Vaccination with B16 melanoma cells expressing a secreted form of interleukin-1 beta induces tumor growth inhibition and an enhanced immunity againstthe wild-type B16 tumor

We have demonstrated previously that gene transfer of the mature human inle rleukin-1 beta (IL-1 beta) gene, fused to a signal sequence (ss), into mous e B16 melanoma cells results in an inhibition of their growth in vivo compa red with control B16 cells. We here extend these results to show that intra peritoneal vaccinations with irradiated IL-1 beta -secreting cells result i n protection against subsequent subcutaneous challenge with wild-type (wt) B16 tumor cells in syngeneic C57BL/6 mice. This protection appears to be lo ng-lasting, because rechallenge of cured mice 4 months after the First chal lenge also demonstrated resistance. In addition, we demonstrate that mice w ith established wt tumors subjected to therapeutic vaccinations with irradi ated B16/ssIL-1 beta cells starting 3 days after challenge isografting have a significantly inhibited tumor growth and 25-40% survival at the challeng e doses given. In vitro coculture of spleen cells from B16/ssIL-1 beta vacc inated animals and wt B16 cells induced an enhanced proliferative response, which correlated with elevated production of IL-2 and interferon-gamma. A significantly enhanced cytolytic activity against B16 wt target tumor cells was observed when spleen cells from B16/ssIL-1 beta vaccinated mice were u sed as effector cells compared with spleen cells from control vaccinated mi ce. In vitro depletion experiments using anti-asialo CM, revealed a promine nt role for natural killer cells as effector cells. The data suggest that l ocal IL-1 beta secretion during the vaccination phase can provoke or augmen t protective immune responses to B16 melanoma cells, which are otherwise no t recorded in mice bearing B16 tumors.