Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic T-lymphocyte-associated
protein 4 (CTLA-4) and programmed death 1 (PD-1) with inhibitory
antibodies has demonstrated effective and durable antitumor activity in subgroups of patients with
cancer. The US Food and Drug Administration has approved several
immune checkpoint inhibitors (ICPis) for the treatment of a broad spectrum of
malignancies. Endocrinopathies have emerged as one of the most common immune-related adverse events (irAEs) of ICPi
therapy.
Hypophysitis, thyroid dysfunction,
insulin-deficient
diabetes mellitus, and
primary adrenal insufficiency have been reported as irAEs due to ICPi
therapy.
Hypophysitis is particularly associated with anti-CTLA-4
therapy, whereas thyroid dysfunction is particularly associated with anti-PD-1
therapy.
Diabetes mellitus and
primary adrenal insufficiency are rare endocrine toxicities associated with ICPi
therapy but can be life-threatening if not promptly recognized and treated. Notably, combination anti-CTLA-4 and anti-PD-1
therapy is associated with the highest incidence of ICPi-related endocrinopathies. The precise mechanisms underlying these endocrine irAEs remain to be elucidated. Most ICPi-related endocrinopathies occur within 12 weeks after the initiation of ICPi
therapy, but several have been reported to develop several months to years after ICPi initiation. Some ICPi-related endocrinopathies may resolve spontaneously, but others, such as central
adrenal insufficiency and
primary hypothyroidism, appear to be persistent in most cases. The mainstay of management of ICPi-related endocrinopathies is
hormone replacement and symptom control. Further studies are needed to determine (i) whether high-dose
corticosteroids in the treatment of ICPi-related endocrinopathies preserves endocrine function (especially in
hypophysitis), and (ii) whether the development of ICPi-related endocrinopathies correlates with
tumor response to ICPi
therapy.