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Introduction: Immune Checkpoint Inhibitors

The development of immunotherapy has revolutionized the treatment of cancer. More specifically, the development of immune checkpoint inhibitors have been of special interest in the treatment of a small subset of predominantly solid tumor types with rapidly expanding indications.

Cancer cells have been known to evade the immune system. One of the mechanisms it goes undetected and continue growth in the host involves immune checkpoint pathways, specifically, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death receptor-1 (PD-1), and programmed death ligand-1 (PD-L1).

The binding of T-cell receptor to antigen-presenting cells activates T-cells. Once activated, T-cells will recognize foreign cells and regulate cell growth. However, when T-cell activation is suppressed by the ligand biding of CTLA-4 receptors and PD-1 receptors, tumor cells are able to proliferate freely. When the inhibition of T-cell activation is no longer present, T-cells are now able to direct a response against tumor cells. The method of preventing T-cell inhibition is by having antibodies bind to CTLA-4 receptors and PD-1 receptors and PD-L1 ligands to prevent the inhibitive interaction.

This unique class of agents differs from cytotoxic chemotherapy from mechanism of action to adverse effects. Additionally, combined CTLA-4 and PD-1 blockade have been used, albeit, with increased toxicity.

Introduction: Immune Checkpoint Inhibitor Mechanism of Action

Immune Checkpoint Inhibitors

Listed below is the current U.S. Food and Drug Administration (FDA) approved immune checkpoint inhibitors and their indications.

CTLA-4 Inhibitor

Ipilimumab (Yervoy®) – Melanoma, renal cell carcinoma, colorectal cancer
PD-1 Inhibitor
Pembrolizumab (Keytruda®) – Melanoma, non-small cell lung cancer, head and neck cancer, Hodgkin’s lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, small cell lung cancer, esophageal carcinoma
Nivolumab (Opdivo®) – Melanoma, non-small cell lung cancer, head and neck cancer, Hodgkin’s lymphoma, urothelial carcinoma, hepatocellular carcinoma, renal cell carcinoma, small cell lung cancer, colorectal cancer
Cemiplimab (Libtayo®) – Cutaneous squamous cell carcinoma

Ipilimumab and nivolumab may be used as combination therapy in the treatment of renal cell carcinoma, melanoma, and colorectal cancer.

PD-L1 Inhibitor

Atezolizumab (Tecentriq®) – Urothelial carcinoma, non-small cell lung cancer, small cell lung cancer, breast cancer
Durvalumab (Imfinzi®) – Urothelial carcinoma, non-small cell lung cancer
Avelumab (Bavencio®) – Merkel cell carcinoma, urothelial carcinoma, renal cell carcinoma

Overview of Immune Related Adverse Effects

Long-term adverse events for immune checkpoint inhibitors are slowly surfacing as their indications expand and post-marketing reporting increases. There are a few published guidelines that serve as a guide for clinicians in managing immune related adverse events, however, all guidelines differ based on general consensus and limited literature available.

The diagnosis and grading of some immune related toxicities are not as well defined since the common terminology criteria for adverse events (CTCAE) developed by the National Cancer Institute have not been fully updated due to the novelty of immune checkpoint inhibitors. Therefore, providing a multidisciplinary team may help to optimize patient care. Mortality and morbidity is correlated with how quickly immune mediated adverse effects are recognized and triaged.

The general concept of managing immune related adverse events involves temporarily holding immune checkpoint inhibitors and the initiation of corticosteroids. If corticosteroids are initiated for immune related adverse events, a long taper is recommended to prevent immune related adverse events from recurring. Additionally, symptoms are considered to be corticosteroid refractory after 48-72 hours. The initiation of corticosteroids has not been found to influence tumor cell response.

Common Immune Related Adverse Effects

Dermatologic

Rash/Inflammatory dermatitis
Bullous dermatoses
Severe reactions (Stevens-Johnson syndrome (SJS), toxic epidermal necrosis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS))

Gastrointestinal Tract

Colitis
Hepatitis

Endocrine

Hyperthyroidism
Hypothyroidism
Hypophysitis
Adrenal insufficiency
Diabetes mellitus

Pulmonary

Pneumonitis

Musculoskeletal

Arthralgia/arthritis

Dermatologic Adverse Events

Cutaneous adverse events are the most common for immune checkpoint inhibitors, with rates up to 50%. The pathophysiology for immune checkpoint inhibitors inducing this response is not completely understood. It is hypothesized that non-specific T-cell activation may have off target effects on keratinocytes and other skin cells.

Clinical Presentation

Dermatologic toxicity may also vary in appearance and severity, with the majority being mild reactions. Dermatologic reactions may include inflammatory dermatitis, eczema, psoriasis, bullous dermatoses, Stevens-Johnson syndrome, toxic epidermal necrosis, and drug reaction with eosinophilia and systemic symptoms. The most common presentation is typically erythematous macules with or without papules. Pruritus will typically accompany these dermatologic adverse events. Most patients will be affected on the trunk and extremities.

Vitiligo may also be present with melanoma. These lesions are bilateral and symmetrically distributed. When dermatologic adverse events present with immune checkpoint inhibitor use in melanoma, it may correlate with better clinical outcomes.

The time to onset of cutaneous events may be within days to weeks of immune checkpoint inhibitor initiation, but rarely, can be delayed and may not appear until months after treatment initiation.

Definition of Toxicity Grading for Maculopapular Rash

The toxicity grading for inflammatory dermatitis does not exist in CTAE. However, a macularpapular rash is the most common presentation of cutaneous toxicity associated with immune checkpoint inhibitors.

Grade 1 toxicity: Macules/papules covering <10% body surface area (BSA) with or without symptoms (e.g., pruritus, burning, tightness)
Grade 2 toxicity: Macules/papules covering 10-30% BSA with or without symptoms (e.g., pruritus, burning, tightness); limiting instrumental activities of daily living (ADL); rash covering >30% BSA with or without mild symptoms
Grade 3 toxicity: Macules/papules covering >30% BSA with moderate or severe symptoms; limiting self care ADL
Grade 4 toxicity: Life-threatening consequences

Management of Inflammatory Dermatitis

Grade 1 toxicity: Patients may continue therapy with immune checkpoint inhibitors and treatment of the cutaneous adverse effects may be managed with topical emollients. Topical corticosteroids may also be used. Examples of topical corticosteroids may include hydrocortisone 2.5% or triamcinolone 0.1%. Other mild to moderate topical corticosteroids may be used as well.
Grade 2 and 3 toxicities: Therapy with immune checkpoint inhibitors should be temporarily held. Cutaneous adverse effects may be managed with topical emollients and medium to high potency topical corticosteroids. If pruritus is present, oral antihistamines may be utilized. Depending on the clinical scenario, patients may be started on oral corticosteroids (prednisone 1 mg/kg/day). For grade 3 toxicity, intravenous (IV) corticosteroids (methylprednisolone 1-2 mg/kg/day) is an option with transition to oral corticosteroids once the condition improves. Oral corticosteroids should be tapered over at least 4-6 weeks.
Grade 4 toxicity: Therapy with immune checkpoint inhibitors should be temporarily held with prompt initiation of IV methylprednisolone 1-2 mg/kg/day. Once the adverse effect resolves, patients may switch from IV to oral corticosteroids with a slow taper. Immune checkpoint inhibitors may also be restarted once the adverse event returns to a grade 1 or lower with the agreement of dermatology. However, alternative cancer treatment therapy should be considered if the adverse event does not improve.

