**1. Introduction**

Immune system detects and destroys abnormal cells through immune surveillance and as a part of this prevents growth of many impending cancers. Immunotherapies work by either activating or suppressing the immune system and have emerged as important part of how we treat different types of cancers in last few decades [1].

Immune inhibitor pathway plays an important role in maintenance of selftolerance, and cancer cells evade immune mediated destruction by upregulation of immune inhibitory pathways. Immunotherapy can be used to suppress these immune checkpoints resulting in antitumor activity. Immune check point inhibitors have significantly improved prognosis for patients with various advanced malignancies like melanoma, non-small cell lung carcinoma, Hodgkin lymphoma, urothelial carcinoma, renal cell carcinoma and head and neck cancer. As medical oncology treatments are changing from anatomical sites to molecular sites – immunotherapies have established role in certain molecular patterns as well (i.e. MSI high, TMB high metastatic tumors).

Immunotherapies include wide array of drugs with different mechanisms including monoclonal antibodies, immunomodulators, cytokines, checkpoint inhibitors, chimeric antigen receptor T cell therapy, cancer vaccines and oncolytic viruses while many other new approaches are being investigated.

Targeting the immune inhibitory pathways for cancer treatment can lead to immunologic self-tolerance imbalance, resulting in immune-related adverse events (irAEs) which can virtually affect all the organ systems; including eye and brain which are usually unaffected by immune system [2–4]. Different immunotherapies usually affect different organs, as Anti-CTLA-4 mAbs are likely to affect colon and pituitary gland, while anti-PD-1 (L1) mAbs affect thyroid gland.

Among Anti-CTLA-4 mAbs, Ipilimumab has been approved for melanoma, kidney cancer and now NSCLC, and has significantly changed the natural history of advanced tumor. Another immunotherapeutic drug tremelimumab is under development. Common side effects associated with anti-CTAL-4 mAbs include pruritis, diarrhea, rash and fatigue with severe to life-threatening adverse events occurring in less than 5% cases. Anti PD-1 and PD-L1 mABs have similar toxicity profile [5]. Nivolumab, pembrolizumab, and cemiplimab are anti PD-1 mABs, while atezolizumab, avelumab, and durvalumab target PD-L1. In general, anti-PD-1 mAbs are associated with far fewer irAEs than Anti-CTLA-4 mAbs. Common side effects associated with Anti PD-1 (L1) mAbs fatigue, rash, pruritus and idea with severe to life-threatening adverse events occurring in 2–3% of cases. The combination of Anti-CTLA-4 and Anti PD-1 (L-1) antibodies have shown better antitumor results but however they have been associated with higher incidence of immune therapy related adverse event than monotherapy [6, 7].

Usually these irAEs arise within 3–6 months of starting the immunotherapy but it may take few years and thus needs close monitoring for years after completion of therapy. These side effects can be graded from mild to moderate as Grade 1–2 and severe to life threatening as Grade 3–4 [2, 8].

In general, mild Grade 1 side effects usually requires symptom management and does not require immunotherapy discontinuation. Grade 2 or moderate side effects usually managed with temporary discontinuation of checkpoint inhibitor. For severe to life-threatening Grade 3 and 4 side effects immunotherapy is permanently discontinued and these patient usually require high dose of corticosteroids.

Some studies have shown association of irAEs with better antitumor efficacy, the data remains conflicting and needs further research confirm whether occurrence of irAEs predicts better outcome [9–13].

### **2. Endocrinological adverse effects of immunotherapy**

Immunotherapy can cause wide array of endocrine side effects. More common irAEs are hypophysitis leading to hypopituitarism, primary or secondary thyroid dysfunction, primary or secondary adrenal insufficiency, autoimmune diabetes mellitus leading to diabetic ketoacidosis.

#### **3. Pituitary dysfunction**

#### **3.1 Incidence**

#### *3.1.1 Anti-CTLA-4 mAbs*

Hypophysitis is one of the more common immunotherapies induced endocrinopathies and is more common after anti CTLA–4 therapy, reaching around 13% after treatment with ipilimumab [14, 15]. Ipilimumab induced hypophysitis (IH) occurs more frequently in males and in older age when compared to lymphocytic autoimmune hypophysitis even when adjusted for melanoma incidence for age and sex [15–17].

**57**

*The Endocrinological Side Effects of Immunotherapies DOI: http://dx.doi.org/10.5772/intechopen.96491*

glucocorticoids treatment [14].

*3.1.2 Anti-PD-1 and anti PD-L1 mAbs*

**3.2 Diagnosis and treatment**

symptoms such as polyuria or polydipsia.

