Good specific treatment for patients with cancer relies on the generation of lymphocytes that recognize tumor antigens and eliminate them in vivo.
Immunotherapy modifies the immune system by augmenting or suppressing immune responses to obtain a desired effect.
IRAE’s of immune checkpoint inhibitors (ICIs) are related to immune stimulation and/or attack on various organs and systems.
IRAE’s from ICIs are often unpredictable and range from asymptomatic laboratory abnormalities to life-threatening diagnoses.
IRAE’s are graded using common criteria for adverse events: grade 1 generally allows for continuation of immune checkpoint, inhibitors (ICIs) , whereas grade 2 or higher may necessitate treatment with corticosteroids or other immunomodulators.
Obesity associated with increased incidence of immune related adverse events among patients receiving immune checkpoint inhibitors.
IRAE’s Can occur at any time after starting checkpoint inhibitors, even after discontinuation, and occur with variable, incidences and severities.
Autoreactive T cell, activation by ICIs is associated with a wide spectrum of toxicity and can affect any organ.
IRAE’s range from 15% for PD-1 and PD – L1 inhibitors to approximately 35% for CTLA-4 antibodies and approximately 55% for the combination of CTLA-4 and PD-1 antibodies.
It is possible immune related adverse events may be a surrogate for tumor control and improved outcomes.
Immunomodulators have found applications in dermatology, rheumatology, immunology, and oncology.
Cutaneous toxicities are the most most common immune related adverse events occurring in approximately 20 to 60% of patients treated with the ICI’s and 60 to 70% of patients receiving combination anti PD1and anti CTLA – 4 agents.
The most commonIRAE’s of the skin are rash and pruritus, but dermatitis, alopecia or vasculitis may appear.
Up to 6% of patients who receive ICI treatment experience lichen plants or lichenoid disease.
IRAEs are strongly associated with beneficial responses, likely reflecting systemic immune competence.
Vaccination programs have been successful in increasing the number of tumor antigen reactive lymphocytes in the circulation of patients, but only sporadic responses have been reported.
Two distinct types of cancer immunotherapy exist: passive immunotherapy using the components of the immune system to direct targeted cytotoxic activity against cancer cells, without necessarily initiating immune response, and active immunotherapy which actively triggers an endogenous immune response.
Passive immunotherapy includes the use of monoclonal antibodies produced by B cells in response to specific antigen.
Adaptive immune responsesare mediated by cellular and humeral components with cytotoxic T lymphocytes (CD4 and CD8 positive T cells) having a key role.
The immune system should recognize alterations in the genetic code within tumor cells as being foreign, and should eradicate abnormal cells through immune surveillance.
Immunotherapy drugs can enhance the immunologic response to MET-expressing tumor cells, or actively by stimulating immune cells and altering differentiation/growth of tumor cells.
The administration of monoclonal antibodies (mAbs) is a form of passive Immunotherapy.
Monoclonal antibodies facilitate destruction of tumor cells by complement-dependent cytotoxicity (CDC) and cell-mediated cytotoxicity (ADCC).
In complement-dependent cytotoxicity , the monoclonal antibody binds to specific antigen, leading to activation of the complement cascade, which in turn leads to formation of pores in tumor cells.
In cell-mediated cytotoxicity (ADCC) the Fab domain of a mAb binds to a tumor antigen, and Fc domain binds to Fc receptors present on effector cells, which are phagocytes and NK cells, thus forming a bridge between an effector and a target cells.
Chronic exposure to tobacco carcinogens and accumulation of mutations overtime can lead to T-cell exhaustion and trigger T Cells to turn it off and this may be manifested through the upregulation of the programmed death ligand (PD-L1) on tumor cells, which can inhibit T cell function by binding to programmed death 1 (PD-1) on T cells.
Immune checkpoint inhibitors toxicity is drug induced autoimmunity an immune related adverse event.
Endocrinopathies are among the most frequent immune related adverse events.
Endocrinopathies clinical manifestations are related to the injured gland, and emerge clinically when hormone deficiency reaches a critical threshold.
Endocrinopathies induced by immune checkpoint inhibitors differ from other immune related adverse events as they are often without symptoms, and the clinical consequences result from hormone deficiency, which is usually permanent.
Checkpoint inhibitors are associated with hypo thyroidism, hyperthyroidism, hypophysitis and adrenal insufficiency.
Patients with sarcopenia more likely to experience more severe treatment related toxicity related to immune checkpoint inhibitors.
