The influence of monoclonal antibodies for cancer treatment on the endocrine system

Cancer results from the outgrowth of a clonal population of cells from the tissue [65]. There were an estimated 3.91 million new cancer cases (excluding non-melanoma skin cancer) and 1.93 million deaths from cancer in Europe in 2018. The most common cancer sites were cancers of the female breast (523,000 cases), followed by colorectal (500,000), lung (470,000), and prostate cancer (450,000) [24]. One quarter of all annual cancer deaths are attributable to cancers of the lung and bronchus, making them the most common cause of cancer death for both men and women [75].

The burden of cancer has increased worldwide. Alarmingly, the World Health Organization (WHO) predicts that the number of new cancer cases is expected to rise by approximately 70% over the next 20 years [80]. Common types of cancers overlap considerably all over the world. Developing countries tend to have a higher incidence and death rates for viral infection-related cancers. The examples are hepatitis-related liver cancer and human papillomavirus (HPV)-related cervical cancer [44, 69]. Known cancer risk factors include social determinants, lifestyle factors, occupational exposures, infectious agents, hormones, radiation, and genetic as well as epigenetic alterations [73]. It is estimated that one third to one half of cancers could be prevented by healthier lifestyle choices. Among the modifiable risk factors, attention is paid to reducing tobacco smoking, moderate alcohol consumption, maintaining normal body weight (within the Body Mass Index (BMI) range of 18.5 to 24.9), a healthy diet and leading an active lifestyle [44, 69]. Screening is a powerful strategy to control some cancers, such as cervical cancer. Challenges remain in studying the effectiveness of screening for other cancers [73].

In recent years, conventional treatments including surgery, chemotherapy and radiotherapy, have been the main approaches in tumor therapy. Cancer immunotherapy is a new type of cancer treatment. It helps to fight cancer by harnessing the power of the patients’ own immune system. Cancer immunotherapy may be more targeted than conventional cancer treatments. Numerous cancer immunotherapy strategies are under investigation. A few have been approved for cancer treatment. These include molecular therapy, cellular therapy, and vaccination therapy [49].

Molecular targeted therapy refers to the use of drugs or other substances that target specific molecules (molecular targets). It blocks the growth and spread of cancer cells. The concept for targeted therapy was derived from the idea of “the magic bullet”, which was first expatiated by Paul Rich in the late 1800s. It was initially used to depict the ability of a chemical that targeted microorganisms specifically, but the method has since been expanded to cancer treatment.

These drugs interfere with specific molecules to block cancer growth, progression, and metastasis. Many molecular targeted therapies approved by the Food and Drug Administration (FDA), have demonstrated remarkable clinical success in the treatment of a myriad of cancer types, including breast, leukemia, colorectal, lung, and ovarian cancer [48]. Targets selected for molecular therapy include growth factors, signaling molecules, cell-cycle proteins, modulators of apoptosis and molecules that promote angiogenesis [11]. Target engagement can be achieved through several modalities. These regulate or interact with cell surface receptors (monoclonal antibodies), intracellular cascade pathways and signaling (small molecule tyrosine kinase inhibitors) or micro-environment effects related to tumor vasculature or hypoxia. Interesting results describing the use of antibody-drug conjugates to increase cytotoxic drug delivery have also been obtained [72]. Improved delivery of targeted agents to cancer cells using nanoparticles, such as porphysomes, presents a tremendous opportunity to precision-bomb cancer cells and reduce bystander or collateral toxicity [64].

Monoclonal antibodies (mAbs) are typically developed for targets that are located outside the cells, as they are relatively too large to enter the cells [40]. MAbs specifically target extracellular proteins and inhibit tumor growth by interrupting the interactions between the receptors and ligands. The antibodies can mediate their actions either through an indirect or direct mechanism, after binding to cancer cells [78]. MAbs are able to act via different mechanisms to exert their action through any of the following means: antibody dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), blockage of signal transduction, induction of apoptosis, or delivery of cytotoxic payloads [70]. The role of CDC is binding of mAb to recruit the classic complement-activating protein C1q which induces the activation of the complement cascade, leading to the formation of the membrane attack complex (MAC), and causes cell lysis. The function of ADCC is binding of mAb, so that it recruits an effector cell, such as a natural killer (NK) cell, a macrophage or monocytes through their Fc receptors, and lyses the cancer cells. In turn, the role of ADCP is binding of mAb to recruit a macrophage, which leads to phagocytosis of the cancer cell. Direct tumor cell killing includes the induction of apoptosis after the binding of mAb to the cancer cells. The binding of mAb to the cancer cell receptor or ligands leads to the disruption of the signaling pathway, inhibiting cell proliferation or activating cell death. What is more, mAb acts as a carrier to deliver toxic payload, such as radioisotopes, toxins, drugs or cytokines, in order to kill tumor cells [48].

MAbs are usually well tolerated in comparison to cytotoxic chemotherapy or chemoradiotherapy; they do have potential adverse effects that are connected to their mechanism of action. Their side effects usually do not overlap with those of cytotoxic chemo-therapy [32]. The most frequent side effects of mAbs are allergic reactions, such as infusion reactions (anaphylactic or less frequently anaphylactoid), hives and/or pruritus, influenza-like symptoms, as well as fatigue, chills, mild fever, headaches, muscular pain, gastrointestinal upset with nausea, vomiting and/or diarrhea, low blood pressure and skin rashes [28].