Definition of Toxicity Grading for Bullous Dermatoses

Grade 1 toxicity: Asymptomatic; blisters covering <10% BSA
Grade 2 toxicity: Blisters covering 10-30% BSA; painful blisters; limiting instrumental ADL
Grade 3 toxicity: Blisters covering >30% BSA; limiting self care ADL
Grade 4 toxicity: Blisters covering >30% BSA; associated with fluid or electrolyte abnormalities; ICU care or burn unit indicated

Management of Bullous Dermatoses

Grade 1 toxicity: Patients may continue immune checkpoint inhibitors with local wound care for the area(s) affected.
Grade 2 toxicity: Immune checkpoint inhibitors should be temporarily held with the initiation of wound care. Class 1 high-potency topical corticosteroids should be initiated. Oral corticosteroids (prednisone 0.5-1 mg/kg/day) may also be initiated with a taper over 4-6 weeks. Patients should be monitored closely with reassessment every 3 days.
Grade 3 toxicity: Immune checkpoint inhibitors should be temporarily held with the initiation of IV methylprednisolone 1-2 mg/kg/day. Dermatology and infectious disease consults may be necessary to rule out infection risk. Patients may be transitioned to oral corticosteroids once symptoms improve with a slow corticosteroid taper over 4-6 weeks.
Grade 4 toxicity: Immune checkpoint inhibitors should be permanently discontinued with prompt initiation of IV methylprednisolone 1-2 mg/kg/day. Infectious disease and dermatology should be consulted as well.

Definition of Toxicity Grading for Stevens-Johnson Syndrome

Stevens-Johnson syndrome is considered to be a severe adverse event, therefore toxicity grading for 1 and 2 do not exist according to CTCAE. However, other guidelines may recognize grade 2 as a toxicity grading for adverse event management.

Grade 3 toxicity: Skin sloughing covering <10% BSA with associated signs (e.g., erythema, purpura, epidermal detachment, and mucous membrane detachment)
Grade 4 toxicity: Skin sloughing covering 10-30% BSA with associated signs (e.g., erythema, purpura, epidermal detachment and mucous membrane detachment)

Management of Severe Cutaneous Adverse Reactions

(SJS/TEN, DRESS)

Grade 2 toxicity: Immune checkpoint inhibitors should be temporarily held with the initiation of topical emollients, oral antihistamines, medium to high potency topical corticosteroids, and oral prednisone 0.5-1 mg/kg/day. Oral corticosteroids should be tapered over 4-6 weeks.
Grade 3 toxicity: Immune checkpoint inhibitors should be temporarily held with the initiation of IV methylprednisolone 1-2 mg/kg/day. Admission to the burn unit may be needed for fluid and electrolyte management and prevention of infections. Patients may be transitioned to oral corticosteroids once symptoms improve with corticosteroids tapered over a 4-6 weeks.
Grade 4 toxicity: Immune checkpoint inhibitors should be permanently discontinued with prompt initiation of IV methylprednisolone 1-2 mg/kg/day. Admission to the burn unit is necessary for these patients to prevent further sequelae.

The use of systemic corticosteroids is controversial for SJS/TEN, however, it is first line therapy for DRESS. For any grade toxicity, the appropriate specialized services should be consulted to optimize patient care.

Gastrointestinal Tract Adverse Events

Gastrointestinal (GI) related toxicities are common adverse events of immune checkpoint inhibitors. The incidence of colitis may be as high as 27%, with the incidence of diarrhea occurring in 54% of patients treated with anti-CTLA-4 antibodies. The incidence of diarrhea also increases with combination therapy of anti-CTLA-4 and anti-PD-1/PD-L1 antibodies. Likewise, the incidence of hepatitis is also increased with combination therapy with the frequency as high as 30% compared to single agent ipilimumab at 10%.

Patients treated with immune checkpoint inhibitors should be cautious with concurrent nonsteroidal anti-inflammatory drug (NSAID) use since it may be associated with enterocolitis.

Clinical Presentation

Patients presenting with colitis typically will have loose or watery stool with increased frequency. Rarely, patients may have more severe symptoms including abdominal pain, fever, and bloody diarrhea.

The majority of patients presenting with hepatitis are asymptomatic with transaminitis. Rarely, patients will present with yellowing of the skin, right quadrant abdominal pain, and dark urine.

The time to onset with colitis and hepatitis typically occur anywhere between 5-10 weeks and 6-14 weeks after treatment initiation, respectively.

Definition of Toxicity Grading for Colitis

Grade 1 toxicity: Asymptomatic; clinical or diagnostic observations only; intervention not indicated
Grade 2 toxicity: Abdominal pain; mucus or blood in stool
Grade 3 toxicity: Severe abdominal pain; peritoneal signs
Grade 4 toxicity: Life-threatening consequences; urgent intervention indicated

Management of Colitis

Grade 1 toxicity: Immune checkpoint inhibitors may be continued or temporarily held until resolution of toxicity. Fluids and electrolytes should be monitored in patients experiencing increased diarrhea.
Grade 2 toxicity: Immune checkpoint inhibitors should be temporarily held. Anti-CTLA-4 agents may be permanently discontinued while anti-PD-1/PD-L1 agents may be resumed once symptoms improve to grade 1 or lower. Loperamide may be initiated once all infectious causes including, Clostridium difficile, are ruled out. Additionally, oral corticosteroids with prednisone 1 mg/kg/day may be initiated for patients.
Grade 3 toxicity: Anti-CTLA-4 agents should be permanently discontinued while anti-PD-1/PD-L1 agents may be resumed once symptoms improve. Hospital admission should be considered for fluid and electrolyte management. Oral corticosteroids should be initiated. If symptoms persists or recur after at least 3 days, IV methylprednisolone or infliximab should be considered.
Grade 4 toxicity: Permanently discontinue all immune checkpoint inhibitors and admit the patient to the hospital. IV corticosteroids with methylprednisolone should be initiated promptly for patients. If symptoms are refractory to corticosteroids or does not improve, infliximab 5-10 mg/kg may be used. Infliximab may be administered again after two weeks if there is no improvement in symptoms. Additionally, vedolizumab may be used for symptoms refractory to infliximab.

