Managing Ipilimumab-Induced Hypophysitis: Challenges and Current Therapeutic Strategies

Abstract

Over the past years, progress has been made in cancer immunotherapy following the development of immune checkpoint inhibitors (ICI) that have been proved effective in the management of many malignancies. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4), has been approved for the treatment of advanced melanoma but has been associated with the development of several endocrine immune-related adverse events (irAEs). Hypophysitis is the most common endocrine irAE related to ipilimumab with a reported incidence ranging from 1.8% to 17%. The mechanism underlying ipilimumab-induced hypophysitis implicates immune, inflammatory and genetic factors, but there are still some points that are not well understood and remain to be elucidated. The diagnosis is based mainly on clinical, biochemical and imaging data. The majority of patients display multiple hormone deficiencies that may recover or persist for a prolonged period of time with corticotroph deficiency usually being permanent. Immune-related hypopituitarism is treated with replacement of deficient hormones while in severe forms of hypophysitis treatment with high-dose glucocorticoids may be required. Proper evaluation and registration of patients in clinical trials and further investigation are needed to precisely clarify the pathophysiology of the ICI-related hypophysitis, define predictive factors and ameliorate the management and outcome of the disease.

Keywords: hypopituitarism; immune checkpoint inhibitors; immune-related adverse effects.

Figure 1

Mechanism of action of anti-CTLA-4 antibodies. (A) Presentation of the tumour-associated antigen by the antigen-presenting cell (APC) and recognition by the T-cell receptor (TCR) on the T-cell surface. T-cell activation requires a second signal that is provided via binding of B7 on the APC cell with the CD28 receptor on the T-cell. (B) CTLA-4 competes with CD28 for binding with B7 on APCs and results to inhibition of T-cell activation. (C) Anti-CTLA-4 antibodies block CTLA-4 and restore T-cell activation.

Figure 2

Proposed algorithm for the management of ipilimumab-induced hypophysitis.