IL-2 ENHANCES THE FUNCTION OF RECOMBINANT POXVIRUS-BASED VACCINES IN THE TREATMENT OF ESTABLISHED PULMONARY METASTASES

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.