Definition of Toxicity Grading for Hepatitis

Grade 1 toxicity: Asymptomatic, intervention not indicated
Grade 2 toxicity: Moderate symptoms; medical intervention indicated
Grade 3 toxicity: Symptomatic liver dysfunction; fibrosis by biopsy; compensated cirrhosis; hospitalization or prolongation of existing hospitalization indicated
Grade 4 toxicity: Life-threatening consequences; severe decompensated liver function (e.g., coagulopathy, encephalopathy, coma)

Management of Hepatitis

Grade 1 toxicity: Immune checkpoint inhibitors may be continued and patients should be closely monitored.
Grade 2 toxicity: Immune checkpoint inhibitors should be temporarily discontinued. Oral corticosteroids with prednisone 0.5-1 mg/kg/day may be initiated for patients if symptoms do not improve. Corticosteroids should be tapered over at least 1 month.
Grade 3 toxicity: Immune checkpoint inhibitors should be permanently discontinued. IV methylprednisolone 1-2 mg/kg/day should be initiated for patients.
Grade 4 toxicity: Permanently discontinue all immune checkpoint inhibitors and initiate IV methylprednisolone 2 mg/kg/day promptly for patients. Patients should be closely monitored.

As a general rule, all hepatotoxic drugs and medications should be discontinued with transaminitis. If patients are refractory to IV corticosteroids, mycophenolate mofetil or azathioprine may be initiated. Additionally, corticosteroids should be tapered over 4-6 weeks. The use of infliximab for corticosteroid refractory disease is controversial. There is a potential that infliximab may worsen immune mediated hepatitis, however, there is limited literature to support this.

Endocrine Adverse Events

Endocrine adverse events occur at a rate of 10% in patients treated with immune checkpoint inhibitors.

Hypothyroidism and hyperthyroidism

Hypothyroidism occurs in about 6% of patients on immune checkpoint inhibitors. Patients with hypothyroidism are typically asymptomatic but symptoms may manifests as fatigue, weight gain, hair loss, cold intolerance, constipation, and depression in addition to a high thyroid stimulating hormone (TSH) and low free T4. Hyperthyroidism is less common than hypothyroidism, is often transient, and leads to hypothyroidism after 2 months of immune checkpoint inhibitor initiation.

Hypophysitis

Hypophysitis is more common with anti-CTLA-4 antibodies compared to anti-PD-1/PD-L1 antibodies as a direct effect on CTLA-4 protein in the pituitary gland. The mechanism for hypophysitis with anti-PD-1/PD-L1 is unknown. The most common clinical presentation includes headache and fatigue. Nausea, vomiting, vertigo, visual changes, and weakness are rare clinical presentations that may occur. The median time to onset is 8-9 weeks. Hypophysitis may cause central hypothyroidism and secondary adrenal insufficiency. If patients present with both adrenal insufficiency and hypothyroidism, treatment for adrenal insufficiency should take precedence.

Adrenal insufficiency

Patients with adrenalitis will typically present with fatigue, hyperkalemia, and hyponatremia. In rare and severe cases, patients may present with hypotension and distributive shock. Patients presenting with this immune related adverse effect may require maintenance management, as loss of gland function is typically irreversible.

Diabetes

Patients with diabetes will present with polyuria, polydipsia, weight loss, and lethargy in addition to hyperglycemia on laboratory monitoring. If a patient with no risk factors for diabetes presents with hyperglycemia, type 1 diabetes should be in the differential. The diagnosis of type 1 diabetes is rare compared to type 2 diabetes.

Definition of Toxicity Grading for Hypothyroidism

Grade 1 toxicity: Asymptomatic; clinical or diagnostic observations only; intervention not indicated
Grade 2 toxicity: Symptomatic; thyroid replacement indicated; limiting instrumental ADL
Grade 3 toxicity: Severe symptoms; limiting self care ADL; hospitalization indicated
Grade 4 toxicity: Life-threatening consequences; urgent intervention indicated

Management of Hypothyroidism

Grade 1 toxicity: Immune checkpoint inhibitors should be continued with close laboratory monitoring for symptomatic changes.
Grade 2 toxicity: Immune checkpoint inhibitors should be temporarily discontinued until symptoms improve. Thyroid replacement therapy may be initiated if patients are symptomatic.
Grade 3 and 4 toxicities: Immune checkpoint inhibitors should be temporarily discontinued until symptoms improve. Thyroid replacement therapy should be initiated for patients. Patients may need to be admitted into the hospital for the treatment of myxedema.

Hypothyroidism associated with immune checkpoint inhibitors is typically irreversible, even after cessation of therapy. Additionally, hypothyroidism is managed similarly to other patient without immune checkpoint inhibitor treatment. If using levothyroxine, dosing should be weight based at 1.6 mcg/kg/day. However, if patients are older or have coronary artery disease, levothyroxine may be dosed at 25-50 mcg/day and titrated as needed.

Definition of Toxicity Grading for Hyperthyroidism

Grade 1 toxicity: Asymptomatic; clinical or diagnostic observations only; intervention not indicated
Grade 2 toxicity: Symptomatic; thyroid suppression therapy indicated; limiting instrumental ADL
Grade 3 toxicity: Severe symptoms; limiting self care ADL; hospitalization indicated
Grade 4 toxicity: Life-threatening consequences; urgent intervention indicated

Management of Hyperthyroidism

Grade 1 toxicity: Immune checkpoint inhibitors should be continued with close laboratory monitoring for symptomatic changes.
Grade 2 toxicity: Immune checkpoint inhibitors may be temporarily discontinued until symptoms improve. Symptom management may include hydration and a β-blocker such as atenolol or propranolol for cardiac symptoms.
Grade 3 and 4 toxicities: Immune checkpoint inhibitors should be temporarily discontinued until symptomsimprove to baseline.
Symptom management may include a β-blocker including atenolol or propranolol for cardiac symptoms.
Hospitalization is recommended if there is concern for a thyroid storm with prompt initiation of oral corticosteroid use with prednisone 1-2 mg/kg/day tapered over 1-2 weeks.
Potassium iodide, methimazole, or propylthiouracil may be used for a thyroid storm as well.
Arthralgia/arthritis

Definition of Toxicity Grading for Hypophysitis

Grade 1 toxicity: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated
Grade 2 toxicity: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL
Grade 3 toxicity: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of existing hospitalization indicated; limiting self care ADL
Grade 4 toxicity: Life-threatening consequences; urgent intervention indicated

Management of Hypophysitis

Grade 1 and 2 toxicities: Immune checkpoint inhibitors may be held and patients may need replacement hormones for symptom management. The agents for symptom management may include hydrocortisone 10-20 mg in the morning and 5-10 mg in the afternoon, levothyroxine, and testosterone or estrogen.

