© 1998 by Oxford University Press
Journal Of The National Cancer Institute, Vol 90, 1881-1887, Copyright © 1998 by Oxford University Press
MW Carroll, WW Overwijk, DR Surman, K Tsung, B Moss and NP Restifo
BACKGROUND: Construction of recombinant viruses that can serve as vaccines
for the treatment of experimental murine tumors has recently been achieved.
The cooperative effects of immune system modulators, including cytokines
such as interleukin 12 (IL-12) and costimulatory molecules such as B7-1,
may be necessary for activation of cytotoxic T lymphocytes. Thus, we have
explored the feasibility and the efficacy of inclusion of these
immunomodulatory molecules in recombinant virus vaccines in an experimental
antitumor model in mice that uses Escherichia coli beta-galactosidase as a
target antigen. METHODS: We developed a "cassette" system in which three
loci of the vaccinia virus genome were used for homologous recombination. A
variety of recombinant vaccinia viruses were constructed, including one
virus, vB7/beta/IL-12, that contains the following five transgenes: murine
B7-1, murine IL-12 subunit p35, murine IL-12 subunit p40, E. coli lacZ
(encodes beta- galactosidase, the model antigen), and E. coli gpt
(xanthine-guanine phosphoribosyltransferase, a selection gene). The effects
of the recombinant viruses on lung metastases and survival were tested in
animals that had been given an intravenous injection of beta-
galactosidase-expressing murine colon carcinoma cells 3 days before they
received the recombinant virus by intravenous inoculation. RESULTS:
Expression of functional B7-1 and IL-12 by virally infected cells was
demonstrated in vitro. Lung tumor nodules (i.e., metastases) were reduced
in mice by more than 95% after treatment with the virus vB7/beta/IL-12; a
further reduction in lung tumor nodules was observed when exogenous IL-12
was also given. Greatest survival of tumor-bearing mice was observed in
those treated with viruses encoding beta- galactosidase and B7-1 plus
exogenous IL-12. CONCLUSION: This study shows the feasibility of
constructing vaccinia viruses that express tumor antigens and multiple
immune cofactors to create unique immunologic microenvironments that can
modulate immune responses to cancer.
ARTICLES
Construction and characterization of a triple-recombinant vaccinia virus encoding B7-1, interleukin 12, and a model tumor antigen
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892- 1502, USA.
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