Immune Checkpoint Inhibitor-Related Myocarditis: Current Understanding and Potential Diagnostic and Therapeutic Strategies

Abstract

Introduction:

Myocarditis associated with immune checkpoint inhibitors presents with an often-severe clinical phenotype with arrhythmias and concurrent myositis. This condition tends to occur early after treatment onset and is associated with a high fatality rate. Diagnosis may be challenging, and treatment algorithms are still evolving.

Areas covered:

This review will provide an overview of immune checkpoint inhibitor mechanism of action and how it relates to myocarditis pathophysiology, diagnostic algorithms and potential pitfalls, and emerging treatment approaches published until May 2023. We will focus on the state of the field and potential new directions in research and patient care. We will also provide consensus based diagnostic and therapeutic algorithms endorsed by major societies.

Expert Opinion:

The field needs more evidence-based approaches to risk stratification so that therapy can be tailored towards less cardiotoxic alternatives in high-risk patients. For diagnostic and therapeutic approaches, data from animal models are unlikely to provide conclusive evidence given the complexity of the human immune system. We strongly invite practitioners in the field to contribute every case to the ongoing multi-center registries.

1. Introduction

Immune checkpoint inhibitors (ICI) have changed the outlook for many cancers with grim prognosis. ICIs are monoclonal antibodies that target immune cell receptors and ligands, namely CTLA-4, PD-1, and its ligand PD-L1, and LAG-3. These checkpoints promote immune-tolerance to cancer cells by attenuating the T-cell activation that should occur upon encountering tumor antigens. Ipilimumab, the first ICI to achieve FDA approval in 2011, was the only CTLA-4 targeting therapy in the US market until tremelimumab was approved in November 2022. These CTLA-4 inhibitors are now largely used in combination with either anti-PD-1 or anti-PD-L1. Anti-PD-1 directed agents include nivolumab, pembrolizumab, cemiplimab, and dostarlimab, whereas anti-PD-L1 therapies include atezolizumab, avelumab and durvalumab. In November 2022, another ICI class, the anti-LAG-3 relatlimab, was approved for use in conjunction with nivolumab in treatment of unresectable or metastatic melanoma [1]. As of March 2023, indications for ICIs include more than 20 cancer types (Table 1). ICIs are used as first or second line therapy, in adjuvant, and neo-adjuvant settings, alone or in combination with other ICIs, chemotherapy, targeted therapy, or radiotherapy [2]. These combination strategies have been shown to provide synergistic effects and decrease resistance, especially in metastatic melanoma, renal cell cancer, and microsatellite instability-high or mismatch repair deficient colon adenocarcinoma [3][4]. Therefore, a multidisciplinary approach should be developed individualized to the characteristics of the tumor and risk factors in a given patient.

Table 1.

Types of Immune Checkpoint Inhibitors and their Indications

Targeted Immune Checkpoint	Anti-CTLA-4		Anti-PD-1				Anti-PD-L1			Anti-LAG-3
Indicated Cancer Types	Ipilimumab in combination with Nivolumab	Tremelimumab in combination with Durvalumab	Pembrolizumab	Nivolumab	Cemiplimab	Dostarlimab	Atezolizumab	Avelumab	Durvalumab	Relatlimab in combination with Nivolumab
Melanoma	X		X	X			X			X
RCC	X		X	X				X
CRC	X		X	X
HCC	X	X	X	X			X		X
NSCLC	X	X	X	X			X		X
PM	X			X
SCLC			X	X			X		X
HNSCC			X	X
cHL			X	X
PMBCL			X
Urothelial Ca			X	X			X	X	X
Gastric Ca			X	X
Esophageal Ca			X	X
Cervical Ca			X
MCC			X					X
Endometrial			X			X
cSCC			X		X
TNBC			X				X
Sarcoma							X
BTC					X				X
BCC					X
Ovarian Ca	X
Prostate Ca	X

RCC: Renal cell carcinoma; CRC: Colorectal cancer; HCC: Hepatocellular carcinoma; NSCLC: Non-small cell lung cancer; PM: Pleural mesothelioma; SCLC: Small cell lung cancer; HNSCC: Head and neck squamous cell carcinoma; cHL: Classical Hodgkin’s lymphoma; PMBCL: Primary mediastinal large B-cell lymphoma; MCC: Merkel cell carcinoma; cSCC: Cutaneous Squamous Cell Carcinoma; TNBC: Triple-Negative Breast Cancer; BTC: Biliary tract cancer; BCC: Basal cell carcinoma