Grade 3 and 4 toxicities: Immune checkpoint inhibitors should be temporarily discontinued until symptoms are stable with hormone replacement. Oral prednisone 1-2 mg/kg/day for 1-2 weeks may be necessary.
If patients require both thyroid replacement therapy and corticosteroids, corticosteroids should be initiated first in order to prevent an adrenal crisis from occurring.

Definition of Toxicity Grading for Adrenal Insufficiency

Grade 1 toxicity: Asymptomatic; clinical or diagnostic observations only; intervention not indicated
Grade 2 toxicity: Moderate symptoms; medical intervention indicated
Grade 3 toxicity: Severe symptoms; hospitalization indicated
Grade 4 toxicity: Life-threatening consequences; urgent intervention indicated

Management of Adrenal Insufficiency

Grade 1 toxicity: Immune checkpoint inhibitors may be held and patients may need replacement hormones for symptom management. Hydrocortisone 10-20 mg in the morning and 5-10 mg in the afternoon or prednisone 5-10 mg daily may be required. For primary adrenal insufficiency, patients will likely require fludrocortisone 0.1 mg/day for mineralocorticoid replacement.

Grade 2 toxicity: Immune checkpoint inhibitors may be held and patients may need two to three times maintenance replacement therapy (hydrocortisone 20-30 mg in the morning and 10-20 mg in the afternoon or prednisone 20 mg daily). Corticosteroid taper should be over 5-10 days.

Grade 3 and 4 toxicities: Immune checkpoint inhibitors should be temporarily discontinued until patients are controlled on replacement therapy. Additionally, patients should receive IV hydration of at least 2L and IV stress-dose corticosteroids. Hydrocortisone 100 mg IV or dexamethasone 4 mg IV may be used for patients. A taper course over 1-2 weeks is required.

If an adrenocorticotropic hormone (ACTH) stimulation test has not been performed, dexamethasone should be used as the optimal choice for stress dose steroids since it does not interfere with the test. However, if testing has already been completed, either hydrocortisone or dexamethasone may be used.

Definition of Toxicity Grading for Diabetes

Grade 1 toxicity: Abnormal glucose above baseline with no medical intervention
Grade 2 toxicity: Change in daily management from baseline for a diabetic; oral antiglycemic agent initiated; workup for diabetes
Grade 3 toxicity: Insulin therapy initiated; hospitalization indicated
Grade 4 toxicity: Life-threatening consequences; urgent intervention indicated

Management of Diabetes

Grade 1 toxicity: Immune checkpoint inhibitors may be continued and oral agents for type 2 diabetes may be initiated. Close follow-up and laboratory monitoring is recommended.
Grade 2 toxicity: Immune checkpoint inhibitors may be temporarily discontinued until diabetes is managed. Oral agents may need to be titrated for type 2 diabetes and insulin may be required for type 1 diabetics. Patients may require hospitalization for ketoacidosis.
Grade 3 and 4 toxicities: Immune checkpoint inhibitors should be temporarily discontinued until diabetes is controlled. Insulin therapy is necessary for type 1 diabetes and type 2 diabetes. Inpatient management is necessary for concern of diabetic ketoacidosis.

All patients should receive an endocrine consult for diabetes management. If the type of diabetes is unknown or diagnosis is pending, treatment with insulin is optimal.

Pulmonary Adverse Events

Pneumonitis is an uncommon immune related adverse event, however, it is a serious reaction and one of the most common cause of immune checkpoint inhibitor related death. The mechanism is not completely understood. The overall incidence of anti-PD-1/PD-L1 agents causing pneumonitis is 2.7%. It is more common with anti-PD-1/PD-L1 agents than anti-CTLA-4 agents. If combination therapy of nivolumab and ipilimumab is used, the incidence of pneumonitis is higher (10%).

Clinical presentation

The clinical presentation of patients may include dyspnea, cough, fever, and chest pain. However, patients may also be asymptomatic with only radiographic findings.

The time to onset of pneumonitis varies greatly from 2-24 months after therapy initiation. Combination therapy appears to shorten the time to onset of pneumonitis.

Definition of Toxicity Grading for Pneumonitis

Grade 1 toxicity: Symptomatic; clinical or diagnostic observations only; intervention not indicated
Grade 2 toxicity: Symptomatic; medical intervention indicated; limiting instrumental ADL
Grade 3 toxicity: Severe symptoms; limiting self care ADL; oxygen indicated
Grade 4 toxicity: Life-threatening respiratory compromise; urgent intervention indicated (e.g., tracheotomy or intubation)

Management of Pneumonitis

Grade 1 toxicity: Immune checkpoint inhibitors should be temporarily held as pneumonitis may be rapidly progressive. Once radiographic improvement is seen, immune checkpoint inhibitors may be resumed. However, if it is not improved, patients should be escalated to grade 2 toxicity.
Grade 2 toxicity: Immune checkpoint inhibitors should be temporarily discontinued until improvement to grade 1 toxicity or less. Additionally, oral prednisone 1-2 mg/kg/day should be initiated for patients. In cases of potential infectious causes, empiric antibiotics should be considered.
Grade 3 and 4 toxicity: Immune checkpoint inhibitors should be permanently discontinued and IV methylprednisolone 1-2 mg/kg/day should be initiated. Empiric antibiotics should be initiated.

If symptoms are refractory to corticosteroids, infliximab 5 mg/kg, mycophenolate mofetil 1g twice daily, immunoglobulin (IVIG) for 5 days, or cyclophosphamide are options for managing pneumonitis. Corticosteroid taper should be slow and cautious as symptom exacerbations may occur with withdrawal.

