Analysis of changes in plasma cytokine levels in response to interleukin 12 therapy in three clinical trials

Abstract

The ability of interleukin 12 (IL-12) to stimulate NK and T cell anti-tumor activity makes it an attractive candidate for the immune therapy of cancer. Our group has demonstrated that IL-12 enhances NK cell responses to antibody-coated tumor cells and conducted three clinical trials utilizing IL-12 with monoclonal antibodies (OSU-9968, OSU-0167 and OSU-11010). To better characterize IL-12-induced immunity, plasma cytokine levels were measured in 21 patients from these trials with favorable and unfavorable responses. t-statistics and linear modeling were used to test for differences within and between response groups by examining levels at baseline and post-IL-12 administration. Patients exhibited significant increases in eleven cytokines post-IL-12 administration when analyzed collectively. However, several cytokines were differentially induced by IL-12 depending on response. GM-CSF was significantly increased in complete/partially responding patients, while stable disease patients had significant increases in IL-10 and decreases in VEGF-C. Patients who experienced progressive disease had significant increases in CCL3, CCL4, IL-18, TNF-α, CXCL10, CCL8, CCL2, IL-6 and IFN-γ. The increases in CCL3, CCL4 and IL-6 in progressive disease patients were significantly higher than in clinically benefitting patients and most prominent within the first two cycles of IL-12 therapy. This correlative pilot study has identified changes that occur in levels of circulating cytokines following IL-12 administration to cancer patients, but this report must be viewed as exploratory in nature. It is meant to spark further inquiry into the topic via the analysis of additional cohorts of patients with similar characteristics who have received IL-12 in a uniform fashion.