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*
Department of Neurosurgery and Georgetown Brain Tumor Center and
Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20007, and
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Intratumoral inoculation of replication-competent, attenuated
herpes simplex virus (HSV) mutants inhibits tumor growth by direct
cytotoxic viral replication and induction of a tumor-specific immune
response. To boost the antitumor response, we describe a defective HSV
vector encoding IL-12 as an adjuvant to in situ vaccination by the
replication-competent HSV helper virus. The defective HSV vector system
consists of defective particles containing tandem repeats of the
cytokine genes (p40 and p35) in combination with a HSV helper virus.
Heterodimeric IL-12 was expressed and secreted after IL-12 defective
vector infection of tumor cells. In a syngeneic, bilateral established
tumor model with CT26 murine colon carcinoma, unilateral intratumoral
inoculation with an IL-12 defective/replication-competent HSV vector
combination significantly reduced tumor growth of the inoculated and
noninoculated contralateral tumors. This antitumor effect was
significantly greater than with a
lacZ-defective/replication-competent HSV vector
combination, which itself was significantly greater than the mock
inoculation. Efficacy is associated with enhancement of tumor-specific
CTL activity, including specificity against the CT26 immunodominant MHC
class I restricted Ag AH1, and IFN-
production. There was no
significant tumor growth inhibition after intratumoral inoculation of
s.c. CT26 tumors in athymic mice. We conclude that this defective HSV
vector system is an effective method for cytokine gene delivery to
tumors in situ and IL-12 expression in tumors synergizes the antitumor
activity mediated by the replication-competent HSV helper virus.
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