IL-12/IL-2 combination cytokine therapy for solid tumours: translation from bench to bedside.

ABSTRACT

A broad range of approaches are under active investigation for the biological therapy of cancer, in particular, strategies directed at host immune response potentiation. These efforts have been fuelled by studies demonstrating the presence of an endogenous, but ineffective, host antitumour immune response and a greater understanding of the key factors which regulate this response. These mechanisms involve complex interactions between various effector cell populations, soluble factors and the tumour itself and are determined by the timing and relative intensity of positive and negative autoregulatory pathways, as well as a variety of immunosuppressive effects capable of mediating tumour self-defence. Based on these observations, immunotherapeutic regimens have been developed to potentiate antigen-specific sensitisation of effector cells with tumour vaccines/adjuvants, expand and amplify the number and function of effector cells, and to counteract suppressive pathways engaged by tumour cells themselves. Significant effort has focused on evaluating the use of exogenous cytokines, administered either systemically or locally into the tumour site via gene therapy. Several cytokines have demonstrated unique activity in the preclinical setting, including IL-2 and IFN-alpha -inducing cytokines such as IL12 and IL18. Most notably, later studies have now attempted to build on the clinical efficacy of IL-2 alone, to define combinations of agents with synergistic immunoregulatory and/or antitumour efficacy. Several lines of evidence suggest that IL-12 and IL-2 provide complementary immunoregulatory signals and have now shown that in combination, these two cytokines mediate synergistic antitumour activity in preclinical tumour models. This paper will review existing data regarding mechanisms of interaction between IL-2 and IL-12 in vitro and in preclinial models and describe future opportunities for the investigation of these potentially promising cytokines in the treatment of cancer.