B

Fig. 2. HSV lytic cycle. (A) The herpes virion attaches to the tumor cell membrane. (B) After envelope fusion with the cell membrane, the large genome enters the nucleus where viral DNA is replicated and transcribed. A cascade of gene expression ensues which culminates in the production and assembly of new viral particles. (C) With viral replication and egress, the tumor cell is lysed and the viral effect amplified. Progeny virions can then infect neighboring tumor cells. The herpes replicative cycle often is completed within 24 h and is the basis of herpes oncolytic viral therapy.

Fig. 2. HSV lytic cycle. (A) The herpes virion attaches to the tumor cell membrane. (B) After envelope fusion with the cell membrane, the large genome enters the nucleus where viral DNA is replicated and transcribed. A cascade of gene expression ensues which culminates in the production and assembly of new viral particles. (C) With viral replication and egress, the tumor cell is lysed and the viral effect amplified. Progeny virions can then infect neighboring tumor cells. The herpes replicative cycle often is completed within 24 h and is the basis of herpes oncolytic viral therapy.

Another widely tested mutant herpes virus is NV1020. Initially failing as a vaccine against HSV-1 and HSV-2, NV1020 subsequently demonstrated potent antitumor properties. This virus differs from G207 in that it contains a deletion in only one copy of y134.5, as well as deletions in the viral genes UL24 and UL56 (Table 1) (26). NV1020 has effectively treated a variety of human tumor xenografts including those of the colon, prostate, pancreas, and head and neck. Moreover, NV1020 is being evaluated in a phase I clinical trial for liver metastases from colorectal cancer (4). To date, 9 patients with hepatic metastases have received a maximum dose of 1.3 x 107 pfu of NV1020 delivered through a percutaneous hepatic arterial catheter. No patients suffered severe reactions related to viral inoculation and all patients demonstrated radiographically stable disease and reduced carcinoembryonic antigen (CEA) levels during the, admittedly, very short 28-d observation period. The adverse effects were mild and consisted of fever (7 of 9), nausea (3 of 9), and headache (2 of 9) (Table 2) (4).

Another virus, 1716, has deletions in both copies of the 7134.5 gene. This virus has been successful in the treatment of a variety of tumors in animal models and has recently completed clinical trials assessing safety (Table 2). In two phase I clinical trials in patients with recurrent gliomas, a maximum dose of 1 x 105 pfu was administered through direct intratumoral injection. No patients suffered adverse effects and viral replication could be demonstrated in resected tumor specimens (6,21). In a third phase I clinical trial involving patients with stage 4 melanoma, 1 x 103 pfu of 1716 was injected into a single nodule. Following treatment, histopathologic necrosis and HSV antigen could be documented in tumor cells (22).

NV1066 is a unique mutant HSV that contains a transgene encoding an enhanced green fluorescent protein (GFP). It is attenuated through a deletion in one copy of

Table 1

Virus

Mutations

Transgene

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