Historically, surgery, chemotherapy, and radiation have been the mainstay of most cancer therapies. Although these modalities have been successful and improved survival outcomes, cancer remains one of the most debilitating diagnoses, often with poor outcomes. The use of immunotherapy to treat cancer is a revolutionary concept that encompasses the use of checkpoint inhibitors (CPIs), chimeric antigen receptor (CAR) T-cell therapy, and therapeutic cancer vaccines.1,2 This article focuses on CPIs and their role in harnessing the immune system to fight cancer.
Although the use of immunotherapy has changed the landscape of cancer treatment, the concept is not entirely new. In 1891, William B. Coley, MD, treated patients diagnosed with inoperable tumors using both live and attenuated pathogen mixtures, which he injected into the tumors. Surprisingly, some of these patients responded with remissions, thus earning Dr Coley the accolade as the pioneer and father of modern-day immunotherapy.3 Over the past few decades, there has been growing interest to better understand how the body’s immune system works, and how cancer cells can evade the immune system. In 2013, the journal Science recognized cancer immunotherapy as a scientific breakthrough, highlighting the reemergence of immunotherapy as a treatment option for patients diagnosed with cancer. Currently, CPIs, including programmed cell death 1 (PD-1) and its ligand PD-L1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors, make up the group of drugs that has been approved by the FDA for cancer treatment. These agents have improved survival outcomes for some patients. However, despite these advances, not all patients with cancer are deriving a benefit from these novel therapies. Research in cancer and immunology is ongoing in attempts to improve outcomes in cancer patients treated with these types of agents.
CPIs are group of immunotherapy drugs that are used to treat different types of both solid and liquid malignancies. These agents fall under 2 broad categories: anti–PD-1 and its ligand anti–PD-L1, and CTLA-4 inhibitors. Anti–PD-1/PD-L1 drugs exert their action by blocking interaction between PD-1 and PD-L1. This action unlocks the ability of the immune cells in the body to recognize and unleash lethal attacks on cancer cells.4 Anti–PD-1/PD-L1 drugs include pembrolizumab, nivolumab, durvalumab, atezolizumab, avelumab, and cemiplimab. In contrast, binding of CTLA-4 to a protein known as B7 disables immune T-cells from recognizing and destroying cancer cells. Anti–CTLA-4 agents such as ipilimumab and tremelimumab are designed to put brakes on or halt the binding process of the B7 protein to CTLA-4. This action releases T-cells to recognize and attack cancer cells.4
Several immunotherapy agents have been approved by the FDA for use across many tumor sites. For example, pembrolizumab, an anti–PD-1 CPI, is approved for the treatment of different types of solid tumors, including glioblastoma (a cancer of the brain), melanoma, head and neck cancer, and lung cancers; others include gastrointestinal and genitourinary cancers as well as select liquid tumors such as lymphomas. In addition, anti–CTLA-4 agents, such as ipilimumab and tremelimumab, are approved for the treatment of patients with melanoma and mesothelioma, respectively.
Serious adverse events (AEs) have been reported with CPIs. Unlike chemotherapy, CPIs present with a unique toxicity profile commonly referred to as immune-mediated AEs or reactions. These reactions are primarily characterized by symptoms that result from an exaggerated immune response due to infiltration of immune T-cells into various tissues and body organs. The frequency and severity of these reactions vary depending on the type of agent used, other underlying disease states, and prior therapy such as radiation to head and neck and the thorax. Serious AEs reported with CPIs include pneumonitis, colitis, nephritis, hepatitis, endocrinopathies, and pancreatitis, among others. In general, the incidence of these serious AEs occurred in less than 5% of the patients across all tumor sites in pooled data in clinical trials and reflects what is reported in clinical practice. Between 1% and 50% of all patients receiving CPI therapy develop thyroiditis. However, the frequency of these events is reported to be slightly higher in patients with a prior history of radiation to the neck and/or thorax and is an irreversible AE.5
The most commonly reported AEs in patients receiving CPIs include fatigue, arthralgias, and skin reactions. In general, these AEs have been reported and occur more frequently in patients receiving CTLA-4 inhibitors than anti–PD-1/PD-L1 inhibitors. These observed differences are in part attributed to global activation of naive and memory T-cells by CTLA-4 inhibitors in the lymph nodes, in contrast to anti–PD-1/PD-L1 inhibitors that modulate local T-cell activity.6 AEs associated with CPIs can occur at any point during treatment—events have been reported as early as a few weeks following initiation of treatment to months later. In general, symptoms tend to occur about 12 weeks after starting treatment. In addition, AEs have been reported more than 1 year after completing therapy in some patients.7 These observations underscore the importance of ongoing monitoring of patients who have received CPI therapy to limit morbidity and mortality.
