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

Cancer. 2006 Jun 1;106(11):2437-44. doi: 10.1002/cncr.21854.


Background: 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.

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 TR-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 (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-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 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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Blocking / immunology*
  • Antibodies, Monoclonal / immunology*
  • Antigens, CD
  • Antigens, Differentiation / immunology*
  • Bone Neoplasms / immunology
  • Bone Neoplasms / secondary
  • CTLA-4 Antigen
  • Female
  • Humans
  • Interleukin-10 / metabolism
  • Interleukin-2 / metabolism
  • Liver Neoplasms / immunology
  • Liver Neoplasms / secondary
  • Lung Neoplasms / immunology
  • Lung Neoplasms / secondary
  • Male
  • Melanoma / immunology*
  • Melanoma / pathology
  • Middle Aged
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism


  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Interleukin-2
  • Interleukin-10