ANTITUMOR-ACTIVITY OF INTERLEUKIN-12 IN PRECLINICAL MODELS

Interleukin 12 (IL-12) is a heterodimeric cytokine with a number of bi ological effects that are consistent with its potential role as an ant itumor agent. The antimetastatic and antitumor activities of IL-12 hav e been demonstrated in a number of murine tumor models. Both the inhib ition of established experimental pulmonary or hepatic metastases and a reduction in spontaneous metastases have been achieved by treatment with murine IL-12. Systemic treatment of mice bearing subcutaneous tum ors with IL-12 results in tumor growth inhibition, prolongation of sur vival, and, in some models, tumor regression. The antitumor effect of IL-12 in these models is dose-dependent and can be initiated against w ell-established tumors. Mice cured of their tumor by IL-12 treatment a re specifically immune to rechallenge with the same tumor. A series of experiments have demonstrated that both T-cells and interferon-gamma (IFN-gamma) induction are necessary for the optimal antitumor effects of IL-12. However, the antitumor efficacy of IL-12 has not been observ ed after exogenous administration of murine IFN-gamma, suggesting that additional factors may be important for the antitumor effects of IL-1 2. In several tumor models, IL-12 is more active or has a larger thera peutic window than either IL-2 or IFN-alpha, two cytokines with demons trated antitumor activity against human malignancies. Combining IL-12 with other cytokines or chemotherapeutic drugs can improve antitumor e ffects.