Analysis of potential biomarkers of response to IL-12 therapy

IL-12 is a proinflammatory cytokine capable of inducing a wide range of effects on both innate and adaptive immune responses. Its stimulatory effects on T cells and NK cells have led to its classification as a potential inducer of antitumor immunity. Clinical trials have been attempting to harness its immune-stimulating capacity since the 1990s and have had much success despite notable toxicity issues early on. Several methods of IL-12 delivery have been employed including i.v., s.c., and local administrations as well as plasmid and gene therapies. However, despite differing methods, dosages, and cancer types utilized in these clinical trials, there are still many patients who do not respond to IL-12 therapy. This creates an opportunity for further investigation into the immunologic differences between responding and nonresponding patients in order to better understand the variable efficacy of IL-12 therapy. This review focuses on a limited collection of IL-12 clinical trials, which further analyzed these individual subsets and detected biologic variables correlating with differential patient responses. A comprehensive review of these potential biomarkers identified 7 analytes that correlated with beneficial patient responses in 3 or more clinical trials. These were increased levels of IFN-γ, IP-10, TNF-α, MIP-1α, MIG, and CD4⁺ and CD8⁺ T cells, with a decrease in VEGF, bFGF, FoxP3⁺ T regulatory cells, and M2 macrophages. These potential biomarkers highlight the possibility of identifying immunologic determinants of patient response to IL-12 therapy to conserve valuable resources and benefit patients.