Potential biomarkers of immune activation in ipilimumab-treated patients with advanced melanoma

Abstract

Ipilimumab is a fully human, monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) − a key negative regulator of T-cell responses to tumor-associated antigens.

Ipilimumab treatment results in durable disease control in patients with advanced melanoma. The most common adverse events are mechanism-based (immune-related adverse events [irAEs]) and primarily affect the gastrointestinal (GI) system. In a randomized, double-blind, placebo-controlled, multicenter, phase II study (CA184-007), patients with unresectable stage III or IV melanoma received ipilimumab induction dosing 10 mg/kg every 3 weeks (Q3W) X 4 + placebo/prophylactic budesonide, an oral steroid with minimal systemic exposure hypothesized to reduce GI irAEs. Objectives of the biomarker analyses were to assess the effect of ipilimumab on peripheral T-cell populations during the induction phase (i.e., to Week 12) and to evaluate potential biomarkers of irAEs, particularly GI. Absolute lymphocyte count (ALC) captured in study CA184-007 was combined with data from 2 other phase II studies of advanced melanoma patients who received ipilimumab 10 mg/kg Q3W X 4 (CA184-008 and CA184-022). Response was assessed by modified World Health Organization (mWHO) criteria; the first efficacy assessment was at Week 12. Flow cytometric analysis on pre- and post-treatment blood and serum samples from 115 treated patients (CA184-007) showed that ipilimumab increased the frequency of activated CD4+ and CD8+ T cells during the first 4 weeks of treatment (96% increase each) which was maintained to Week 12 (an additional 33% and 57% increase, respectively). Ipilimumab decreased naïve T cells by Week 12 (91% and 81% decrease for CD4+ and CD8+ T cells, respectively). There was a small, overall mean increase in the frequency of central memory CD4+ and CD8+ T cells from baseline at Weeks 4 and 12, but no meaningful changes in effector memory T cells. In the multi-study analysis (n = 329), responding patients had higher ALC levels, and no patient with an ALC decrease over the induction period responded; these results were highly statistically significant (P = 6 x 10^-4). These results suggest that ipilimumab activates the immune system, and that ALC may predict response to treatment. No predictive biomarkers of irAEs were identified.

This abstract was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.