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Immune-Related Adverse Events for Anti-Cancer Immunotherapy
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24032769

Immune checkpoint inhibitors (ICIs) have changed how we think about tumor management. Combinations of anti-programmed death ligand-1 (PD-L1) immunotherapy have become the standard of care in many advanced-stage cancers, including as a first-line therapy. Aside from improved anti-tumor immunity, the mechanism of action of immune checkpoint inhibitors (ICIs) exposes a new toxicity profile known as immune-related adverse effects (irAEs). This novel toxicity can damage any organ, but the skin, digestive and endocrine systems are the most frequently afflicted. Most ICI-attributed toxicity symptoms are mild, but some are severe and necessitate multidisciplinary side effect management. Obtaining knowledge on the various forms of immune-related toxicities and swiftly changing treatment techniques to lower the probability of experiencing severe irAEs has become a priority in oncological care.

irAEs ICI anti-PD1 immunotherapy gut microbiome

1. Introduction

Immune checkpoint inhibitors (ICI) and their combination with conventional chemotherapy and/or radiotherapy are currently the standard of care in cancer, and the number of patients receiving ICI as a first-line therapy is rising. Currently, the CTLA-4 inhibitor ipilimumab; PD-1 inhibitors pembrolizumab, nivolumab, and cemiplimab; and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab are approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma, non-small cell lung cancer (NSCLC), Hodgkin’s lymphoma, head and neck squamous cell carcinoma, urothelial carcinoma, renal cell carcinoma, and hepatocellular carcinoma [1]. PD-L1 inhibitors are also approved for the treatment of triple-negative breast cancer and Merkel cell tumors [2].
ICIs have now been in use for a decade and, in addition to their positive effects, there is growing evidence of their side effects. The efficacy of ICIs, including their toxicity, has been demonstrated in murine models to have a significant link to the gut microbiome [3]. All aspects of the gut, including the microbiome, micro-organism composition, and metabolic products, induce effects on host immune defenses [4]; however, in healthy individuals, tolerance and antigenic response are generally in balance. In recent years, numerous independent research groups discovered an intriguing link between the gut flora and ICI efficacy in a clinical setting [5][6]. Multiple investigations and an impartial meta-analysis in malignant melanoma demonstrated a connection between microbial metagenomic and metatranscriptomic markers and ICI efficacy [7][8][9]. Despite the fact, that causality and the biological background of such a connection are still disputed and under scrutiny, multiple studies have shown at least partial or indirect evidence regarding such mechanisms. The most likely supported hypothesis is the “molecular mimicry” phenomenon, where epitopes produced by gut microbial species as part of their native gene expression programs resemble tumor neoantigens, prompting “autoreactive” T cells and powerful anti-tumor immunity [10][11]
Similar to other anti-cancer therapies, ICI comes with its own set of adverse effects; about 70–90% of patients receiving ICI show immune-related adverse events (irAEs) [12][13][14][15]. irAEs are commonly attributed to the inability of the immune system to distinguish between tumors and self-antigens, hence the cross-reactivity [16]. This dysregulation of the immune system’s self-tolerance leads to an over-activation of innate and adaptive immunity that translates to cytokine-mediated inflammation, autoreactive B and T cells, and autoantibodies [17][18]. irAEs can be observed in almost all organs of the human body, more commonly the skin, thyroid, lungs, colon, liver, and pituitary are affected; however, in rare cases even the nervous and cardiac systems can be damaged, with the possibility of a fatal outcome [18][19]. The mechanisms underlying these toxicities are diverse and differ in each organ; in contrast, irAEs can have similar manifestations in the affected organ regardless of the cancer type [20][21][22].