2. How do immune checkpoint inhibitors work?

T-cells are the major players in anti-cancer immune response. Self-tolerance mechanisms during development and later life ensure appropriate T-cell activation. After T-cells mature in the thymus during development, they move to secondary lymphoid organs (spleen, lymph nodes, mucosal lymphoid tissue) as naïve T-cells that need priming. Priming occurs when an antigen is presented to the T-cell receptor (TCR) by antigen presenting cells (APC) [5]. To limit autoimmunity, priming also requires co-stimulatory signals through binding of co-stimulatory ligands, CD80 (B7–1) and CD86 (B7–2) on APCs to the co-stimulatory receptors that are constitutively present on T-cells (CD28). Once primed, the T-cells exert effector functions (secreting cytokines by CD4+ helper T-cells and killing target cells by CD+8 cytotoxic T-cells) in the periphery when they encounter their specific antigens [5]. Effector T-cells must separate self from foreign antigens; this could develop in the thymus by negative selection during T-cell maturation [6] or in the periphery [7]. One mechanism for peripheral tolerance is decreased expression of co-stimulatory receptors on T-cells or decreased co-stimulatory ligands on APCs for weak antigens (those with low degree of “foreignness”) such as in cancer [8]. Another mechanism is through upregulation of co-inhibitory receptors such as CTLA-4 and PD-1 on T-cells [7]. These receptors which render antigen-specific T-cells functionally unresponsive are known as immune checkpoints. CTLA-4 is homologous to CD28 and bind to CD80/86 albeit with a higher affinity and results in the opposite effect, T-cell inhibition [9]. PD-1, on the other hand, does not interfere with co-stimulation, but inhibits T-cell effector functions by suppressing T-cell receptor signaling. Its ligands PD-L1 and PD-L2 are expressed on many cell types including cancer cells and engage with PD-1 when upregulated on T-cells upon TCR engagement of [9]. The blocking of CTLA-4 is more proximal and occurs in the lymph node causing global disinhibition of the immune response, whereas blockage of the PD-1 and PD-L1 exerts its effects within the tumor microenvironment where the tumor cells and T-cells interact. The more central the disinhibition is, the more likely it is to develop irAEs outside of the tumor microenvironment which explains the increased cardiotoxicities seen with combined ICI regimens. Immune checkpoint inhibitors are monoclonal antibodies that exhibit anti-tumor effects by blocking the immune evasion brought on by these co-inhibitory receptors, CTLA-4, PD-1 and PD-L1.

2.1. Anti-CTLA-4 antibodies:

CTLA-4 was discovered due to its amino acid similarity to the CD28 and was shown to oppose the effects of CD28 [10]. Similar to CD28, CTLA-4 recognizes C80/86 expressed on APCs but remains sequestered in intracellular vesicles until T-cell activation [11]. On the contrary, CTLA-4 is constitutively expressed in regulatory T-cells (Treg) that are required for self-tolerance [12]. One of the ways Tregs induce immune tolerance is by transendocytosis of CD80/86 on APCs through CTLA-4 engagement [13]. Genetic or functional defects on pathways ablating the CTLA-4 function in Tregs result in autoimmunity similar to the autoimmune activation observed in patients who receive anti-CTLA-4 therapy [14]. Upon binding of ipilimumab to Tregs on the Fab domain and to myeloid and NK cells on the Fc domain, Tregs are depleted. The effector T-cells in the tumor also express increased amount of CTLA-4, a marker of chronic stimulation. Binding of ipilimumab to cytotoxic effector T-cells (Teff) results in activation of the effector T-cell through engagement of APCs via the Fc domain of ipilimumab. Therefore, the net result in the tumor upon treatment with ipilimumab is an increased Teff/Treg ratio [15,16].

2.2. Anti-PD1/PD-L1 antibodies:

In 1996, Nobel laureate Honjo and colleagues reported a protein that was induced on T- and B-cells upon antigen receptor stimulation [17]. Subsequently the same group reported that PD-1 deficient mice showed augmented T-cell proliferation upon stimulation and cardiomyopathy mediated by cardiac troponin 1 autoantibody [18,19]. PD-L1, a homologue of CD80/86 was then identified as the ligand for PD-1 and together they played a role in T-cell inhibition [20]. Chen and colleagues then showed that PD-L1 was expressed on a variety of human cancer cells and their expression enabled tumor survival through increased apoptosis of T-cells [21]. This paved the way for development of anti-PD-1 and PD-L1 antibodies as cancer immunotherapies [22]. It is now well established that blocking PD-1 restores cytotoxic activity of CD8 T-cells against tumor cells and that tumor-specific PD-L1 expression correlates with immunotherapy response [23]. PD-1, as well as PD-L1 and PD-L2, are also expressed on tumor resident macrophages and dendritic cells which support tumor growth. Therefore, blocking PD-1 and its ligands may also result in decreased tumor growth, independent of T-cell activation, by increased tumor-infiltrating macrophage activity [24,25]. As noted, combination PD-1/CTLA-4 blockade, and PD-1/LAG-3 blockade are approved in numerous cancers and improve survival compared with monotherapy [26–32]. ICIs are commonly combined with traditional chemotherapy, targeted therapies such as VEGF inhibitors or tyrosine kinase inhibitors, and radiotherapy, and routinely used in numerous cancers [2].