CPI-Related Adverse Events: Management
Treatment of CPI-induced AEs primarily consists of interrupting therapy and initiating corticosteroid therapy, including other immunomodulatory agents. The use of corticosteroids and immunomodulatory agents requires great caution in prescribing as they can lead to significant complications. It is unclear whether prophylactic antibiotics should be prescribed routinely to reduce the risk of infections in these patients receiving long-term corticosteroids and requires discretion by the treating providers.
Treatment of AEs related to CPIs is based on the Common Terminology Criteria for Adverse Events (CTCAE) grading of presenting symptoms, with corticosteroids as the mainstay of therapy. The CTCAE grading tool is the most commonly used tool and is useful to guide appropriate management of these AEs. A major disadvantage of the CTCAE tool is the potential risk of misreporting the severity of AEs, which can adversely impact clinical decision-making.
In general, patients who are asymptomatic or develop grade 1 symptoms can remain on treatment with low-dose steroid therapy based on provider discretion. Patients with grade 2 or higher toxicities should have treatment interrupted and corticosteroids initiated immediately.
Pneumonitis in patients receiving CPI therapy is a serious and potentially fatal AE.8 The diagnosis of pneumonitis is based on both clinical presentation and radiographic findings. In some cases, a diagnosis of pneumonitis can be challenging as there can be an overlap between infectious causes and disease progression and symptoms can mimic other conditions, especially in patients with primary thoracic malignancies.9 However, if CPI-induced pneumonitis is suspected, treatment with corticosteroid therapy should be initiated immediately as patients with pneumonitis can deteriorate quickly and ultimately die. In clinical trials, most patients experienced grade 1/2 events. Patients who develop progressive dyspnea and shortness of breath should be evaluated immediately with a contrast-enhanced CT scan of the chest, which is considered to be the gold standard for evaluation of pneumonitis. In select cases, shortness of breath may be preceded by a cough. In patients presenting with acute, severe, and worsening symptoms, hospitalization with IV corticosteroids or immunomodulatory agents should be a priority. A consult to pulmonary and bronchoscopy evaluation should be considered to rule out other causes, such as infections or disease progression, as clinically indicated. Rarely, a biopsy may be necessary.2
In select patients with asymptomatic pneumonitis, withholding treatment may be an option; however, starting corticosteroid therapy must be considered. Patients with grade 2 or higher should be treated with corticosteroids and tapered over a 4- to 8-week period, depending on symptoms. Patients with pneumonitis who are not hospitalized should be evaluated every 2 to 3 days, and if symptoms are not improving, they should be hospitalized for IV steroid therapy, especially if symptoms are severe. Repeat imaging with contrast-enhanced CT scan of the chest should be considered and performed at 3- to 4-week intervals as clinically indicated. Immunosuppressive therapy with mycophenolate mofetil or infliximab should be considered for patients with severe or refractory symptoms.2,8,9 It is important to involve pulmonary specialists in the care of these patients on an ongoing basis, as clinically indicated.
Therapy with a CPI can be restarted when symptoms improve to grade 1 or completely resolve after corticosteroid therapy. However, in patients with grade 4 or recurrent grade 2 or higher pneumonitis, CPI therapy should be permanently discontinued.
Colitis associated with CPI therapy is characterized by an increase in the number of stools—4 or more stools or a mild increase in ostomy output per day compared with baseline. In patients receiving anti–CTLA-4, approximately 18% develop grade 3 or higher AEs.10 Stool consistency may range from soft to watery, with or without mucus. In severe cases, abdominal pain, hematochezia, weight loss, fever, and vomiting may be present. If not treated promptly, symptoms can progress resulting in bowel perforation and colostomy.8,11 All patients suspected of having colitis should undergo evaluation of the abdomen with a contrast-enhanced CT scan and an infectious workup to rule out other causes. Stool samples should be sent for Clostridium difficile toxin bacterial culture, viral polymerase chain reaction, and ova and parasite analyses. Treatment with corticosteroids should be initiated immediately and should not wait for the results of the stool analyses.
