Endocrine Toxicities of Immunotherapy

Mechanism of Action

IL-2, after binding to its receptor, causes phosphorylation of Janus tyrosine kinases (JAK) which leads to the activation of signal transducer and activator of transcription (STAT), phosphoinositol-3-kinases (PI3K), and SCH-MAP-RAS pathways which lead to further downstream signaling. IL-2 acts as a double-edged sword in cancer immunotherapy. It regulates both T cell expansion and differentiation into memory and effector cells, natural killer (NK) cell proliferation, and increases cytolytic activity which forms the basis of its antitumor activity. On the other hand, IL-2 also leads to the expansion of regulatory T (Treg) cells, and prolonged exposure to IL-2 leads to activation-induced cell death of T cells, which leads to suppression of antitumor immune responses.

Mechanism of Endocrine Toxicity

Thyroid dysfunction is the most common endocrine toxicity with IL-2. Autoimmune destruction is the likely mechanism. An increase in lymphocytic infiltration of the thyroid gland has been seen in patients treated with IL-2. ^, An increase in the levels of thyroid autoantibodies (Tab) during treatment with IL-2 has also been reported. Whether this leads to thyroid dysfunction is not clear, as a few studies have failed to show the association between increased Tab and hypothyroidism. ^,

Reported Toxicities

New or worsening of thyroid function is reported in 16% to 47% of patients on IL-2 alone. ^{, ,} In a study of 281 patients treated with IL-2 by Krouse et al., hypothyroidism was more common than hyperthyroidism with about 35% of patients developing hypothyroidism and 7% developing hyperthyroidism. Most patients had subclinical hypothyroidism and only a few required hormone replacement therapy. The median duration of hypothyroidism was around 60 days with an increase in its incidence seen with successive cycles of treatment. No statistical difference in incidence was seen based on age, gender, tumor type, or IL-2 dose. Similar incidences have been reported when IL-2 is used in combination with other agents. ^, The use of thyroid dysfunction as a predictive marker for response is controversial, with inconsistent results in several studies. ^{, ,} This has been attributed to the fact that patients who respond to therapy were likely to receive more cycles of IL-2, which would increase their risk of thyroid dysfunction.

Two cases of acute adrenal insufficiency have been reported: one was due to IL-2 and another due to IL-2/tumor infiltrating lymphocyte combination therapy. ^, Cases of new onset insulin dependent diabetes mellitus (DM), ^, and changes in levels of β-endorphin, cortisol, and adrenocorticotrophic hormone (ACTH) have been reported. Transient decrease in levels of testosterone, dehydroepiandrosterone, and increase in levels of estradiol have also been reported in men treated with IL-2. These changes suggest a definite endocrine effect caused by IL-2 therapy.

Mechanism of Action

INF-α acts by binding to its receptor on the cell membrane and phosphorylating the intracellular domain along with JAK and tyrosine kinase 2, which are attached to it. This leads to further activation and dimerization of STAT which translocate to the nucleus and leads to the expression of the interferon-regulated genes. INF exerts its anticancer action by (1) inducing apoptosis of tumor cells; (2) inducing activation, proliferation, and cytotoxic activity of dendritic cells, NK cells, CD4+ and CD8+ T cells, and B cells; and (3) decreasing the immunosuppressive action of myeloid-derived suppressor cells and Treg cells.

Mechanism of Endocrine Toxicities

Thyroid dysfunction is common with the use of INF-α. Autoimmune thyroiditis (which is mediated by increase in MHC-I expression in thyroid tissue, switching of the immune response to the Th1 pathway, activation of other mediating immune cells, and release of other cytokines) is the likely mechanism, but direct effects of INF-α on thyroid tissue have also been implicated. In-vitro experiments have shown that INF can inhibit thyroid function by a decrease in iodine uptake and secretion of thyroxine.

Reported Toxicities

Thyroid dysfunction can present as Hashimoto’s thyroiditis, Graves’ disease, presence of thyroid antibodies with no clinical disease, and destructive thyroiditis, which presents with biphasic thyroiditis leading to thyrotoxicosis followed by hypothyroidism and resolution. Between 2% and 10% of patients develop hypothyroidism, with a median time of 4 months after beginning therapy, and nearly 60% of these patients will have persistent hypothyroidism. The presence of thyroid autoantibodies is a risk factor for the development of thyroid dysfunction, and prior autoimmune thyroid disorder has been associated with severe hypothyroidism.

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  New onset insulin dependent diabetes has also been reported and is associated with high titers of pancreatic autoantibodies with almost all patients requiring insulin even after cessation of treatment. INF-α also causes an increase in the levels of cortisol and adrenocorticotrophic hormone. The effect of INF on sex hormones is unclear. A study in men treated with INF showed a decrease in total and free testosterone and dehydroepiandrosterone-sulphate (DHEAS), and showed a correlation between low testosterone and loss of libido. Another study, however, showed no significant changes, highlighting the need for further investigation.

Mechanism of Action of ICIs

CD28 is present on the surface of naïve T cells. It binds to CD80/86 present on the surface of activated antigen presenting cells (APC) providing a costimulatory signal to the interaction between major histocompatibility protein (MHC) and the T cell receptor (TCR). CTLA-4 acts as a competitive antagonist of CD28 expressed on activated T cells and Tregs, and binds to CD80/86 providing an inhibitory signal leading to decrease in T cell activation, proliferation, and IL-2 production. There is some evidence that CTLA-4 might cause trans-endocytosis of CD80/86 leading to its degradation, thereby reducing the number of ligands for CD28. CTLA-4 also enhances the activity of Treg cells leading to more immunosuppression. Blocking of CTLA-4 using monoclonal antibodies (mAbs) was shown to increase T cell activation and proliferation in vitro and decrease tumor growth and tumor rejection in mice models. PD-1, similar to CTLA-4, is also found on the T cell surface, although, unlike CTLA-4, its action is mostly restricted to effector T cells, and peripherally in the tumor microenvironment by binding with its ligands PD-L1 and PD-L2 expressed extensively on tumor cells. This leads to apoptosis and downregulation of T-cell effector functions, which is blocked by antibodies targeting PD-1/PD-L1.

Mechanism of Endocrine Toxicity