Analysis of Changes in Plasma Cytokine Levels in Response to IL12 Therapy in Three Clinical Trials

The ability of IL12 to stimulate natural killer (NK) cell and T-cell antitumor activity makes it an attractive candidate for the immune therapy of cancer. Our group has demonstrated that IL12 enhances the NK cell response to antibody-coated tumor cells and conducted three clinical trials utilizing IL12 with mAbs (OSU-9968, OSU-0167, and OSU-11010). To better characterize IL12-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-IL12 administration. Patients exhibited significant increases in 11 cytokines post-IL12 administration when analyzed collectively. However, several cytokines were differentially induced by IL12 depending on response. GMCSF was significantly increased in complete/partially responding patients, while stable disease patients had significant increases in IL10 and decreases in VEGF-C. Patients who experienced progressive disease had significant increases in CCL3, CCL4, IL18, TNF alpha, CXCL10, CCL8, CCL2, IL6, and IFN gamma. The increases in CCL3, CCL4, and IL6 in progressive disease patients were significantly higher than in clinically benefitting patients and most prominent within the first two cycles of IL12 therapy. This correlative pilot study has identified changes that occur in levels of circulating cytokines following IL12 administration to patients with cancer, 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 IL12 in a uniform fashion.Significance: IL12 activates immune cells and is used to treat cancer. The profile of circulating cytokines was measured in an exploratory fashion in patients with cancer that received IL12 in combination with mAbs. This correlative pilot study could serve as the basis for additional studies of IL12 effects on the production of immune cytokines.