Patients with the family, history of autoimmune disease, tumor infiltration, previous viral infection such as HIV or hepatitis, and the concomitant use of medications with known auto immune toxicities such as antiarrhythmics, antibiotics, anticonvulsants, or antipsychotics are associated with increased risk of drug related immune adverse related events.
Some common endocrine side effects of immune checkpoint inhibitors:
1. Thyroid dysfunction: including both an overactive (hyperthyroidism) and underactive (hypothyroidism) thyroid gland.
2. Adrenal insufficiency:ICIs can cause inflammation of the adrenal glands, leading to adrenal insufficiency.
3. Hypophysitis: ICIs can cause inflammation of the pituitary gland, leading to hypophysitis.
4. Diabetes mellitus: ICIs can cause insulin deficiency or insulin resistance, leading to the development of diabetes mellitus.
5. Gonadal dysfunction: ICIs can interfere with normal hormone production in the ovaries or testes, leading to gonadal dysfunction.
Thyroid disease is the most common endocrinopathies affecting 20 to 30% of patients treated with immune checkpoint inhibitors.
Hypothyroidism is the most common endocrine toxicity, with an overall incidence of 6.6% among all IC regiments.
The most common clinical course includes initial thyrotoxicosis.
Some data suggest that endocrine adverse effects baby associated with better cancer survival outcomes.
Hypophysitis is mostly induced by ipilimumab, rather than other immune checkpoint inhibitors and usually results in pan hypopituitarism.
Meta-analysis reports frequency of hypophysitis of 6.4 percent with combination immune checkpoint inhibitors, 3.2% with CTLA- 4 inhibitor monotherapy and less than 1% with PD-1/PD-L1 inhibitor monotherapy.
ICI induced pancreatic injury ranges from asymptomatic, hyperlipasemia to symptomatic acute pancreatitis.
Hyperlipipasemia or hyperamylasemis has been observed approximately 1 to 4% of patients receiving ICIs.
High-dose steroids have a little role in endocrine adverse events unlike other immune related adverse events.
Unlike other immune related adverse effects endocrine toxicity often cause permanent organ damage that results in the need for lifelong hormone replacement.
Management of endocrine irAEs is unique in their corticosteroids are not the mainstay therapy except for acute symptomatic hypophysitis and primary adrenal insufficiency.
Hormone replacement is the cornerstone of therapy for endocrine related toxicities to checkpoint inhibitors and most therapies are permanent in nature, unlike other immune adverse events.
IRAEs may resemble infections, cancer progression, or other inflammatory processes.
Tissue biopsies may guide care in supporting or rejecting an immune mediated process as the cause of a sign or symptom, it may provide information regarding other causes of the sign and symptom that is present, and can provide information regarding the severity, duration or resolution of an IRAE.
Diarrhea is common and occurs in 5% to 20% of patients receiving PD-1/PD-L1 antagonists and 20 to 45% of those receiving CTLA-4 antagonists alone or in combination with PD-1 agents.
Diarrhea onset can occur 1 to 3 months after inhibitor therapy.
Diarrhea may be related to interferon gamma producing CD8 T cells.
Elevated calprotectin or lactoferrin in stools are highly sensitive and specific for intestinal inflammation from any cause: includes active colitis in inflammatory bowel disease and immune checkpoint inhibitor induced colitis.
Endoscopic biopsy should be considered in all patients suspected of ICI induced colitis.
The incidence of ICI liver injury ranges from less than 1% to 15% depending on the use of a CTLA-4 antagonist or a PD-L1 antagonist alone or in combination.
Most cases of ICI induced hepatitis are asymptomatic:Grade 3/4 live injury occurs in 1 to 3% of treat patients, but jaundice and liver failure are exceedingly rare.
ICI induced hepatitis is defined as aminotransferase elevations of greater than five times or greater than 20 times the upper limit of normal, respectively, and it is reported to occur in 1 to 2% of patients with ICI monotherapy and 10% of patients receiving combination therapy.
Hepatitis is the second most common G.I. immune related adverse effect with an incidence of 1 to 7% among patients on single agent PD-1– PD-L1 or CTLA=5 inhibitors and 13 to 30% among those on treatment with combination therapy.
ICI therapy is associated with gastritis that often occurs with other G.I. toxicities.
Common patterns of inflammation are chronic active gastritis, reactive gastropathy, and focal enhanced gastritis.
Gastrointestinal IRAEs consisting of diarrhea, colitis, gastritis, enterocolitis, hepatitis, and pancreatitis are common in patients treated with ICs.
Asymptomatic elevation in amylase and lipase is more frequent than acute pancreatitis, which is rare.