2. Adverse Events and Their Clinical Management in Anti-Cancer Immunotherapy

irAEs are classified by the American International Cancer Institute according to the Common Terminology Criteria for Adverse Events (CTCAE), which is divided into mild (1), moderate (2), severe (3), life-threatening (4), and fatal (5) categories [23]. PD-1 and PD-L1 inhibitors are generally better tolerated than CTLA-4 inhibitors and grade 3 and 4 irAEs are also more common with CTLA-4 inhibitors than with PD-1 inhibitors (31% vs. 10%). There is also a difference in the organ specificity of adverse events, for example, colitis, hypophysitis, and skin rashes occur more frequently with CTLA-4 inhibitors, while pneumonia, hyper- or hypothyroidism, joint pain, and vitiligo are more common with PD-1 inhibitors [23]. Generally, at least one negative event is detected in two-thirds of anti-PD-1/PD-L1 immunotherapies. One-seventh of patients experience a high-grade irAE (3–5) and 0.45% of patients die, most commonly due to pneumonitis [24]. The most common symptoms of treatment-associated irAEs (at any grade) were fatigue, pruritus, diarrhea, hyperthyroidism, hypothyroidism, and vitiligo; while the most common high-grade irAE symptoms were fatigue, liver enzyme elevation (AST and ALT), pneumonitis and diarrhea [13][15][25]. Figure 1 demonstrates the most common and severe irAEs organized by organ systems.
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Figure 1. Most common and significant irAEs of PD-1/PD-L1 inhibitors. Figure shows the most common side effects organized by organ system. The most common treatment-associated systemic irAE at any grade was fatigue. Among all irAEs, diarrhea and thyroid dysfunction (hypo- or hyperthyroidism) occurred most frequently. Pneumonitis was the most common high-grade symptom and most frequent cause of irAE-related death.

2.1. Dermatological irAEs

Dermatological toxicity is one of the most common irAEs among all organ systems, occurring in 25–30% of treated patients. Clinically, immune-related cutaneous toxic effects are mainly skin rashes, pruritus, and vitiligo [26][27] the latter being a side effect specific to the treatment of melanoma. It has been shown that the treatment of skin tumors is most frequently associated with the highest incidence of dermatological side effects (7.3 times more frequent than other tumors, [28]). Interestingly, the presence of cutaneous irAEs showed a positive correlation with treatment response and long-term relapse-free survival, according to a recent meta-analysis [27]. Topical agents or low-dose systemic steroids are often sufficient to treat skin-related irAEs [29].

2.2. Gastrointestinal irAEs

Pooled meta-analysis data suggest that diarrhea (13% vs. 33%) and colitis (1.4% vs. 9.1%) are less frequent with PD-1/PD-L1 inhibitors compared to CTLA-4 therapy, but symptoms persist longer (2 months vs. 1.4 months) [30][31][32]. Unlike CTLA-4 therapy, the severity of diarrhea as an adverse effect of PD-1/L1-blockade is not dose-dependent [33]. The most common symptom of colitis is diarrhea, which occurs in almost all patients, followed by abdominal pain (25%), loss of appetite (19%), hematochezia (12.5%) and mucoid stools (10%). GI pathology includes inflammatory infiltrates, villi shortening, and crypt or mucosal fragility. GI irAEs present clinically as described above—colitis, ileitis, decreased transit time, diarrhea, and/or blood in stool (ICI-therapy associated colitis/ileitis, CIC) [34][35]. The risk of colitis is increased by taking NSAIDs and is decreased in the case of vitamin D supplementation [30]. Autoimmune diseases increase the risk of developing CIC, and CIC occurrence in underlying IBD patients receiving anti-CTLA4 therapy was reported at 30% [36][37]. In contrast, IBD patients better tolerate anti-PD1/PD-L1 ICI [31].
Low-grade GI toxicity is usually managed based on clinical symptoms. The gold standard for the diagnosis of CIC is biopsies, but to exclude a more severe situation, such as toxic megacolon or perforation, CT scans are required. An infection can be excluded by obtaining a stool sample for culture [31]. Treatment of colitis in grade 1 is supportive, with antimotility agents (loperamide), hydration, and an appropriate diet to reduce symptoms, which can be continued during therapy. In the case of grade 2, systemic steroid treatment should commence, after the exclusion of infection. In grades 3 and 4, immediate discontinuation of ICI therapy is required, and hospital admission for monitoring is recommended, along with IV administration of 1–2 mg/kg/day methylprednisolone with electrolyte and fluid therapy. If symptoms do not improve after 2–4 days, biological therapy (infliximab and vedolizumab) should be administered. While therapy should not be restarted at grade 4, opinions differ at grade 3, but if symptoms can be managed and reduced to grade 1 or below, PD-1/PD-L1 therapy may be restarted [33]. In grades 3–4 cases, 1–1.5% of patients develop colon perforation, which is treated with emergency colon resection surgery [30].
The most common hepatic irAE is hepatitis, with around 1–2% occurrence in PD-1/PD-L1 monotherapy, but this can be as high as 20% in a combination of ICI therapy with ipilimumab [37]. Blood testing of liver enzymes is essential before therapy initiation, as is monitoring ICI throughout the therapy and before each dose [38]. Treatment in the first two grades is based on continuous monitoring of enzyme levels, and at grade 2, initiation of oral steroid therapy. In grades 3 and 4, glucocorticoids are given in a high dose for the first two days, followed by 1–2 mg/kg/day of oral prednisolone until enzyme levels settle [32]. To date, there are some published case reports of pancreas involvement [39][40] but research has shown that PD-1/PD-L1 inhibitors do not increase the risk of pancreatitis [41].