Musculoskeletal Adverse Events

Musculoskeletal adverse events due to immune checkpoint inhibitors are one of the more common adverse effects with up to 40% of patients affected. Combination therapy with anti-CTLA-4 and anti-PD1/PD-L1 antibodies has a higher incidence of musculoskeletal adverse event than either class of agents alone. The vast majority of patients will have mild symptoms, however, some may have more severe and debilitating symptoms. The most common adverse events consist of arthritis, polymyalgia-like syndromes, and myositis.

Clinical presentation

Patients presenting with arthritis may have a range of symptoms that mimic oligoarthritis, reactive arthritis, and/or rheumatoid arthritis. The time to onset varies vastly and can occur at any point during treatment.

Myalgia is another common manifestation of immune related adverse events with severe fatigue. Patients who develop polymyalgia-like syndromes present with pain but not weakness.

Myositis is the rarest of musculoskeletal adverse events and occurs more frequently with anti-PD-1/PD-L1 antibodies compared to anti-CTLA-4 agents. Patients present with weakness of extremities with or without myalgia.

Definition of Toxicity Grading for Inflammatory Arthritis

Grade 1 toxicity: Mild pain with inflammation, erythema, or joint swelling
Grade 2 toxicity: Moderate pain associated with signs of inflammation, erythema, or joint swelling; limiting instrumental ADL
Grade 3 toxicity: Severe pain associated with signs of inflammation, erythema, or joint swelling; irreversible joint damage; limiting self-care ADL
Grade 4 toxicity: None defined

Management of Inflammatory Arthritis

Grade 1 toxicity: Immune checkpoint inhibitors should continue. Analgesics may be initiated for symptom management.
Grade 2 toxicity: Immune checkpoint inhibitors should be temporarily discontinued until symptoms subside. Analgesic doses may be increased or oral corticosteroid use with prednisone 10-20 mg/day may be initiated with a slow taper over 4-6 weeks. If symptoms do not improve after taper and patients are unable to discontinue corticosteroids, disease-modifying antirheumatic drugs (DMARD) may be initiated. For large joints, intra-articular corticosteroid injections should be considered.
Grade 3 and 4 toxicities: Immune checkpoint inhibitors should be temporarily discontinued until symptoms subside. Oral prednisone 0.5-1 mg/kg daily should be initiated. If symptoms do not respond to oral corticosteroids, initiation of DMARD may be beneficial.

Patients experiencing musculoskeletal adverse events from immune checkpoint inhibitors would benefit from a rheumatology consult. Additionally, DMARD such as methotrexate, leflunomide, TNF-α or interleukin-6 (IL-6) receptor inhibitors may be used in corticosteroid refractory disease. If DMARD treatment is recommended, patients should be tested for viral hepatitis and tuberculosis prior to therapy initiation.

Definition of Toxicity Grading for Myalgia

Polymyalgia-like syndrome is not defined by the CTCAE.

Grade 1 toxicity: Mild pain
Grade 2 toxicity: Moderate pain; limiting instrumental ADL
Grade 3 toxicity: Severe pain; limiting self care ADL
Grade 4 toxicity: None defined

Management of Polymyalgia-like Syndrome

Grade 1 toxicity: Therapy with immune checkpoint inhibitors should continue. For symptomatic management, analgesics may be initiated.
Grade 2 toxicity: Immune checkpoint inhibitors should be temporarily discontinued until symptoms subside. Oral prednisone 20 mg daily should be initiated with a slow taper over 3-4 weeks.
Grade 3 and 4 toxicities: Immune checkpoint inhibitors should be temporarily discontinued until symptoms subside. Oral prednisone 20 mg daily should be initiated. Patients may need inpatient care for optimizing pain control.

In all cases, involving a rheumatologist to assist in treatment may be optimal for patient care. Alternative agents for corticosteroid refractory disease include methotrexate or IL-6 inhibition with tocilizumab. If tocilizumab is used, it’s important to note that it is contraindicated in patients with colitis for gastrointestinal metastases due to the risk of gastrointestinal perforation.

Definition of Toxicity Grading for Myositis

Grade 1 toxicity: Mild pain
Grade 2 toxicity: Moderate pain associated with weakness; pain limiting instrumental ADL
Grade 3 toxicity: Pain associated with severe weakness; limiting self care ADL
Grade 4 toxicity: Life-threatening consequences; urgent intervention indicated

Management of Myositis

Grade 1 toxicity: Immune checkpoint inhibitors should be continued. For symptomatic management, analgesics may be initiated. Additionally, oral corticosteroids may be used for muscle weakness.
Grade 2 toxicity: Immune checkpoint inhibitors should be temporarily discontinued until symptoms subside. In some cases, immune checkpoint inhibitors may need to be permanently discontinued based on the patient’s clinical scenario. Analgesics may be initiated as needed for symptom management. Oral prednisone 0.5-1 mg/kg may be initiated for creatinine kinase elevation.
Grade 3 and 4 toxicities: Immune checkpoint inhibitors should be temporarily discontinued until symptoms subside. Oral prednisone 1 mg/kg daily should be initiated. If patients have severe symptoms, IV methylprednisolone 1-2 mg/kg should be utilized.

In all cases, involvement with a rheumatologist or neurologist may be optimal for patient care. Additionally, if there is myocardial involvement, immune checkpoint inhibitors should be permanently discontinued. Alternative agents for corticosteroid refractory disease include plasmapheresis, IVIG, rituximab, methotrexate, azathioprine, or mycophenolate mofetil.

Infusion Related Adverse Events

Grade 1 toxicity: Mild transient reaction; infusion interruption not indicated; intervention not indicated
Grade 2 toxicity: Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications indicated for < 24 hours
Grade 3 toxicity: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae
Grade 4 toxicity: Life-threatening consequences; urgent intervention indicated

Clinical presentation

Infusion related adverse events due to immune checkpoint inhibitors are rare with the exception of avelumab. The incidence of infusion related adverse events constitute up to 25% of patients receiving avelumab. With other immune checkpoint inhibitors, the incidence is less than 10%.

The clinical presentation may include fever, rigor, urticaria, angioedema, pruritus, hypotension, dyspnea, chest discomfort, rash, wheezing, tachycardia and/or anaphylaxis.

Management

Providing premedication with acetaminophen and an antihistamine could mitigate infusion related reactions.

If patients experience mild to moderate reactions, the infusion should be stopped or continued at a decreased rate. For severe cases of infusion reactions, grades 3 and 4, immune checkpoint inhibitors should be permanently discontinued and patients treated based on institutional standards.