ICI induced pneumonitis occurs in approximately 5 to 19% of patients receiving ICI therapy.
Immune mediated pneumonitis the median onset of 60 to 90 days from the start of ICI therapy and carries a high mortality rate of 20 to 30%.
Immune mediated pneumonitis that is cortical steroid refractory carries a significant risk for mortality.
The incidence is higher with dual immune checkpoint inhibition in patients with interstitial lung disease and with advanced non-small cell lung cancer.
Diagnosis of ICI induced pneumonitis is one of exclusion.
Patients with ICI induced pneumonitis often present with dry cough, shortness of breath, and hypoxia.
The median time to onset of pneumonitis symptoms is 2.8 months.
CT chest scans can provide evidence of immune mediated pneumonitis showing ground glass opacities, organizing pneumonitis and hypersensitivity pneumonitis
There is no pathognomonic imaging studies for ICI induced pneumonitis.
The diagnosis of immune checkpoint inhibitor pneumonitis is one of exclusion based on signs, symptoms, and clinical imaging.
The differential diagnosis of checkpoint inhibitor pneumonitis is broad with numerous possibilities: A transbronchial biopsy or bronchoalveolar lavage may be considered, but the value has not been established.
Pre-existing interstitial abnormalities on CT chest exam, and prior chest radiation are independent risk factors that strongly are associated with immune checkpoint inhibitor pneumonitis in patients with lung cancer.
Cardiovascular toxicities consist of myocarditis, cardiomyopathy, cardiac fibrosis, heart failure, and pericarditis.
The incidence of ICI related major adverse cardiac events is about 0.6%, with a higher rate in those who undergo combination therapy and targeted therapy; Most cases,45%, are myocarditis.
ICI induce myocarditis is rare, but potentially fatal with a median onset of approximately 30 days from the start of ICI therapy.
Myocarditis related to immune checkpoint inhibitors is estimated to occur in 0.5 to 1.5% of patients with significantly associated mortality.
ICI induced myocarditis has a high mortality rate ranging from 25 to 50%.
The diagnosis of myocarditis associated with ICI therapy is difficult and the role of endomyocardial biopsy has not been fully evaluated:It is mainly a diagnosis of exclusion, relying on a comprehensive cardiac and clinical evaluation.
ICI myocarditis should suggest cessation of ICI therapy, and prompt initiation of corticosteroid therapy.
Renal immune adverse events or reported with an overall incidence of approximately 2.2% and grade toxicities 3/4 less than 1%.
The most common manifestations are elevated creatinine levels, and the patients are rarely symptomatic.
Pathologically, acute interstitial nephritis is the most common manifestation.
The use of escalated immunosuppression compared with the management by steroids alone in patients who develop immune related adverse effects is associated with harmful effects om progression free survival and overall survival.
Disimmune toxicities can develop at any time at the beginning, under treatment, and after immunotherapy terminates.
The majority of disimmune toxicityoccurs within the first four months, late toxicities include pulmonary, endocrine and renal.
Advanced urothelial cancers treated with immune checkpoint inhibitors with immune related adverse events, especially those of the skin , was associated with significantly improved clinical outcomes compared to those who did not have immune related adverse events.
Neurologic immune related adverse events (nirAEs) following immune, checkpoint, inhibit therapy for cancer or frequent, varied, and associated with higher overall survival rates.
The vast majority of CNS irAE patients have encephalopathy.
Musculskeleton and rheumatic irAEs may occur with IC therapy and include arthralgia, myalgia, inflammatory arthritis, myositis, polymyalgia rheumatica, and sicca syndrome.
Arthralgia and myalgia are the most common ranging from one to 43%, and 2 to 20%, respectively.
Acute kidney injury related to ICI’s occurs in approximately 2-5% of patient’s treated with such therapy.
Neurologic irAEs include myasthenia gravis, Gillian-Barre syndrome, peripheral neuropathy, aseptic meningitis, encephalitis, cerebral vasculitis, optic neuritis, and transverse myelitis may occur.
The incidenCE of neurologic irAEs is 4% with CTLA-4 inhibitors and 6% with anti-PD –1 inhibitors and 12% with combination therapy.
Corticosteroids, immunosuppressive drugs, and withholding ICI therapy are the primary efforts in treating irAEs.
Deciding on whether to rechallenge a patient who has manifested immune adverse reactions to drugs is complicated.
Such a decision takes into account the severity of irAEs, and anticipated clinical benefits of ICI therapy.
In general guidelines support restarting ICI after adequate treatment of all initial irAEs.
Exceptions to this guideline is where certain irAEspose an extreme risk.