Patients with mild symptoms or grade 1 diarrhea can be treated symptomatically with antidiarrheal agents, a BRAT (bananas, rice, applesauce, toast) diet, and increasing fluid intake. Whether treatment is withheld may depend on the discretion of the provider.9 Treatment should be withheld in patients with grade 2 or higher colitis and corticosteroid therapy initiated immediately. Patients who present with severe or refractory symptoms should be hospitalized for treatment with IV steroids or immunosuppressive therapy such as infliximab as clinically indicated,12 and IV fluid support. A consult to gastroenterology is required. Evaluation with colonoscopy should be considered based on the severity of symptoms.11
Therapy with CPIs should be withheld until symptoms resolve or return to grade 1, and corticosteroids can be tapered over 4 to 6 weeks, or longer in some patients. Patients with grade 2/3 events receiving anti–PD-1/PD-L1 can resume CPI therapy with improvement or resolution of symptoms. However, patients receiving anti–CTLA-4 agents should permanently discontinue treatment. All patients with refractory grade 2/3 events or with grade 4 events should have treatment permanently discontinued.
The incidence of hepatitis in patients receiving anti–PD-1/PD-L1 is approximately 1% to 2% versus 11% in patients receiving anti–CTLA-4 agents.10 Hepatitis resulting from CPI therapy can be difficult to distinguish in patients with liver metastasis or other underlying liver diseases.9 A major distinguishing feature between hepatitis associated with CPI and other types of hepatitis is that CPI-induced hepatitis is sterile and generally does not require treatment with antibiotics.9 The onset and course of symptoms in patients who develop hepatitis vary. Patients generally present with varying degrees of transaminitis (an elevation in ALT and AST with or without an elevated bilirubin level). In some patients who have baseline elevated liver function tests (LFTs), the degree of increase should be considered based on baseline values. Typically, these patients do not have any reportable symptoms, and the changes in the liver enzymes are noted on routine evaluation of blood work performed while on CPI therapy.10 As symptoms progress, in addition to LFT elevations, these patients may develop pain in the right upper quadrant of the abdomen with or without nausea and vomiting. A diagnosis of hepatitis is generally made based on physical examination, laboratory findings, and imaging of the abdomen with ultrasound or a contrast-enhanced CT scan. It is critically important that other potential disease-related causes, such as infections and concomitant drug and alcohol use, are ruled out, and all potentially hepatotoxic drugs should be discontinued.7
Patients with asymptomatic grade 1 hepatitis may continue therapy with close monitoring. LFTs should be obtained weekly, or more frequently as clinically indicated, as liver toxicity can progress rapidly and could lead to liver failure. Patients with grade 2 or higher hepatitis with or without elevation of bilirubin levels must have treatment withheld and oral or IV corticosteroids initiated promptly. This includes patients who do not have any physical symptoms. These patients should have LFTs monitored every 2 to 3 days. Hepatology must be consulted as appropriate, especially for those patients not responding to corticosteroid therapy 3 days after initiating therapy.9,10 These patients may require immunosuppressive therapy with drugs such as mycophenolate. Infliximab, another immunosuppressive agent, is generally not recommended due to an increased risk of hepatic failure. When symptoms improve to grade 1 or less, corticosteroids can be tapered over 4 to 6 weeks. Patients with recurrent grade 2 or higher events should have treatment permanently discontinued, as should all patients with grade 4 hepatitis.
Endocrinopathies that result from CPI therapy can be complex due to the risk of simultaneous multiple organ involvement on the endocrine system axis that includes the pituitary, thyroid, pancreas, and adrenal glands.
Both hypothyroid and hyperthyroid states have been reported in patients receiving CPI therapy. These conditions are commonly seen in patients receiving anti–PD-1/PD-L1 agents. The incidence of hypothyroidism is higher than that of hyperthyroidism, with the latter often presenting as a transient state that precedes the hypothyroid state.5,7 Diagnosis of both conditions is generally made with thyroid hormone level analyses—thyroid-releasing hormone, triiodothyronine, and thyroxine. Patients who develop hypothyroid states usually require hormone replacement with a thyroid hormone such as levothyroxine. For patients who develop hyperthyroid states, beta- blockers such as propranolol and antithyroid agents such as methimazole are prescribed. Unlike other CPI-related AEs, patients who develop thyroid disorders can continue treatment without interruption.
A consult to endocrinology may be necessary depending on the clinical presentation. Very rarely do patients need to permanently discontinue treatment.