*3.2.1 Monitoring*

*3.2.2 Diagnosis*

*3.2.3 Treatment*

IH is a type II hypersensitivity reaction in which CTLA-4 antibodies bind to antigen expressed on pituitary cells resulting in compliment activation and gland destruction [18, 19]. Some studies have suggested that IH development may be associated with better antitumor outcomes in terms of morbidity and mortality [14]. The data on whether other agents and radiotherapy can alter the risks of hypophysitis is limited. In the reported studies the average time to IH diagnosis is about 9 weeks; though time to endocrine abnormalities development has not been routinely reported in trials. The radiographic changes seen on MRI including heterogenous pituitary enlargement with thickening of stalk are the sensitive and specific indicator of hypophysitis and may be the first signs of pituitary dysfunction occurring before hormonal disturbances or development of symptoms [1, 20]. The degree of pituitary enlargement can be mild in the patient's with IH and resolves quickly after

Most common laboratory abnormalities observed at the time of diagnosis includes central hypothyroidism with reduction of TSH and secondary adrenal insufficiency. Hyponatremia secondary to adrenal insufficiency and hypothyroidism is frequently noted but central diabetes insipidus is rare with IH. Also growth hormone or prolactin axis disturbances occur less compared to other hormonal deficiencies. Usually, other hormonal deficiencies improved with treatment except for adrenal insufficiency which requires lifelong with steroid treatment [14, 21, 22].

Multiple studies have shown that incidence of Anti-PD-1 and anti PD-L1 mAbs

Patients receiving immunotherapy treatments should have baseline pituitary function test done. Routine thyroid function test monitoring with monthly TSH and free T4 level checks is recommended during the treatment and when patient develops symptoms suggestive of hypophysitis. Those patients who receives anti-CTLA-4 agents routine monitoring of ACTH and cortisol level should be done.

A clinician must have high index of suspicion for the hypophysitis diagnosis as patient may present with vague symptoms or use of exogenous glucocorticoids may mask their presentation so regular monitoring is critical. When suspected, MRI should be performed to assess pituitary and rule out other causes of pituitary dysfunction along with hormone profile evaluation including TSH and free T4, ACTH, cortisol, LH, FSH, prolactin, estradiol and females and distress return in males. It is recommended to investigate for diabetes insipidus only if patient is presenting with

High dose glucocorticoids course is given when hypophysitis is suspected which may reverse inflammatory process and prevent the need for longer term hormone

associated hypophysitis is less compared to Anti-CTLA-4 antibodies. Average incidence of hypophysitis was 0.6% in patients treated with pembrolizumab and

novilumab, <0.1% in durvalumab and 0.2% with atezolizumab [23–26].

#### *The Endocrinological Side Effects of Immunotherapies DOI: http://dx.doi.org/10.5772/intechopen.96491*

*Advances in Precision Medicine Oncology*

inhibitors, chimeric antigen receptor T cell therapy, cancer vaccines and oncolytic

Targeting the immune inhibitory pathways for cancer treatment can lead to immunologic self-tolerance imbalance, resulting in immune-related adverse events (irAEs) which can virtually affect all the organ systems; including eye and brain which are usually unaffected by immune system [2–4]. Different immunotherapies usually affect different organs, as Anti-CTLA-4 mAbs are likely to affect colon and

Among Anti-CTLA-4 mAbs, Ipilimumab has been approved for melanoma, kidney cancer and now NSCLC, and has significantly changed the natural history of advanced tumor. Another immunotherapeutic drug tremelimumab is under development. Common side effects associated with anti-CTAL-4 mAbs include pruritis, diarrhea, rash and fatigue with severe to life-threatening adverse events occurring in less than 5% cases. Anti PD-1 and PD-L1 mABs have similar toxicity profile [5]. Nivolumab, pembrolizumab, and cemiplimab are anti PD-1 mABs, while atezolizumab, avelumab, and durvalumab target PD-L1. In general, anti-PD-1 mAbs are associated with far fewer irAEs than Anti-CTLA-4 mAbs. Common side effects associated with Anti PD-1 (L1) mAbs fatigue, rash, pruritus and idea with severe to life-threatening adverse events occurring in 2–3% of cases. The combination of Anti-CTLA-4 and Anti PD-1 (L-1) antibodies have shown better antitumor results but however they have been associated with higher

viruses while many other new approaches are being investigated.

pituitary gland, while anti-PD-1 (L1) mAbs affect thyroid gland.

incidence of immune therapy related adverse event than monotherapy [6, 7].

discontinued and these patient usually require high dose of corticosteroids.