Rare Adverse Events

Neurologic toxicities

Myasthenia gravis
Guillain-Barré syndrome
Peripheral neuropathy
Autonomic neuropathy

Renal toxicities

Nephritis

Hematologic toxicities

Autoimmune hemolytic anemia
Acquired thrombotic thrombocytic purpura
Aplastic anemia
Immune thrombocytopenia
Acquired hemophilia

Cardiovascular toxicities

Arrhythmia
Heart failure
Cardiogenic shock

Ocular toxicities

Episcleritis
Uveitis/iritis
Blepharitis

Rare Adverse Events: Neurologic Toxicities

Clinical Presentation

Neurologic toxicities are reported in about 3% of patients on anti-CTLA-4 antibodies, 6% on anti-PD-1 antibodies, and 12% on combination therapy. The majority of neurologic toxicities are mild with the most common manifestations being headache and peripheral sensory neuropathy. Severe neurologic toxicities account for <1% of adverse events with checkpoint inhibitors. Patients presenting with neurologic toxicities may warrant a neurology consult after other causes have been ruled out, such as disease progression.

Management

In general, immune checkpoint inhibitors may be continued with grade 1 toxicities. However, with grade 2 toxicity or higher, immune checkpoint inhibitors should be temporarily discontinued until symptoms subside. Additionally, corticosteroids with IV methylprednisolone 1-4 mg/kg daily may be initiated in toxicities grade 2 or higher. Severe reactions of grades 3 or higher may require pulse dose corticosteroids with IV methylprednisolone 1 g daily for 5 days. Severe reactions may also warrant the use of IVIG or plasma exchange.

Rare Adverse Events: Renal Toxicities

Clinical Presentation

The pathology of renal toxicity is unknown. Renal toxicity presents in 2-5% of patients and occurs within the first 3-10 months after anti-PD-1/PD-L1 therapy initiation and 2-3 months after anti-CTLA-4 therapy initiation. Combination anti-CTLA-4 and anti-PD-1/PD-L1 therapies increase the incidence of renal toxicity. Patients are typically asymptomatic however, clinical presentations of oliguria, hematuria, peripheral edema, and anorexia have been reported.

Management

Patients with mild toxicity may continue immune checkpoint inhibitors with close monitoring, while patients experiencing moderate toxicity should have immune checkpoint inhibitors temporarily held. Permanent discontinuation of therapy is recommended for severe renal toxicity. Moderate doses of corticosteroids may be initiated starting with grade 2 toxicity. Patients who continue to have recurrent renal toxicity may receive prophylactic corticosteroids following the administration of immune checkpoint inhibitors.

Pre-existing renal impairment from a cause not related to autoimmune disease, such as nephrectomy, old age, and hypertension are not direct contraindications for treatment with immune checkpoint inhibitors. However, patients with prior renal transplants are at high risk of graft rejection and potentially requiring dialysis, therefore, extreme caution is necessary if using immune checkpoint inhibitors in this patient population.

Rare Adverse Events: Hematologic Toxicities

The incidences of hematologic toxicities are similar between all immune checkpoint inhibitors. Unlike chemotherapy, hematologic toxicities are rare with immune checkpoint inhibitors, occurring at a rate of <1%. It is hypothesized that T-cell activation may lead to an attack on hematopoietic progenitor cells causing immune mediated hematologic toxicities. Combination therapy may increase the risk of overall hematologic toxicities. Anemia may also be increased with immune checkpoint inhibitor use in renal cell carcinoma; however, underlying kidney disease may also be a contributor to this toxicity.

Clinical presentation

Patients are often asymptomatic with laboratory values supporting hematologic toxicities.

Management

Management of hematologic toxicities includes withholding immune checkpoint inhibitors, initiating corticosteroids, IVIG, and growth factor support. The presentation of mild toxicities does not necessarily warrant discontinuation of immune checkpoint inhibitors. Since hematologic toxicities are uncommon with immune checkpoint inhibitors, there is less information guiding clinicians in managing these adverse events.

Rare Adverse Events: Cardiovascular Toxicities

Cardiovascular toxicities are rare and have only been described in case reports with an incidence of <0.1%. However, cardiovascular toxicities are one of the most fatal toxicities associated with immune checkpoint inhibitors. The risk of cardiovascular toxicity increases with combination therapy.

Clinical presentation

Clinical presentation of cardiovascular toxicities associated with immune checkpoint inhibitors vary widely and includes arrhythmia, palpitations, chest pain, or signs and symptoms of heart failure. The most fatal events associated with cardiovascular toxicities include cardiogenic shock and arrhythmia. The time to onset ranges from 2-32 weeks after initiation of immune checkpoint inhibitors.

Management

The management of cardiovascular toxicities requires discontinuation of immune checkpoint inhibitors at any grade of toxicity. Oral or IV corticosteroids at 2 mg/kg daily may be initiated for mild to moderate toxicities. For severe toxicities of grades 3 and 4, high dose corticosteroids of IV methylprednisolone 1 g daily in combination with mycophenolate, infliximab, or antithymocyte globulin may be used. Infliximab should be avoided in symptoms refractory to corticosteroids in heart failure patients due to the risk of worsening heart failure. Since cardiovascular events are rare, the management options for these patients are based on case reports and not on a large pool of literature.

Rare Adverse Events: Ocular Toxicities

Ocular toxicities are rare and may be more common with combination therapy than either anti-CTLA-4 antibodies or anti-PD-1/PD-L1 antibodies alone. The incidence is up to 1% for all ocular toxicities.

Clinical presentation

Clinical presentation may include blurred vision, photophobia, color vision, distortion, tenderness, swelling, and pain with eye movement.

Management

In most cases of mild toxicities, temporarily discontinuing immune checkpoint inhibitors, initiation of artificial tears, and topical corticosteroids should be sufficient in mitigating the adverse effects. Severe cases may warrant systemic corticosteroid treatment, although these cases are rare. For grade 4 toxicity or if adverse events recur, permanent discontinuation of immune checkpoint inhibitors is necessary. In symptoms that are refractory to corticosteroids, infliximab may be used. However, the data for treatment of refractory cases is sparse.

Reinitiating Immune Checkpoint Inhibitors

After temporarily discontinuing therapy with immune checkpoint inhibitors due to adverse events, there should be careful consideration with re-initiation of therapy.

If adverse events experienced were mild to moderate, immune checkpoint inhibitors may be considered if there was a response to therapy.

After moderate adverse events, caution should be advised for reinitiating immune checkpoint inhibitors. In the majority of cases, immune checkpoint inhibitors should be permanently discontinued after a severe adverse event.

Non-immune checkpoint inhibitor therapy should be considered, if those options are available for patients.

