Although immune-based
therapies have made remarkable inroads in
cancer treatment, they usually must be combined with standard treatment modalities, including cytotoxic drugs, to achieve maximal clinical benefits. As
immunotherapies are further advanced and refined, considerable efforts will be required to identify combination
therapies that will maximize clinical responses while simultaneously decreasing the unpleasant and sometimes life-threatening side effects of standard
therapy. Over the last two decades, evidence has emerged that Th1
cytokines can play a central role in protective antitumor immunity and that combinations of Th1
cytokines can induce senescence and apoptosis in
cancer cells. To explore the possibility of combining targeted drugs with Th1-polarizing
vaccines, we undertook a study to examine the impact of combining Th1
cytokines with the relatively broad-spectrum
receptor tyrosine kinase antagonist,
sunitinib. We found that when a panel of five phenotypically diverse human
breast cancer cell lines was subjected to treatment with
sunitinib plus recombinant Th1
cytokines IFN-γ and TNF-α, synergistic effects were observed across a number of parameters including different aspects of apoptotic cell death. Interestingly,
sunitinib was found to have a profoundly suppressive effect of T cell's capacity to secrete IFN-γ, indicating that in vivo use of this drug may hinder robust Th1 responses. Nonetheless, this suppression was circumvented in a mouse model of HER-2pos
breast disease by supplying recombinant
interferon-gamma to achieve a combination
therapy significantly more potent than either agent.