Corticosteroid administration does not affect viral oncolytic activity, but inhibits antitumor immunity in replication-competent herpes simplex virus tumor therapy.
A multimutated, conditionally replicating herpes simplex virus type 1, G207, has been developed as an effective means of treating human malignant brain tumors. We have shown that intraneoplastic inoculation of G207 induces a specific and systemic antitumor immune response that plays an important role in the antitumor activity, in addition to the direct oncolytic action of G207. Since a large number of malignant brain tumor patients are treated with corticosteroids, it is important to evaluate whether the therapeutic efficacy of G207 is affected by corticosteroid-induced immunosuppression. For a tumor model, we used G207-permissive N18 murine neuroblastoma cells implanted subcutaneously in syngeneic A/J mice. Intraneoplastic inoculation of G207 (10(7) PFU) induced significant suppression of tumor growth whether or not dexamethasone (5 mg/kg) was given. When dexamethasone was given for an extensive time (16 days starting on day -2), all G207-treated mice showed tumor growth despite initial shrinkage, whereas in the saline group, four of eight of the G207-treated mice were cured. Dexamethasone administration significantly reduced serum neutralizing antibodies against G207 at 14 and 21 days after intraneoplastic G207 inoculation. However, there was no difference between the dexamethasone and saline groups in terms of the amount of infectious G207 isolated from tumors. Dexamethasone administration completely abolished G207-induced cytotoxic T lymphocyte activity against N18 cells. These results indicate that the oncolytic activity of G207 is retained under corticosteroid administration. However, intensive immunosuppression may diminish the long-term efficacy of G207 owing to suppression of tumor-specific cytotoxic T lymphocyte induction.
Todo
T
T
Department of Neurosurgery, Georgetown University Medical Center, Washington, DC 20007, USA. todot@odrge.odr.georgetown.edu
Rabkin
S D
SD
Chahlavi
A
A
Martuza
R L
RL
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001691:Biological Therapy; D003131:Combined Modality Therapy; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy*; D018139:Simplexvirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D018931:Antineoplastic Agents, Hormonal; D003907:Dexamethasone