V. Bronte et al., IL-2 ENHANCES THE FUNCTION OF RECOMBINANT POXVIRUS-BASED VACCINES IN THE TREATMENT OF ESTABLISHED PULMONARY METASTASES, The Journal of immunology, 154(10), 1995, pp. 5282-5292
Neoplastic cells are generally poor immunogens. Transfection of the mu
rine tumor CT-26 with beta-galactosidase (beta-gal), a protein from Es
cherichia coli, did not alter its growth rate in vivo, or its lethalit
y, and did not elicit a measurable anti-beta-gal immune response. Immu
nization with beta-gal-expressing recombinant vaccinia viruses (rVV) e
licited specific anti-beta-gal cytolytic T lymphocytes, but rVV-beta-g
al was only marginally therapeutic when given to tumor-bearing mice. W
ith the aim of expanding the immune response against beta-gal, used he
re as a model tumor Ag, we gave mice exogenous IL-2 starting 12 h afte
r the poxvirus. The therapeutic effectiveness of the combination of po
xvirus and IL-2 was far greater than either of these treatments alone.
When the cDNA for IL-2 was inserted into the viral genome of the rVV
construct to make a double recombinant (drVV), antitumor activity was
further augmented. One mechanism of action may be the enhanced activat
ion or expansion of cytotoxic T cells, because a marked increase in pr
imary cytotoxic responses against vaccinia determinants was observed.
interestingly, other cytokines (mGM-CSF, mTNF-alpha, and mIFN-gamma) i
nserted into the rVV genome did not modify the efficacy of the rVV con
structs. The increase in specific CTL responses against beta-gal by dr
VV expressing the tumor-associated Ags (TAA) and IL-2 was more pronoun
ced in mice bearing the lacZ-transduced tumor than in those bearing th
e parental cell line, suggesting that the TAA presented by growing tum
or cells can either pre-activate or otherwise amplify the immune respo
nse induced by the rVV. Unfortunately, in several long-term surviving
mice, tumor recurred that no longer expressed beta-gal. These results
indicate that treatment of disseminated tumors by using recombinant vi
ruses expressing TAA can be enhanced by IL-2 provided exogenously, or
encoded within the recombinant virus.