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

Abstract

BACKGROUNDT‐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.METHODSThirty 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.RESULTSFour 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 TR 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).CONCLUSIONSAntitumor responses in patients with metastatic melanoma who were treated with ticilimumab were found to be correlated with reductions in TR 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 TR 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.

Tremelimumab (CP-675,206), a Cytotoxic T Lymphocyte–Associated Antigen 4 Blocking Monoclonal Antibody in Clinical Development for Patients with Cancer

“…It was reported that patients with objective response or disease stabilization had a decrease in CD4 ϩ /CD25 ϩ Treg cells and in constitutive IL-10 secretion compared with patients with progressive disease. However, functional assays were not reported [66]. In contrast, CTLA-4 blockade with ipilimumab did not alter the number or function of circulating Treg cells when tested by functional assays of suppressor activity (the gold standard for Treg cell quantitation) [44], mRNA levels of the Treg-specific transcription factor Foxp3 [67], and flow cytometric analysis of surface markers on Treg cells [26].…”

“…Studies were conducted in a subset of patients within the Study 1002 phase II study to determine the potential role of modulating Treg cells on antitumor activity [66]. It was reported that patients with objective response or disease stabilization had a decrease in CD4 ϩ /CD25 ϩ Treg cells and in constitutive IL-10 secretion compared with patients with progressive disease.…”

Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients

“…The therapeutic efficacy of CTLA-4 blockade in murine models involves enhanced antitumor cytotoxicity, which reflects an increased proportion of CD8 ϩ T effector cells to FoxP3 ϩ Tregs within intratumoral infiltrates (12). Although CTLA-4 may contribute to Treg-induced immune suppression in some settings (13,14), the infusion of anti-CTLA-4 antibodies triggers an overall expansion of Treg numbers in tumor-bearing hosts, especially in regional lymph nodes (12). Thus, a complex dynamic between effector and regulatory pathways underlies the antitumor effects of CTLA-4 blockade.…”

Therapeutic Agents for Advanced Melanoma

“…Tremelimumab is thought to stimulate patients' immune systems to attack their tumors. It has been shown to induce durable tumor responses in patients with metastatic melanoma in phase 1 and phase 2 clinical studies [44].…”