2.3. Respiratory irAEs

Most fatal adverse events are caused by pneumonitis (35%) [42] compared to other irAEs, but the severe, life-threatening grade is found in less than 2% of cases [38]. The real-world incidence of immune-related pneumonitis in ICI-treated patients is between 2.49% and 13.2% [43][44][45]. The most common symptoms are a persistent, unproductive cough, dyspnea, fever, and chest pain; however, one-third of patients remain asymptomatic [46]. Risk factors include elderly age, smoking, male gender, previous lung disease (emphysema, COPD, or asthma), previous chest irradiation, and combination with other therapies [42]. Diagnosis is based on a CT scan and clinical symptoms. Bronchoscopy or BAL helps with differential diagnosis to rule out an infection [47].
Treatment of ICI-related grade 1 pneumonitis includes the temporary suspension of the drug until the normalization of CT findings. Grade 2 treatments include 1 mg/kg/day of oral prednisolone and in grades 3–4, complete abandonment of ICI therapy is required with 2–4 mg/kg/day IV methylprednisolone for 4–6 weeks and initiation of antibiotic therapy to rule out infection [47].

2.4. Endocrine irAEs

Hypothyroidism, hyperthyroidism, and hyperglycemia are the most common endocrine irAEs. Grade 3 or higher side effects are mostly due to hypoglycemia, adrenal insufficiency and Type 1 DM [25]. Approximately 40–50% of patients experience some change in thyroid function during therapy [46][48][49]. Subclinical hyperthyroidism occurs in 18%, overt hyperthyroidism in 12%, subclinical hypothyroidism in 5% and overt hypothyroidism in 3% of all cases [46]. A total of 7.7% of patients who develop persistent hypothyroidism require levothyroxine administration [48]. Onset of overt thyrotoxicosis occurred after a median of 5 weeks of the receipt of first cycle. Combination ICI therapy, female gender, and younger age were strongly associated with the development of overt thyrotoxicosis [46]. Intriguingly, even in real-world practice, ICI treatment-induced thyroid dysfunction was associated with better outcomes [50][51][52].
Immunotherapeutic monoclonal antibodies can damage healthy tissues directly, for example, anti-CTLA4 treatment directly damages the pituitary [53]. The incidence of hypophysitis is 1–18% in metastatic melanoma patients treated with anti-CTLA4, and 0.5–1.5% for PD-1 inhibitors [54][55]. However, the incidence can rise to up to 13% in the case of combination therapy [56][57]. There have also been cases of PD-1/PD-L1 therapy-induced diabetes (0.2%). Although uncommon, 81% of cases occurred with diabetic ketoacidosis and, unlike thyroiditis, all cases developed fully even with prednisolone usage [58]. Generally, endocrine side effects are always treated with hormone replacement and non-steroidal therapy after the acute phase [59].

