Article

Cancer Immunity, Vol. 8, p. 9 (27 May 2008) Submitted: 27 March 2008. Accepted: 22 April 2008.

Concurrent decrease in IL-10 with development of immune-related adverse events in a patient treated with anti-CTLA-4 therapy

Jingjing Sun1*, Jade Schiffman2*, Anitha Raghunath2, Derek Ng Tang1, Hong Chen1 and Padmanee Sharma1,3

1Department of Genitourinary Medical Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA

2Department of Ophthalmology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA

3Department of Immunology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA

*These authors contributed equally to this work

Communicated by: JP Allison

Keywords: clinical trial, bladder cancer, ipilimumab, IL-10, adverse event

Abstract

The cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule on T cells acts to maintain homeostasis by regulating the proliferation of recently activated T cells. Blockade of CTLA-4 by anti-CTLA-4 antibody enhances T cell responses and has elicited significant tumor regression in some cancer patients. Clinical trials are ongoing to investigate the efficacy of anti-CTLA-4 antibody as a cancer therapeutic. Reports from several clinical trials have documented the occurrence of adverse events in patients treated with anti-CTLA-4 antibody which have some similarities with autoimmune conditions and have been termed immune-related adverse events (irAEs). Most irAEs are reversible with corticosteroid therapy. Some investigators suggest that irAEs occur in the same patients who have anti-tumor responses as a result of the anti-CTLA-4 antibody. Immunologic mechanisms to explain why irAEs occur in some patients have not been reported. Here we report that bladder cancer patients treated with anti-CTLA-4 antibody have increased levels of the Th1 cytokine IFN-γ detected in plasma samples. Although IFN-γ is a potent anti-tumor and inflammatory cytokine, increased levels of IFN-γ were not associated with irAEs in our patients. However, in one patient who experienced an irAE consisting of ischemic papillopathy and optic neuritis, we documented high pre-therapy levels of the Th2 cytokine IL-10 which decreased after treatment with anti-CTLA-4 antibody. The decrease in plasma IL-10 concentration coincided with the patient's irAE. We propose that decreased levels of IL-10 after treatment with anti-CTLA-4 therapy may be responsible for irAEs in some patients and needs to be further investigated in larger studies.