Mutant herpes simplex virus induced regression of tumors growing in immunocompetent rats

Abstract

Herpes simplex virus (HSV) mutants kill dividing tumor cells but spare non-proliferating, healthy brain tissue and may be useful in developing new treatment strategies for malignant brain tumors. Two HSV mutants, a thymidine kinase deficient virus (TK-) and a ribonucleotide reductase mutant (RR-), killed 7/7 human tumor cell lines in tissue culture. The TK-HSV killed Rat RG2 glioma and W256 carcinoma lines but not the rat C6 glioma in culture. TK-HSV replication (12 pfu/cell) was similar to wild-type HSV (10 pfu/cell) in rapidly dividing W256 cells in tissue culture, but was minimal (< 1 pfu/cell) in serum-starved cells, suggesting that the proliferative activity of tumor cells at the site and time of TK-HSV injection may influence efficacy in vivo. Subcutaneous W256 tumors in male Sprague-Dawley rats were injected with TK-HSV or free inoculum. A significant effect of TK-HSV therapy on W256 tumor growth was demonstrated compared to controls (p = 0.002). Complete regression was observed in 4/9 experimental tumors, with no recurrence over 6 months. Tumor growth in the remaining 5/9 animals was attenuated during the first 3 to 5 days after treatment, but not beyond 5 days compared to 9 matched control animals; no tumor regression was observed in any of the control animals. These results suggest that HSV mutants are potentially useful as novel therapeutic agents in the treatment of tumors in immunocompetent subjects.

A Herpes Simplex Virus Type 1 γ34.5 Second-Site Suppressor Mutant That Exhibits Enhanced Growth in Cultured Glioblastoma Cells Is Severely Attenuated in Animals

“…Several groups have demonstrated that mice inoculated intracranially with either syngeneic or xenogeneic glioma cells exhibit enhanced survival if the glioma implants are challenged by HSV infection (1,4,7,17,18,24,27,28,29,35). While animals in initial experiments succumbed to encephalitis due to extensive lytic growth of the virus, later studies were thwarted by viruses that were overattenuated due to mutation of the ␥34.5 gene, causing the animals to die from regrowth of the tumor.…”

Herpes simplex virus 1 (HSV-1) for cancer treatment

“…Intraneoplastic administration of the TK-deleted strains induced tumor regression in several animal tumor models, with severe necrosis of the tumor tissue. [130][131][132][133][134] However, in tumor models in severe combined immunodeficient (SCID) mice, these mutants were shown to spread into normal tissues, 135 indicating a lack of tumor specificity. This, along with concerns that lack of TK would render these mutants insensitive to treatment with the anti-viral drug ACV, has led to the development of many other replication-conditional HSV-1 vectors.…”

Hepatoma-specific antitumor activity of an albumin enhancer/promoter regulated herpes simplex virus in vivo

“…The reasons for inserting the transgene into the tk locus include: easy selection of recombinant tk − mutants with the aid of ganciclovir, HSVtk − mutants grow poorly in nondividing cells 24,54,55 and have reduced neurovirulence. 33,56 Replication of HSVtk − mutants in mouse liver was reported to be much less than wild-type HSV, except after partial hepatectomy when liver cells are replicating.…”