Additionally, consultants assisting with adverse event management should provide input on the risks and benefits of initiating immune checkpoint inhibitors again.

Furthermore, patients should be included in the decision making of re-initiation of immune checkpoint inhibitors as well.

Summary of Immune Checkpoint Inhibitors

Immune checkpoint inhibitors are a cornerstone in immunotherapy and have achieved success at extending patient survival in various tumor types. However, immune checkpoint inhibitors are not without adverse events. These adverse events are distinct and differ vastly from cytotoxic chemotherapy.

The common adverse events associated with immune checkpoint inhibitors include dermatologic, gastrointestinal, endocrine, pulmonary, musculoskeletal, and infusion related toxicities. Other adverse events include neurologic, hematologic, cardiovascular, and ocular toxicities. The management of the majority of these adverse events utilizes corticosteroids and discontinuation of immune checkpoint inhibitors.

Since the severity of these adverse events can be fatal, prompt recognition via a multidisciplinary medical team is necessary for optimal patient outcomes. Once adverse events subside, immune checkpoint inhibitors may be re-initiated depending on the clinical scenario.

Introduction: CAR T-Cell Therapy

Adoptive cell transfer is another facet of immunotherapy. It is a method that utilize a patient’s own immune cells to treat cancer. Chimeric antigen receptor (CAR) T-cell has been the most successful adoptive cell transfer treatment.

Similarly to immune checkpoint inhibitor, T-cells are the focus of this treatment. CAR T-cell therapy works by the removal of blood from the host with subsequent apheresis to separate out the host’s T-cells. The T-cells are genetically engineered to produce receptors on their surface by exposing the cells to a virus. The receptors produced on surface of T-cells are referred to as chimeric antigen receptors. After T-cells have multiplied and produce CAR, they are infused back into the patient. Prior to CAR T-cell infusion, a lymphodepleting chemotherapy regimen must be administered to the patient to allow for T-cell expansion after therapy infusion. The chimeric antigen receptors on T-cells allow them to recognize and attach to tumor cell protein, leading to tumor cell apoptosis. More specifically, CAR T-cells are programmed to target CD19 tumor cells.

The process of creating chimeric antigen receptors on T-cells is quite time intensive and takes approximately one week for completion.

Unlike immune checkpoint inhibitors that are mainly used for solid tumors, CAR-T therapy is primarily used in hematologic malignancies. CAR-T therapy has shown promising results in the setting of lymphoid malignancies refractory to chemotherapy.

Tisagenleucel (KymriahTM) and axicabtagene ciloleucel (YescartaTM) are the approved CAR T-cell agents.

There is significant risk for severe adverse events with CAR T-cell therapy; therefore, close monitoring is required for therapy administration. Preferably, patients receiving CAR T-cell therapy should be hospitalized.

Laboratory values including coagulation profile, C-reactive protein, and ferritin should be reviewed at baseline and continued after administration of therapy.

On the day of the planned infusion, patients should receive seizure prophylaxis with levetiracetam 500-750 mg orally every 12 hours due to the potential for neurotoxicity with CAR T-cell therapy. Seizure prophylaxis should continue for a total of 30 days.

Patients with a large tumor burden should receive tumor lysis monitoring and prophylaxis.

If patients experience cytokine release syndrome (CRS), cardiac monitoring is necessary.

Assessment for CRS and neurotoxicity should be performed twice daily or when the patient’s status changes.

CAR T-Cell Related Toxicities

Adverse events related to CAR T-cell therapy may be severe and fatal. The two most common adverse events associated with CAR T-cell therapy are CRS and neurotoxicity.

Cytokine release syndrome (CRS)

CRS is one of the most common adverse events associated with therapy.
A vast majority of patients will experience CRS to differing degrees of severity.
Due to the mechanism of action of T-cells stimulating the immune system for targeting tumor cells, cytokines are released in the blood stream.
The high amount of cytokines released over a short period of time leads to CRS.
Typically, patients with more extensive disease will likely experience more severe CRS due to the direct mechanism of action of T-cells.

Neurotoxicity

The majority of neurotoxicity cases are transient and reversible.
There is variability in the occurrence of neurotoxicity ranging from 0-50%.

Clinical presentation – CRS

CRS occurs due to the proliferation of CAR T-cells and is prevalent in 13-43% of patients.
Risk factors for CRS includes tumor burden, dose of CAR T-cell therapy, and the use of lymphodepleting chemotherapy.
The clinical presentation of cytokine release syndrome includes fever, hypotension, tachycardia, hypoxia, and chills. Hypotension may progress to capillary leak syndrome, which is a severe reaction as patients may have respiratory adverse events.
The time on onset of cytokine release syndrome is typically 2-3 days and lasts for about 1 week.

Clinical presentation – neurologic toxicity

The exact mechanism of CAR T-cell therapies inducing neurologic toxicities is unknown, however, it has been hypothesized that it may related to CAR T-cell infiltration or cytokine mediated.
Neurologic toxicity consists of encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, anxiety, seizure, and autonomic neuropathy.
Rare presentation may include agitation, hyperactivity, and psychosis.
The time to onset is 4-10 days and lasts anywhere between 2-3 weeks.
Neurologic toxicity may occur with CRS.

Definition of Toxicity Grading for CRS

Grade 1 toxicity: Fever (>38°C)
Grade 2 toxicity: Fever with hypotension not requiring vasopressors and/or hypoxia requiring low-flow nasal cannula or blow-by oxygen
Grade 3 toxicity: Fever with hypotension requiring a vasopressor with or without vasopressin and/or hypoxia requiring high-flow cannula, face mask, nonrebreather mask, or Venturi mask not attributable to any other cause
Grade 4 toxicity: Fever with hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure (eg, CPAP, BiPAP, intubation and mechanical ventilation) not attributable to any other cause

Management of CRS

Grade 1 toxicity: Anti-IL-6 therapy with tocilizumab should be considered if patients have CRS for an extended period of time (>3 days). Other management strategies may include empiric broad-spectrum antibiotics and IV fluids for hydration. If patients are neutropenic, granulocyte colony-stimulating factor may be initiated.
Grade 2 and 3 toxicities: Tocilizumab 8 mg/kg infused over 1 hour should be initiated with a fluid bolus. If patients are still symptomatic after one dose of tocilizumab, another dose may be repeated in 8 hours with no more than 3 doses in 24 hours and a maximum of 4 total doses. Hypotension may also be managed in conjunction with dexamethasone 10 mg IV every 6 hours after 1-2 doses of tocilizumab. Vasopressors may also be used for hypotension if patients are refractory to tocilizumab and fluid boluses. For severe symptoms, patients should be transferred to the ICU. Oxygen may also be necessary.
Grade 4 toxicity: Pharmacologic management is similar to grades 2 and 3. If patients are refractory to dexamethasone, methylprednisolone 1 g IV daily may be used. Patients should be transferred to the ICU with mechanical ventilation, if needed.

