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

Cancer
James M ReubenLuis H Camacho

Abstract

T-regulatory (TR) 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. 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 TR-related genes in peripheral blood mononuclear cells (PBMC) from a subset of patients was studied by real-time polymerase chain reaction. 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 (chi2=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...Continue Reading

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