2.5. Cardiovascular irAEs

Cardiovascular side effects of ICI therapy pose the greatest challenge to physicians and include myocarditis, pericardial disease, supraventricular arrhythmia, and vasculitis. Anti-PD1 antibodies can directly damage heart tissue, causing concomitant myositis and rhabdomyolysis and robust infiltration of macrophages and T cells [60][61][62][63]. A systematic review reported that the most frequent underlying biological mechanisms were the recruitment of CD4+ and CD8+ T cells, autoantibody-mediated cardiotoxicity and substantial inflammatory cytokine release [64]. Supraventricular arrhythmias are almost always associated with cardiac irAEs and are therefore thought to be secondary events [65]. In a review of several meta-analyses, myocarditis was found to be among the less common irAEs at about 1% prevalence, but has an extremely high mortality (27–46%) compared to others [66]. Risk factors include elderly age (70–80 years), male sex, ethnicity, and pre-existing autoimmune or cardiovascular disease [67][68]. Symptoms usually occur in the form of palpitations, dyspnea, and left ventricular pump dysfunction, as well as chest pain, hypotension, lower limb edema or heart block, but less specific symptoms such as fatigue, malaise, ptosis, diplopia, paresis, nausea, and vomiting can also dominate. In severe cases, hemodynamic instability, cardiogenic shock, and sudden death may happen [66][67].
Close cardiological monitoring and temporary drug suspension are considered in asymptomatic cardiac involvement due to asymptomatic arrhythmias or structural abnormalities of the myocardial wall. If symptoms are present, discontinuation of therapy is recommended, then, depending on improvement, restarting treatment can be considered [38]. If myocarditis is suspected, immediate hospital admission is necessary and high dose of corticosteroid should be administered as the first choice. In severe or life-threatening cases, pulsatile methylprednisolone at 1 g/day for 3–5 days is recommended and, in refractory cases, mycophenolate mofetil or tacrolimus should be used. If the patient has symptoms of chronic heart failure, β-blockers and ACE inhibitor/ATR2 antagonists are administered as treatment [66].

2.6. Musculoskeletal irAEs

Musculoskeletal side effects caused by PD-1/PD-L1 inhibitors occur in between 2 and 12% of cases, with around one in 15 patients requiring rheumatological treatment [69]. The most common presentations are arthralgia, inflammatory arthritis, sicca syndrome, myositis, vasculitis, and polymyalgia rheumatica. Treatment with NSAIDs is recommended for grade 1 arthritis, a low dose (10–20 mg/day) and a high dose (0.5–1 mg/kg/day) of prednisone is recommended for grade 2 and grade 3 arthritis, respectively, with the temporary discontinuation of therapy. Disease-modifying antirheumatic drugs (DMARDs) are recommended as steroid-sparing agents in steroid-resistant cases and for steroid reduction [70].

2.7. Neurological irAEs-Peripheral Nervous System

Neurological irAEs include involvement of the peripheral nervous system (PNS) and the neuromuscular unit and central nervous system afflictions. The most common manifestations of ICI-related peripheral neurological syndromes are myositis, myasthenia gravis (MG), and Guillain–Barré Syndrome (GBS). Immune-related myositis is a rare irAE and has been reported mainly in melanoma patients [71]. Its clinical symptoms differ significantly from those of idiopathic and paraneoplastic inflammatory myopathies such as dermatomyositis (DM) and polymyositis (PM) [72][73]. There have also been reports of dyspnea, dysarthria, and dysphonia. Despite this, the clinical pattern is very consistent, with myalgia being the most prevalent and early symptom, even in the absence of creatine kinase (CK) elevation [73].
ICI-related MG is a well-known neurological irAE that has been extensively documented in case reports and case series. This condition rarely arises without associated myositis, according to growing data [74]. Individuals suspected of having an irMG should receive a thorough evaluation that includes a CK, an electromyogram, and, if possible, a muscular MRI and a biopsy in order to discover associated myositis and alter treatment and follow-up. The presence of irMG and ir-myositis at the same time raises the likelihood of a myasthenic crisis, which may necessitate ventilator support and hospitalization in an intensive care unit. Bulbar symptoms, dysarthria, dysphagia, and dyspnea occur in 50% of the cases [75].
In terms of treatment regarding irMG and irMyositis, pyridostigmine is commonly used, but rarely as a singular therapy (3–9%). Often, immune modulatory treatment is required, either with steroid alone (27–45%) or in combination with immunoglobulin infusion and/or plasma exchange (50–63%) [76][77].
GBS is an uncommon complication among irAEs, occurring in around 0.1–0.3% of patients treated with ICIs [78][79][80]. However, according to an earlier meta-analysis, this peripheral neuropathy was more common (up to 3% for anti-PD-L1 drugs and 7% for anti-PD-1) [81]. In addition, a systemic evaluation of 86 patients treated with ipilimumab or pembrolizumab found that 23% had some form of demyelinating polyradiculoneuropathy [82]. Acute classical GBS begins with subtle paresthesia, followed by leg weakness, then arm, face and oropharyngeal weakness as it spreads proximally (ascending paralysis). Pain is prevalent, manifesting as bilateral sciatica or pain in the large muscles of the upper legs [83].