If corticosteroid therapy is initiated, prophylactic antifungal therapy may be considered as well. Additionally, if symptoms improve, a rapid corticosteroid taper can be utilized. One important item to note is the use of corticosteroids is toxic to CAR T-cells and may decrease the efficacy of its use. Typically, corticosteroid therapy is reserved for symptoms that do not respond to tocilizumab.

Other agents that may be used for tocilizumab refractory cases include siltuximab, etanercept, infliximab, and anakinra.

Definition of Toxicity Grading for Neurotoxicity

Immune effector cell-associated encephalopathy (ICE) assessment consists of five categories including, orientation, naming, following commands, writing, and attention. If patients are oriented to year, month, city, and hospital, a total of 4 points may be earned. The naming of 3 objects warrants 3 points. One point each may be awarded for the ability to follow simple commands, write a standard sentence, and ability to count backwards.

Grade 1 toxicity: ICE score 7-9
Grade 2 toxicity: ICE score 3-6
Grade 3 toxicity: ICE score 0-2
Grade 4 toxicity: ICE score 0

Management of Neurotoxicity

Grade 1 toxicity: Supportive care
Grade 2 toxicity: Patients will require supportive care in addition to dexamethasone 10 mg IV every 6 hours or methylprednisolone 1 mg/kg IV every 12 hours for symptomatic progression.
Grade 3 toxicity: Dexamethasone 10 mg IV every 6 hours or methylprednisolone 1 mg/kg IV every 12 hours should be promptly initiated. Patients should also be receiving care in the ICU.
Grade 4 toxicity: High-dose corticosteroids with methylprednisolone 1 g IV daily for 3 days should be initiated. Once symptoms improve, a rapid taper can be considered. Mechanical ventilation may also be needed for patients. If status epilepticus occurs, patients may be treated based on institutional standards.

If patients receive corticosteroid therapy, antifungal prophylaxis may also be warranted. If patients experience cytokine release syndrome with neurotoxicity, tocilizumab 8 mg/kg IV infused over 1 hour should be initiated as well. Corticosteroids are typically more efficacious at managing neurotoxicity associated with CAR T-cells compared to tocilizumab. Dexamethasone may be preferred for neurotoxicity due to increased blood brain penetration compared to other corticosteroids.

Summary of CAR T-Cell Therapy

CAR T-cell therapy is a form of adoptive cell transfer immunotherapy. CAR T-cell therapy has shown promise in hematologic malignancies refractory to chemotherapy. This novel approach to chemotherapy has its own set of toxicities including cytokine release syndrome and neurotoxicity. The cornerstone to managing CAR T-cell therapy associated toxicities includes tocilizumab, an anti-IL-6 agent, and corticosteroids.

General Immunotherapy Patient Education

Patients should receive information on the potential adverse events of immune checkpoint inhibitors and CAR T-cell therapy prior to and during therapy. Patients may be of assistance in identifying adverse events to the medical team for prompt adverse event management.

Open communication between the patient and health care team is key since adverse events can be managed effectively with early detection.

Patients should document any medical conditions including autoimmune diseases prior to therapy initiation.

All medications including over-the-counter medications and herbal supplements should be provided to the medical team.

Birth control should be used for during and at least 5 months after completion of immunotherapy. The consequences of reproduction with immunotherapy are unknown at this time.

Breastfeeding is contraindicated during and for at least 5 months after completion of immunotherapy.

Patients should receive education on stress dosing of corticosteroids and wear a medical alert bracelet for adrenal insufficiency.

Patients should alert any health care professional of receiving or previously received immunotherapy in the past due to the long lasting effect on the immune system after cessation of therapy.

Providers should be notified for any new presentation of severe fatigue, headache, rash, cough, shortness of breath, chest pain, abdominal bloating, change in bowel pattern, weight loss, vision changes or eye pain, severe muscle weakness, and severe muscle or joint pains. Patients should continue to monitor for these symptoms for at least one year after completion of therapy.

Providers should be notified of any new medications or vaccinations. Live vaccines are not recommended while receiving immunotherapy due to the lack of evidence for concurrent use.

Conclusion

Immune checkpoint inhibitors and CAR T-cell therapy have revolutionized the treatment of cancer in the past decade. As these therapies are gaining rapid FDA approved indications for the treatment of multiple malignancies, more immune related adverse events have been reported with post-marketing experience.

This unique type of cancer treatment comes with its own unique adverse events not previously associated with cancer therapy. There are still varying consensus guidelines for managing immune checkpoint inhibitor related adverse events. Although guidelines may differ on the treatment algorithm of immune checkpoint inhibitors, it is clear that the use of corticosteroids is the pillar to treating immune checkpoint inhibitor associated adverse events. Additionally, withholding immune checkpoint inhibitor therapy temporarily will help symptom improvement as well. The timing of when to withhold immune checkpoint inhibitors and when to restart therapy depends on the clinical scenario.

Adoptive cell transfer with CAR T-cell therapy is a novel approach at targeting hematologic malignancies with two very distinguished and serious adverse events. The basis of managing CAR T-cell therapy associated adverse events utilizes tocilizumab and corticosteroids.

Patients should be educated by health care providers on adverse events associated with immunotherapy for early detection and management.

Active Learning

Managing toxicities associated with immune checkpoint inhibitors: The Society for Immunotherapy of Cancer provides recommendations for managing adverse events associated with immune checkpoint inhibitors in this article. While immune checkpoint inhibitors are effective for certain types of malignancies, it is not without adverse events. Common adverse events include skin, gastrointestinal tract, endocrine, pulmonary, and musculoskeletal. Corticosteroids are utilized in different doses depending on the grade of severity of the adverse event.

https://jitc.biomedcentral.com/articles/10.1186/s40425-017-0300-z

CAR T-cells: Engineering Patients’ Immune Cells to Treat Their Cancers: Patients with relapsed leukemia and lymphomas did not have many options at prolonging survival prior to the development of CAR T-cells. It is the most successful type of adoptive cell therapy since it has shown the most promise in adult and pediatric patients. Cytokine release syndrome and neurotoxicity are the main adverse events of CAR T-cell therapy. Management of these toxicities utilize tocilizumab and corticosteroid therapy.

https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

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