**2. Endocrinological adverse effects of immunotherapy**

severe to life threatening as Grade 3–4 [2, 8].

rence of irAEs predicts better outcome [9–13].

mellitus leading to diabetic ketoacidosis.

**3. Pituitary dysfunction**

*3.1.1 Anti-CTLA-4 mAbs*

**3.1 Incidence**

Usually these irAEs arise within 3–6 months of starting the immunotherapy but it may take few years and thus needs close monitoring for years after completion of therapy. These side effects can be graded from mild to moderate as Grade 1–2 and

In general, mild Grade 1 side effects usually requires symptom management and does not require immunotherapy discontinuation. Grade 2 or moderate side effects usually managed with temporary discontinuation of checkpoint inhibitor. For severe to life-threatening Grade 3 and 4 side effects immunotherapy is permanently

Some studies have shown association of irAEs with better antitumor efficacy, the data remains conflicting and needs further research confirm whether occur-

Immunotherapy can cause wide array of endocrine side effects. More common irAEs are hypophysitis leading to hypopituitarism, primary or secondary thyroid dysfunction, primary or secondary adrenal insufficiency, autoimmune diabetes

Hypophysitis is one of the more common immunotherapies induced endocrinopathies and is more common after anti CTLA–4 therapy, reaching around 13% after treatment with ipilimumab [14, 15]. Ipilimumab induced hypophysitis (IH) occurs more frequently in males and in older age when compared to lymphocytic autoimmune hypophysitis even when adjusted for melanoma incidence for age and sex [15–17].

**56**

IH is a type II hypersensitivity reaction in which CTLA-4 antibodies bind to antigen expressed on pituitary cells resulting in compliment activation and gland destruction [18, 19]. Some studies have suggested that IH development may be associated with better antitumor outcomes in terms of morbidity and mortality [14]. The data on whether other agents and radiotherapy can alter the risks of hypophysitis is limited.

In the reported studies the average time to IH diagnosis is about 9 weeks; though time to endocrine abnormalities development has not been routinely reported in trials.

The radiographic changes seen on MRI including heterogenous pituitary enlargement with thickening of stalk are the sensitive and specific indicator of hypophysitis and may be the first signs of pituitary dysfunction occurring before hormonal disturbances or development of symptoms [1, 20]. The degree of pituitary enlargement can be mild in the patient's with IH and resolves quickly after glucocorticoids treatment [14].

Most common laboratory abnormalities observed at the time of diagnosis includes central hypothyroidism with reduction of TSH and secondary adrenal insufficiency. Hyponatremia secondary to adrenal insufficiency and hypothyroidism is frequently noted but central diabetes insipidus is rare with IH. Also growth hormone or prolactin axis disturbances occur less compared to other hormonal deficiencies. Usually, other hormonal deficiencies improved with treatment except for adrenal insufficiency which requires lifelong with steroid treatment [14, 21, 22].

#### *3.1.2 Anti-PD-1 and anti PD-L1 mAbs*

Multiple studies have shown that incidence of Anti-PD-1 and anti PD-L1 mAbs associated hypophysitis is less compared to Anti-CTLA-4 antibodies. Average incidence of hypophysitis was 0.6% in patients treated with pembrolizumab and novilumab, <0.1% in durvalumab and 0.2% with atezolizumab [23–26].

#### **3.2 Diagnosis and treatment**

#### *3.2.1 Monitoring*

Patients receiving immunotherapy treatments should have baseline pituitary function test done. Routine thyroid function test monitoring with monthly TSH and free T4 level checks is recommended during the treatment and when patient develops symptoms suggestive of hypophysitis. Those patients who receives anti-CTLA-4 agents routine monitoring of ACTH and cortisol level should be done.

#### *3.2.2 Diagnosis*

A clinician must have high index of suspicion for the hypophysitis diagnosis as patient may present with vague symptoms or use of exogenous glucocorticoids may mask their presentation so regular monitoring is critical. When suspected, MRI should be performed to assess pituitary and rule out other causes of pituitary dysfunction along with hormone profile evaluation including TSH and free T4, ACTH, cortisol, LH, FSH, prolactin, estradiol and females and distress return in males. It is recommended to investigate for diabetes insipidus only if patient is presenting with symptoms such as polyuria or polydipsia.

#### *3.2.3 Treatment*

High dose glucocorticoids course is given when hypophysitis is suspected which may reverse inflammatory process and prevent the need for longer term hormone

replacement in some cases. However, in most patient's long-term hormonal supplementation for affected hormones is required with thyroid hormone replacement for central hypothyroidism or steroid replacement for secondary adrenal insufficiency. In premenopausal female estradiol replacement and in men testosterone placement should be considered.
