Combination therapy comprising interferon - α plus molecular targeted agents in patients with advanced renal cell carcinoma

Since 2008, several molecular targeted agents, such as tyrosine kinase inhibitors of vascular endothelial growth factor receptor (VEGFR-TKIs) and mammalian target of rapamycin (mTOR) inhibitors, have been approved in metastatic renal cell carcinoma (RCC) in Japan. Although these agents significantly improve progression-free survival among such patients compared to IFN α, there is still a critical need to increase the number of complete responses since it is rarely attainable with these agents. For the purpose of strengthening their effect, physicians have so far attempted "sequential" or "combinational" targeted therapy in clinical trials using two different targeted agents, under the expectation of an additive/synergistic effect by "vertically" or " horizontally" blocking the crucial signal pathways required for the development of renal cell carcinoma. However, such attempts in general have backfired due to increased toxicities, eventually resulting in termination of the studies. On the other hand, IFN α, which activates host immune via cytotoxic T cell (CTL) and natural killer (NK) cell stimulation in addition to its direct anti-tumor action, is still regarded by many Japanese urologists as a useful option if patients are properly selected, and seems to offer an enhanced anti-tumor effect when combined with anti-VEGF/VEGFR agents, as has been reported in recent clinical trials outside Japan. The current article summarizes the outcomes of clinical trials using the above combination therapies and provides a brief introduction to an ongoing domestic trial of combination therapy comprising sorafenib plus low-dose IFN α. Possible mechanisms of how this combination therapy works, as demonstrated by an animal experiment, are also discussed.