2.8. Neurological irAEs-Central Nervous System

The most common manifestations of CNS irAEs are encephalitis, meningitis [84][85] transverse myelitis [86][87][88] multiple sclerosis (MS)-like demyelination syndromes [89], vasculitis [90] and cranial neuropathies (CNDs) [91], however, myelitis, MS, vasculitis and CNDs are extremely rare irAEs and evidence of their presence is mainly based on case reports and case series.
The most common and severe irAEs with CNS involvement are aseptic meningitis and encephalitis. In cases of acute or subacute onset of headache, altered mental status, psychiatric symptoms, speech impairments, seizures or neurological deficits with/without fever, immune-related encephalitis (irEncephalitis) should be suspected and be differentiated from infectious encephalitis, CNS metastasis or metabolic encephalopathy [92]. According to Larkin and colleagues, irEncephalitis occurred in 0.16% of patients treated with ICI and accounted for 0.44% of all irAEs [84]. A total of 82% of encephalitis cases occurred alone without the manifestation of other irAEs [85]. The incidence of encephalitis is higher following anti-PD-1/PD-L1 treatment compared to after anti-CTLA-4 therapy and is more associated with combination therapy compared to monotherapy [93]. Given the high fatality rate of CNS irAEs (encephalitis, 6.3–12.8%, and meningitis, 7.4–8.3 [93][94] a prompt recognition of suspected patients is required and treatment with immune-modulating agents should start without delay. Diagnostic tests to confirm neurological irAEs include lumbar puncture, cytology, and tests for infectious diseases with neuroimaging.
irAEs often occur in a non-specific form that is difficult to diagnose and may onset several months after therapy [95]. In addition, the side effects that are more likely to cause death vary from drug to drug. In the case of CTLA-4 inhibitors colitis is more likely; in the case of PD-1/PDL1 inhibitors pneumonitis, hepatitis, and neurotoxicity are more likely; and in the case of combination therapy, colitis, and myocarditis are more likely [19]. Therefore, a complex multidisciplinary approach is essential in the clinical management of ICI treatment to prevent severe and life-threatening irAEs, including early monitoring or even prophylactic supportive care. 