Type 1 Diabetes Mellitus
Type 1 diabetes, or insulin-dependent diabetes, is an uncommon autoimmune reaction that occurs in approximately 1% of patients receiving treatment with anti–PD-1/PD-L1 inhibitors.13 Patients who develop diabetes typically present with elevation in blood glucose levels. The complexity of managing patients who develop diabetes depends on the severity and other underlying comorbid conditions. In general, all patients should be referred to an endocrinologist for close monitoring and ongoing management. However, patients who present with severe symptoms should be admitted to the hospital; typically, intensive-level care is required for metabolic control, especially for patients who present with severe hyperglycemia or ketoacidosis.
For patients with grade 1 to 3 toxicities, treatment can be resumed when symptoms resolve or improve to grade 1, keeping in mind that these patients will likely require ongoing treatment with exogenous insulin. For patients with recurrent and severe symptoms or grade 4 events, consideration should be given to permanently discontinuing CPI therapy.
Although inflammation of the pituitary gland, also known as hypophysitis, is a rare AE in patients receiving CPI therapy, patients who present with symptoms can decline very quickly. It is therefore critical to monitor patients for potential toxicities to limit morbidity and mortality. Symptoms of hypophysitis generally include fatigue and headache. Depending on the severity, other symptoms may include photophobia, nausea and vomiting, fever, and dizziness. Diagnosis of this condition is based on imaging with either MRI (pituitary protocol) or a contrast-enhanced CT scan of the head to assess the pituitary gland for swelling. Physical and laboratory findings include analyses of growth hormone, prolactin, adrenocorticotropin (ACTH), luteinizing hormone, and follicle-stimulating hormone levels.14 Treatment with corticosteroids should be initiated immediately, and patients presenting with severe symptoms should be hospitalized for further management.
Adrenalitis (Adrenal Insufficiency)
A diagnosis of adrenal insufficiency is considered a medical emergency and requires hospitalization for management of symptoms. This diagnosis can be challenging as patients often present with symptoms that mimic other conditions. Typical symptoms of this condition include fatigue, electrolyte abnormalities, hyperkalemia and hyponatremia, and, in severe cases, hypotension and distributive shock.10 Diagnosis of adrenal insufficiency is based on ACTH levels, which is considered as the gold standard. Analysis of serum levels may be useful but is not always confirmatory.15 Treatment with corticosteroids should be initiated immediately and electrolyte abnormalities corrected accordingly. Treatment should be withheld for all grade 3/4 events and permanently discontinued for recurrent grade 2 or higher events. For grade 2 or less, consideration should be given to interrupting treatment unless the patient is completely asymptomatic and safe to continue treatment with corticosteroid therapy. It is important to enforce the need for a medical alert bracelet for adrenal insufficiency as stress doses may be required in emergencies.
Acute kidney injury associated with CPI therapy is a rare complication that may present as an autoimmune nephritis or acute renal failure. Acute tubulointerstitial nephritis and immune complex–mediated glomerulonephritis have also been reported.2,16 When patients develop CPI-related kidney injury, they may present with changes in urine output (less than normal), proteinuria, and elevation in blood urea and nitrogen and serum creatinine.17 It is therefore important that patients with suspected nephritis are evaluated and treated promptly. Hospitalization with close monitoring may be required. Evaluation for CPI nephritis includes urinalysis to assess the presence of protein and to determine the protein/creatinine ratio. A renal ultrasound may be necessary depending on the clinical symptoms. When a diagnosis of nephritis is made, all nephrotoxic drugs must be discontinued. For patients who develop renal failure, strict adherence to fluid intake and output must be maintained. Nephrology should be consulted when indicated. Patients with a difficult differential diagnosis should have a biopsy to confirm diagnosis.7 Patients with grade 1 to 3 toxicities may resume CPI therapy once symptoms improve or resolve. However, treatment should be permanently discontinued for patients diagnosed with recurrent grade 2 or higher and grade 4 toxicities.
Fatigue is one of the most commonly reported AEs with anti–PD-1/PD-L1 therapy and can be debilitating in some patients. Although the pathogenesis of fatigue is not clearly understood, patients receiving combination therapies with chemotherapy may be at increased risk. The severity of fatigue associated with CPI therapy varies, with most patients reporting mild episodes and not requiring intervention. Permanently discontinuing treatment in patients with debilitating symptoms should be considered as clinically indicated. Most patients who experience fatigue can continue treatment and do not require any interruptions in their treatment.
