Biologic and immunomodulatory events after CTLA‐4 blockade with ticilimumab in patients with advanced malignant melanoma

Abstract

BACKGROUND T‐regulatory (T_R) cells expressing cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4) maintain peripheral immune tolerance and negatively affect host immune responses against cancer. The immunobiologic effects of ticilimumab, a human monoclonal antibody against CTLA‐4, was administered to patients with metastatic melanoma who participated in a Phase I/II clinical trial. METHODS Thirty patients who received ticilimumab at a dose of 10 mg/kg monthly (n = 20) or 15 mg/kg every 3 months (n = 10) were studied at study entry and at 14‐day intervals thereafter to assess lymphocyte immunophenotypes, interleukin (IL)‐2 and IL‐10 production, and the expression of T_R‐related genes in peripheral blood mononuclear cells (PBMC) from a subset of patients was studied by real‐time polymerase chain reaction. RESULTS Four of 12 patients with immune‐related adverse events (IRAE) attained objective antitumor responses (ATR), whereas only 1 of 18 patients without IRAE attained ATR (χ² = 4.0; P = .0455). Patients with ATR had significant reductions in T_R cells and constitutive IL‐10 production accompanied by a significant increase in IL‐2 production by activated T cells. Although IRAE⁺/ATR⁺ patients demonstrated a positive correlation between CTLA‐4 and glucocorticoid‐induced tumor necrosis factor receptor (GITR) transcripts (Spearman rho = .522; P = .015), IRAE⁻/ATR⁻ patients had a positive correlation between the transcripts of CTLA‐4 and program death‐1 (PD‐1) receptor (Spearman rho = .891; P = .000). CONCLUSIONS Antitumor responses in patients with metastatic melanoma who were treated with ticilimumab were found to be correlated with reductions in T_R cells and constitutive secretion of IL‐10, an increase in IL‐2 production, and a positive correlation between transcripts of CTLA‐4 and GITR. Conversely, a lack of ATR was found to be correlated with steady levels of T_R cells and constitutive IL‐10 secretion, and a positive correlation between the transcripts of CTLA‐4 and PD‐1. Cancer 2006. © 2006 American Cancer Society.