Evaluation of cytokine toxicity induced by vaccinia virus-mediated IL-2 and IL-12 antitumour immunotherapy.

Single intratumoural treatment of nude mice with a vaccinia virus (VV)-expressing interleukin-1 (IL-2) or IL-12 induced significant tumour growth inhibition associated with clear signs of toxicity. At a low virus dose, only some treated animals showed signs of toxicity. We characterized and compared the activity of NK and B cells and major pro-inflammatory factors (IFN-gamma, TNF-alpha) in treated animals with and without toxicity. One week after treatment animals exhibiting signs of cytokine-related toxicity showed dramatic increases in several measured parameters. High leukocyte and lymphocyte counts in blood and marked increases in NK and CD25(+)cells in both blood and spleen were associated with IL-2-induced toxicity, while IL-12-induced toxicity was related to a great elevation of CD25(+)cells in blood and CD71(+)cells in the spleen. In contrast, immune activation in animals free of toxicity was observed on day 2 after the treatment, which drastically declined by day 7. Thus, immune responses induced by IL-2 and IL-12 therapy appear to play important roles in both tumour inhibition and the accompanying toxicity. Short-term effects induced by IL-2 and IL-12 could be critical for antitumour therapy that prolongs survival and protects from adverse side effects.