Mild cutaneous reactions, such as pruritus and rash, are common AEs seen in patients receiving CPI therapy. However, serious and severe reactions have been reported, including Stevens-Johnson syndrome (SJS) and vitiligo, with the latter commonly seen in patients receiving treatment for melanoma with anti–CTLA-4 agents. Although rare, other cutaneous reactions reported in patients receiving CPI therapy include photosensitivity, alopecia areata (patchy hair loss), stomatitis, and xerosis cutis (extremely dry and scaly skin).7 In general, treatment interruption is not required for mild events. These patients can be treated with topical steroids, moisturizing creams, and antipruritic agents. Patients should also be instructed to avoid skin irritants and sun exposure. However, treatment should be discontinued for patients who develop severe skin reactions such as SJS. Consideration should also be given to evaluating these patients for other causes of cutaneous reactions, such as infections and drug reactions.7
Several other rare AEs have been reported with CPI therapy, including pancreatitis, uveitis, Guillain-Barre syndrome, vasculitis, hemolytic anemia, small-bowel enteritis, and pericarditis. Although these are rare toxicities, patients who develop symptoms that are concerning for possible CPI-induced AEs should be evaluated and treated promptly. In addition, appropriate referrals must be initiated. For patients requiring hospitalizations, corticosteroid therapy and/or other appropriate therapy must be initiated quickly and discontinued once a CPI AE has been ruled out.7
Identification and early intervention of CPI-related AEs should be a multidisciplinary effort and should include individualized patient care. Clinicians need to be educated about these AEs as the associated morbidity and mortality can be high. Patients should also be educated about these risks, with emphasis on early reporting of symptoms.
Response rates with CPI therapy remain low across tumor sites. Therapy with CPI enhances tumor immunity but not autoimmunity and can therefore induce the latter, limiting the use of these therapies in patients with autoimmune diseases. Cancer and immunology researchers continue to work on gaining a better understanding of why only select patients respond, and how to improve the efficacy, specificity, and safety of these drugs.
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- Linardou H, Gorgas H. Toxicity management of immunotherapy for patients with metastatic melanoma. Ann Transl Med. 2016;4:272.
- Allison JP. A brief history of immunotherapy. www.targetedonc.com/view/a-brief-history-of-immunotherapy. 2014.
- Barros L, Pretti MA, Chicaybam L, et al. Immunological-based approaches for cancer therapy. Clinics (Sao Paulo). 2018;73(suppl 1):e429s.
- Delivanis DA, Gustafson MP, Bornschlegl S, et al. Pembrolizumab-induced thyroiditis: comprehensive clinical review and insights into underlying involved mechanisms. J Clin Endocrinol Metab. 2017;102:2770-2780.
- Myers G. Immune-related adverse events of immune checkpoint inhibitors: a brief review. Curr Oncol. 2018;25:342-347.
- Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv119-iv142.
- Postow M, Wolchok J. Toxicities associated with checkpoint inhibitor immunotherapy. UpToDate. www.uptodate.com/contents/toxicities-associated-with-checkpoint-inhibitor-immunotherapy. 2019.
- Kottschade LA. Incidence and management of immune-related events in patients undergoing treatment with immune checkpoint inhibitors. Curr Oncol Rep. 2018;20:24.
- Gerson JN, Ramamurthy C, Borghaei H. Managing adverse effects of immunotherapy. Clin Adv Hematol Oncol. 2018;16:364-374.
- Prieux-Klotz C, Dior M, Damotte D, et al. Immune checkpoint inhibitor-induced colitis: diagnosis and management. Target Oncol. 2017;12:301-308.
- Wang Y, Abu-Sbeih H, Mao E, et al. Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson. J Immunother Cancer. 2018;6:37.
- Stamatouli AM, Quandt Z, Perdigoto AL, et al. Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes. 2018;67:1471-1480.
- Illeana-Dumbrava E, Subbiah V. Autoimmune hypophysitis. Lancet Oncol. 2018;19:e123.
- Villadoid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res. 2015;4:560-575.
- Koda R, Watanabe H, Tsuchida M, et al. Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis: a case report. BMC Nephrol. 2018;19:48.
- Daniels GA, Guerrera AD, Katz D, Viets-Upchurch J. Challenge of immune-mediated adverse reactions in the emergency department. Emerg Med J. 2019;36:369-377.