3. The Biological Basis of irAEs in Anti-Cancer Immunotherapies

T cells are the most important players in the immune defense and play an equally important role in irAEs. Mechanisms by which T cells induce toxic effects are diverse and can be organ dependent but most commonly include an imbalance in the ratio of CD8+ and CD4+ cells [96]. Apart from activating tumor cell-specific T cells, systemically delivered ICI can activate previously inactivated self-recognizing T cells, which leads to autoimmune reactions [97]. Furthermore, an increase in cytokine and chemokine production can lead to inflammation, which can have adverse effects in that it promotes [98]. In many cases, ICI reduces regulatory T (Treg) cell proliferation and activity, abolishing T cell response regulation, and thereby increasing CD8+ T cells in the tumor peripheral area, which promotes autoimmune inflammation [99][100]. Treg cells further reduce the cytotoxic activity of T cells by hindering the function of antigen-presenting cells (APCs) and cause T cell exhaustion by an enhanced expression of anti-inflammatory IL-6 [101]. ICI causes diversification of the CD8+T cell repertoire [102] as an increase in highly proliferative and cytotoxic phenotype of CD8+T cells was observed in the colon of patients treated with anti-PD1 ICI. Similarly, an increase in CD8+T cell diversity was observed in patients receiving anti-CTLA4 therapy. This diverse repertoire of immunological actions could interestingly both benefit and harm the patient, as the combination of toxicity and benefits results from a complex and divergent pathway that converges at the diversification of T cells [54][96][103].
CD4+T cells are classified into different T helper types, namely Th1, Th2, Th17, and follicular T cells (Tfh). Both the IFN-γ-producing Th1 cells and IL-17-producing Th17 cells promote autoimmune reactions, leading to colitis, nephritis, liver damage, and skin complications [16]. Furthermore, patients receiving ICI often have a much higher Th17/Th1 cell ratio [104]. This increase in Th17 cells leads to increased inflammation and autoimmune adversities in patients [105]. Melanoma patients receiving anti-PD1 therapy demonstrated an increase in Th-1-mediated IL-6 production which led to severe colitis [106].
ICIs directly affect B cell function by reducing the number of circulating B cells while increasing the production of the CD21-low phenotype. These CD21-low B cells have high IFN-γ production that enhances immune response and might be responsible for B cell exhaustion [107]. B cells produce auto-antibodies in response to ICI against self-reactive T and B cells [108][109] which commonly damage the thyroid and islet cells of the pancreas leading to thyroiditis, hypothyroidism, and diabetes, respectively [50][110].
Other cells of the immune system also partake in irAEs directly or indirectly. Activated neutrophils promote T and B cell-mediated response and lead to distant inflammation and organ damage with their long-lasting effects [111][112]. Likewise, eosinophils promote irAEs by producing inflammation-promoting IL-17, which can elicit an inflammatory response; however, the effects mediated by eosinophils do not seriously affect patient survival [113]. NK cells are classically tumor suppressive; however, their functionality is altered in response to ICI in many cancers [114]. Either the NK cells become hyperactive and produce pro-inflammatory cytokines, or they modulate the immune functions of dendritic cells, T and B cells, and the epithelium, resulting in an exaggerated inflammatory response and damage to hepatocytes [115].
ICI treatment can induce macrophage activation and accumulation in patients with anti-PD1 treatment, which is translated to muscle weakness, atrophy, and myopathy [116]. In response to ICI, exhausted T cells release IFN-γ, which recruits monocyte-derived macrophages. These macrophages acquire cytotoxic abilities and are reported to damage the pancreas leading to diabetes [117]. Furthermore, with an active T cell response and Treg reduction, the infiltration of type 2 macrophages promotes further inflammation and leads to progressive organ damage [118]. In patients receiving ICI, activated monocytes were reported to promote liver inflammation, coagulation and fibrinolysis pathways, and hyperactivation of the innate immune system, leading to dermatitis [94][119][120].
Although the involvement of these immune cells in promoting irAEs is clinically evident, the mechanistic basis and potential cross-talks need further elucidation. Moreover, the role of other factors such as genetics, epigenetics, environment, and predisposition to autoimmune disease cannot be neglected. Equivalently, the gut microbiota is another contributing factor that can alter immune function by cross-reactivity, as an elevated level of microbial antibodies has been detected in ICI-receiving patients [121] which might result in the competition with self or tumor antigens or the recruitment and activation of immune cells [102]. Species of Bacteroides and Burkholderiales provide protection against irAEs; Bacteroides fragilis, for example, reduces irAEs by promoting Treg cell development and production of anti-inflammatory IL-10 [122]. On the contrary, high Firmicutes phylum can promote colitis in melanoma patients by supposedly sequestering Treg cells [123].
The mechanisms by which the immune system reacts to and regulates the effects of ICI are diverse and complex. Several pre-clinical and clinical trials are currently underway to identify specific antibodies, cytokines, and/or pathways to circumvent these mild to severe irAEs and improve the usability of ICI treatments worldwide [124]. Figure 2 shows the immune-modulatory role of ICI treatment in different immune cells.
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Figure 2. Immune modulatory role of immune cells in response to ICI blockade. Immunotherapy mediates the functional alteration of immune cells and the microbiome, leading to hyperactivation, reduced proliferation, self-cytotoxicity, autoantibody production and cross-reactivity. This complex modulation of the immune system facilitates a pro-inflammatory and autoreactive immune environment which translates to immunotherapy-related adverse events.

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