Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-mediate gastrointestinal adverse events.

Abstract

8593 Background: Treatment with ipilimumab, a fully human anti-CTLA-4 antibody approved for treatment of metastatic melanoma (MM), is associated with a number of immune-mediated Adverse Events (imAEs) such as colitis and skin rash. Predictive biomarkers that can help identify patients (pts) who might experience these imAEs could enhance the management of these toxicities. Methods: Gene expression profiling (using Affymetrix gene chip HT-HG-U133A) was performed on the whole blood samples from 162 MM pts at baseline, 3 and 11 weeks after the start of ipilimumab treatment in two phase II clinical trials (CA184004 and -007). Overall, 49 pts experienced Grade 2 or higher GI-imAE (G2+) during the course of treatment. A repeated measures ANOVA was used to evaluate the differences in mean expression levels between the two groups and at the three time points. Uncorrected p-value of 0.05 was used as a cutoff for this analysis. Results: In baseline samples, 27 probe sets showed differential mean expression (≥ 1.5 fold, p < 0.05) between G2+ pts and others. Most of these genes belonged to three functional categories: immune system, cell cycle or intracellular trafficking. Changes in gene expression over time were also characterized. In the G2+ pts, 58 and 247 genes had a ≥ 1.5 fold (p < 0.05) change in expression from baseline to week 3 and 11 post-treatment, respectively, compared to 17 and 73 in other pts. In particular, the on-treatment increases of the expression of CD177 and CEACAM1, two neutrophil activation markers, were closely associated with G2+ GI-imAE, suggesting a possible role of neutrophils in ipilimumab associated GI-imAEs. In addition, the expression of several Ig genes increased over time, with higher increases in the G2+ pts. These observations were reproduced in another ipilimumab monotherapy study in MM (CA184078). Conclusions: Gene expression profiling of peripheral blood resulted in the identification of a set of potential biomarkers that may be predictive of severe GI-imAEs before, or early in the course of treatment with ipilimumab. Further validation of these biomarkers in a larger patient cohort is warranted.