Hypophysitis is a very rare acute or chronic inflammation of the pituitary gland [50]. It may occur as an adverse effect during therapy with ICPis. Ipilimumab is an antibody that has been more strongly related to this immune-related adverse event [26, 46].

Histopathological findings in patients with Ipilimumab-induced hypophysitis revealed the pathogenesis of this disorder. The evidence of pituitary antibodies in the serum of these patients and in animal models of anti-CTLA-4-induced hypohysitis suggested that the pathogenesis involved type II and IV hypersensitivity, as well as the humoral immune response [8, 38]. However, de Filette and coworkers confirmed that hypophysitis is more common during therapy with ipilimumab (5.6%) compared to nivolumab (0.5%) and pembrolizumab (1.1%) [18].

The CTLA-4 antibody binds to the pituitary CTLA-4 antigen. It induces complement activation and infiltration with macrophages and other inflammatory cells, leading to phagocytosis and enhanced antigen presentation. Afterwards, autoreactive T-lymphocytes infiltrate the anterior pituitary, which leads to pituitary cytotoxicity and inflammation. What is more, patients with induced hypohysitis develop pituitary antibodies that recognize thyroid-stimulating hormone-(TSH-), follicle-stimulating hormone-(FSH-) and adrenocorticotropic hormone-(ACTH-) secreting cells. Therefore, central hypothyroidism, central adrenal insufficiency, and hypogonadotropic hypogonadism are the most common pituitary abnormalities in anti-CTLA-4-related hypophysitis [8, 9, 38]. Almost 90% of patients who evolve hypophysitis have ACTH deficiency, and cases of mortal acute adrenal insufficiency have been described [33]. An early onset of ipilimumab-related hypophysitis has been reported. It typically presents itself ~2 to 3 months after the ipilimumab initiation, but it can also appear several months after the initiation of treatment with antibodies [67, 81].

Patients suffer from non-specific symptoms, like headache, nausea, fatigue and myalgia. Visual disorders occur rarely and central diabetes insipidus is highly uncommon [16, 83]. Other symptoms may also occur, e.g. memory loss, confusion, hallucinations, insomnia, decreased appetite, cold intolerance or chills [74]. In imaging, a normal-appearing pituitary gland does not rule out hypophysitis. Clinical and biochemical evaluation should define the therapeutic management [14].

Diabetes insipidus (DI) is extremely rare. DI can be due to an ADH deficiency. The symptoms are polyuria and the production of diluted urine, which, in turn, can cause hypernatremia, if fluid loss is greater than fluid gain [19, 83].

It is necessary to monitor the general condition of the patients and conduct hormonal tests during the treatment with immune checkpoint inhibitors. The treatment involves supportive management and hormone replacement with levothyroxine, corticosteroids and estrogen/testosterone, depending on the pituitary hormone deficiency [14].

ICPi-related hypoparathyroidism is a rare disorder. To date, there have been only two case reports on severe hypocalcemia with confirmed hypoparathyroidism. The first melanoma patient, treated with nivolumab/ipilimumab, developed the symptoms of acute hypocalcemia 6 weeks after the first dose of ICIs. The second case of hypocalcemia was observed in a patient with a small cell lung cancer receiving nivolumab treatment [62, 79]. Hypocalcemia has been found to be considerably associated with the PD-1 inhibitor pembrolizumab treatment in a recent meta-analysis by Manohar et al., notably as a rare (11 out of 604 patients) adverse effect [51]. The pathomechanism is still unknown. Typically, the calcium sensing receptor (CaSR) of the parathyroid glands stimulates the release of PTH upon sensing of low blood calcium. CaSR autoantibodies and CaSR-activating autoantibodies have been described in a patient treated with nivolumab. Another pathomechanism includes cross-presentation of tumor-antigens. It leads to the expansion of T cell clones that then infiltrate healthy tissue and cause inflammation [42, 62].

Thyroid dysfunction belongs to one of the most frequently endocrine-related irAEs connected with ICPi therapy. ICI-thyropathy manifests itself as hyperthyroidism, hypothyroidism, and/or thyroiditis. Graves’ disease (GD) appears to be very rare, but it has been reported [14]. Compared to anti-CTLA-4, these conditions are a more characteristic result of anti PD-1 therapy (up to 40%), while, according to available reports, they appear in 1–7% of patients with anti-CTL4 therapy. Immune checkpoint inhibitors are also associated with a significant risk of thyroid autoimmunity. This risk is higher for the anti-PD-1 treatment and increases during therapy with combination of checkpoint inhibitors [12]. Thyroid-related adverse effects are more common in women and include the whole spectrum of thyroid dys-functions [66].

