single intrahepatic arterial injection of NV1020. Although this virus replicates more robustly than 7134.5 null strains, it is substantially more virulent, presumably because it produces the 7134.5 gene product, and is unsuitable for use in the CNS. As this strain is non-neuroinvasive and cannot gain entry into the CNS, it may be useful in treating non-CNS tumors that are refractory to traditional therapies. Extensive prior study of R7020, the parent of NV1020, as a putative vaccine strain demonstrated its safety for non-CNS administration to rabbits, rodents, and nonhuman primates (61,62). However, one must not lose sight of the fact that this strain is neurovirulent and, unlike strains with 7134.5 null alleles, could prove harmful if it was somehow introduced into the CNS.

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