Corticosteroid administration does not affect viral oncolytic activity, but inhibits antitumor immunity in replication-competent herpes simplex virustumor therapy
T. Todo et al., Corticosteroid administration does not affect viral oncolytic activity, but inhibits antitumor immunity in replication-competent herpes simplex virustumor therapy, HUM GENE TH, 10(17), 1999, pp. 2869-2878
A multimutated, conditionally replicating herpes simplex virus type 1, G207
, has been developed as an effective means of treating human malignant brai
n tumors. We have shown that intraneoplastic inoculation of G207 induces a
specific and systemic antitumor immune response that plays an important rol
e in the antitumor activity, in addition to the direct oncolytic action of
G207. Since a large number of malignant brain tumor patients are treated wi
th corticosteroids, it is important to evaluate whether the therapeutic eff
icacy of G207 is affected by corticosteroid-induced immunosuppression. For
a tumor model, we used G207-permissive N18 murine neuroblastoma cells impla
nted subcutaneously in syngeneic A/J mice. Intraneoplastic inoculation of G
207 (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 t
umor growth despite initial shrinkage, whereas in the saline group, four of
eight of the G207-treated mice were cured. Dexamethasone administration si
gnificantly reduced serum neutralizing antibodies against G207 at 14 and 21
days after intraneoplastic G207 inoculation. However, there was no differe
nce between the dexamethasone and saline groups in terms of the amount of i
nfectious G207 isolated from tumors. Dexamethasone administration completel
y abolished G207-induced cytotoxic T lymphocyte activity against N18 cells.
These results indicate that the oncolytic activity of G207 is retained und
er corticosteroid administration. However, intensive immunosuppression may
diminish the long-term efficacy of G207 owing to suppression of tumor-speci
fic cytotoxic T lymphocyte induction.