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Mutant herpes simplex virus induced regression of tumors growing in immunocompetent rats
M G Kaplitt1, J G Tjuvajev, D A Leib
1Laboratory of Neurobiology and Behavior, Rockefeller University, New York, NY 10021.
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.
Insights
Herpes simplex virus (HSV) mutants show promise for treating malignant brain tumors by selectively killing dividing cancer cells. These HSV mutants effectively reduced tumor growth in preclinical models, suggesting potential as novel cancer therapies.
Area of Science:
- Oncolytic virology
- Cancer biology
- Virology
Background:
- Malignant brain tumors remain a significant therapeutic challenge.
- Herpes simplex virus (HSV) mutants offer a potential strategy for targeted cancer therapy.
- HSV mutants can selectively target and kill rapidly dividing tumor cells while sparing healthy, non-proliferating tissues.
Purpose of the Study:
- To evaluate the efficacy of two HSV mutants, thymidine kinase deficient (TK-) and ribonucleotide reductase mutant (RR-), against human tumor cell lines and in a preclinical tumor model.
- To assess the impact of tumor cell proliferation on TK-HSV efficacy.
Main Methods:
- In vitro testing of HSV mutants against seven human tumor cell lines.
- Assessment of TK-HSV replication in proliferating versus serum-starved cells.
- In vivo studies involving subcutaneous W256 tumor xenografts in rats, treated with TK-HSV.
Main Results:
- Both TK- and RR- HSV mutants demonstrated efficacy against 7/7 human tumor cell lines in vitro.
- TK-HSV showed minimal replication in non-proliferating cells, indicating a dependence on tumor cell division.
- In vivo, TK-HSV therapy significantly inhibited W256 tumor growth (p = 0.002), leading to complete regression in 4/9 tumors without recurrence.
Conclusions:
- HSV mutants, particularly TK-HSV, are effective in reducing tumor growth and inducing regression in preclinical models.
- The selective killing of dividing tumor cells by HSV mutants highlights their potential as oncolytic agents.
- HSV mutants represent a promising novel therapeutic approach for treating tumors in immunocompetent individuals.