The mechanisms underlying thyroid dysfunction after treatment with immune checkpoint inhibitors remain to be clarified, similarly to other adverse effects that are not associated with the thyroid [12]. CTLA-4 is a major susceptibility gene for autoimmune thyroid disorders (AITDs), including GD and Hashimoto thyroiditis (HT). Whether polymorphisms in these genes have an influence on susceptibility to ICPi-related thyroid dysfunction remains unclear. Elevated levels of TPO Ab and TgAb have been identified in many patients with ICPi-related thyroid dysfunction. It is unclear whether these autoantibodies are the reason of ICPi-related thyroid dysfunction, and whether their elevated levels at baseline increase the risk of the occurrence of ICPi-related thyroid dysfunction [14]. Interaction between environmental and genetic factors influences the development of ATIDs. In one of the meta-analyses the authors evaluated polymorphism in the CTLA-4 gene. This study suggested that CT60 polymorphism (rs3087243) in CTLA-4 gene might confer susceptibility to the AITDs (GD/HT) [55]. Monoclonal antibodies are not the only drugs that cause thyroid disorders. Also, antivirals, including IFN-α and ribavirin, can induce AITDs [20].

Checkpoint blockade associated adrenal insufficiency is a potentially life-threatening complication of hypophysitis or adrenalitis in this patient group. Its symptoms are unspecific and include nausea, fatigue, appetite loss, abdominal pain, weight loss, hypotension, and hypoglycemia [18]. Life-threatening adrenal crisis, if untreated, may also occur and lead to shock and death [14]. Hyponatremia and hyperkalemia are frequently due to the presence of glucocorticoid and mineralocorticoid deficiency, while hypoglycemia and hypercalcemia are rare [6]. The overall incidence is low and appears more frequently when patients are treated with PD1 antibodies (0–4.3% with pembrolizumab and 0–3.3% with nivolumab) than with CTLA-4 inhibitors (ipilimumab 0.3–1.5%) [66]. The pathogenesis of ICPi-related PAI is unclear [14].

Diabetes mellitus (DM) was present in less than 1% of patients treated with immune checkpoint inhibitors. Almost all cases of ICPi-related DM are caused by anti-PD-1 therapy. The patients commonly follow a fulminant course, with diabetic ketoacidosis and a rapid destruction of beta-cells. The pathophysiologic mechanism and predictive biomarkers have not yet been determined. The result of ICPi-related DM is permanent insulin-dependence (type 1 diabetes mellitus, T1DM). Patients with ICPi-related T1DM have a propensity to have relatively low levels of hemoglobin A1C (HbA1C), in comparison to the degree of hyperglycemia at presentation. This points to the rapidity of hyperglycemia progression [14, 76]. It is important to note that ICPi-induced diabetes tends to be irreversible [27]. Therefore, such symptoms as polyuria, polydipsia and weight loss should indicate a possibility of T1DM development [13].

Because ICPi modulates immune responses, high-dose corticosteroid treatment is suggested for some adverse effects. β-blockers appear to be adequate in managing the thyroiditis in the thyrotoxic phase. The manifestations of hypothyroidism are so unspecific that using them in deciding on the initiation of thyroid replacement therapy would be unsafe. It is proposed to introduce levothyroxine when the TSH levels are > 10mUI/L, as is commonly recommended in adult primary hypothyroidism. In case of central hypothyroidism, the introduction of thyroxine should be based on the FT4 levels, when they fall below the lower limit of the normal range, irrespectively of the TSH levels. The decision whether ICPi treatment should be continued, should not be based on the appearance of endocrine toxicity, excluding situations of life-threatening endocrine toxicity that are unsuitable for effective therapy [36]. This decision should be grounded in the risk involved in withdrawing therapy in patients under treatment for controlled or responsive malignant tumor. There are no indications to stop ICPi therapy in patients with grade 1 (mild) hypophysitis. In case of a higher degree of toxicity, it is recommended to discontinue the therapy and include systemic high-dose glucocorticoids. In case of clinical enhancement, immunotherapy can be resumed in combination with appropriate hormone replacement therapy (HRT) [30].

It is difficult to systematize objective recommendations to avoid severe endocrine adverse effects. Clinicians should choose an individual and specific to each patient treatment regimen. Current guidelines, research data and clinical experience can be used to limit adverse effects of therapy. As hypopituitarism, thyroid dysfunction, and diabetes mellitus are the three primary types of endocrine toxicity, TSH, FT4, cortisol, ACTH and glucose measurements should be done before starting ICPi treatment. Creation of objective recommendations for follow-up seems to be problematic due to frequently missing information on the timing of onset of the side effects from large trials [36].

Figure 1A and B show suggested endocrine parameters that should be monitored in patients during monoclonal antibody treatment.

Fig. 1

Many molecular targeted therapies approved by the FDA have demonstrated remarkable clinical success in the treatment of various cancer types. Among them, we distinguish specific mAbs. However, we should be aware of the potential side effects in the endocrine system that can be dangerous for the patients. Immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1, or its ligand PD-L1, can cause a variety of autoimmune adverse effects. Among the most common ones are hypopituitarism, thyroid dysfunction, adrenal insufficiency and diabetes mellitus. It is necessary to monitor the general condition of patients and appropriate diagnostic parameters. This will allow choosing individual anticancer therapy and proper ICPi-related endocrinopathy treatment.