3. Immune Related Adverse Effects

Given that ICIs are used to overcome immune self-tolerance, autoimmune-like events known as immune-related adverse effects (irAEs) may complicate therapy. These irAEs can be acute or chronic and can involve almost any organ, most commonly skin, thyroid, colon, lungs, and liver (i.e., those with environmental interfaces or high rates of autoimmunity) [2,33]. Overall, the most common irAE involves the skin and occur in up to 30% of patients, followed by colitis and endocrine dysfunction [34]. Immune-related adverse events can be fatal in 0.4–1.2% of the patients [35]. The most common fatal irAE is colitis (70% of all fatal irAEs) with a mortality of 2–5% and whereas the irAE with the highest fatality is myocarditis with a mortality of 40% [35]. Therefore, clinical vigilance and early diagnosis are of paramount significance to be able to decrease mortality with timely treatment. Moreover, recently, data have suggested that ICIs could alter the natural course of other immune mediated diseases such as atherosclerosis, hepatic steatosis, or hypertension [36–39]. Specifically, [anonymised]et al. showed in melanoma treated with the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab as combination therapy, systolic blood pressure (BP) increased by 5.5 mmHg, while there were no statistically significant changes in systolic BP or diastolic BP in patients treated with the PD-1 blockers alone [34]. Park et al. showed decreases in liver enzymes in patients with pre-existing steatosis/steatohepatitis [36]. Finally, very recently, [anonymised]et al. showed decreased volume of calcification in aortic atherosclerotic plaques after ICI therapy [37].

4. ICI Myocarditis

4.1. Epidemiology

ICI myocarditis occurs in up to 0.3–1.4% of the cases treated with ICIs [40,41]. However, the true incidence is difficult to define due to distinctive methodologies for screening, reporting, and diagnoses. The incidence we quote is mostly based on post-marketing surveillance studies and registries which started accumulating after anonymized et al. published the first two cases of ICI myocarditis [40]. Moreover, cases of subacute or smoldering myocarditis are recently reported [42,43]. These milder forms may be reported to the registries not as myocarditis but as demand ischemia since low-level troponin elevations are frequently seen with comorbidities such as anemia, atrial fibrillation, hypotension, sepsis, obstructive coronary artery disease that are common in cancer patients either due to shared risk factors or cancer treatment [44]. ICI myocarditis seems to have a male preference, with largest cohort studies reporting a 67–71% of male preponderance [41][45–47]. Older age appears to be more commonly represented with 65–67 years of age being the most commonly reported mean age [45–47]. However, the population of patients with cancer also tends to skew towards older and male.

4.2. Risk Factors

Based on reported myocarditis cases, combination ICI is a more frequent culprit compared to ICI monotherapy. In their disease defining paper, anonymized et al. found that the relative risk of myocarditis in those who received ipilimumab and nivolumab combination compared to nivolumab alone was 4.5 [40]. Similarly, a study using the World Health Organization’s (WHO) pharmacovigilance database (VigiBase) found a reporting odds ratio of 4.3 for combined therapy as opposed to monotherapy [45]. As explained above, this could be due to more central and robust inhibition of immune-tolerance when anti-CTLA-4 antibodies are added to anti-PD-(L)1. In addition to these observational studies, more recently a randomized clinical trial of nivolumab vs nivolumab with relatlimab 0.6% vs. 1.7% [48]. Most commonly reported risk factors in comparison with controls, appear to be diabetes mellitus, hypertension, and smoking [41,45–47]. However, Zhang et al found that 28% of their cohort of 103 patients had no identifiable any risk factors [47]. Thus, identifying a high-risk population remains challenging. In the most recent European Society of Cardio-Oncology Guidelines, high-risk patients for ICI myocarditis were defined as those who will undergo combination ICI therapy, regimens combined with other cardiotoxic therapies, patients with baseline cardiovascular disease, and patients with ICI-related non-CV events or prior cancer therapy related cardiotoxicity (due to anthracyclines, HER-2 targeted therapies, VEGF, BCR-ABL, RAF and MAK inhibitors) [49].

4.3. Pathophysiology:

Axelrod et al. recently published an elegant study elucidating the pathophysiological basis for myocarditis. Authors sequenced the RNA and T-cell receptors of the T-cells infiltrating the myocardium in a genetically engineered mouse model of ICI myocarditis. These T-cells were clonally expanded effector CD8+ T cells that were capable of inducing myocarditis upon adoptive transfer to healthy mice. The cardiac-specific protein α-myosin was identified as the recognized antigen in mice with fulminant myocarditis [50]. Axelrod’s study also tested relevance of α-myosin as a potential autoantigen in 3 patients with histologically proven ICI myocarditis. They found that α-myosin specific T-cell receptors were expanded in the diseased heart and skeletal muscles of these patients. Gergely et al. provided an alternative explanation for the pathologic basis of myocarditis. They treated C57BL6J mice with anti-PD1 antibody and found that 9 genes related to cardiac structure, signaling and inflammation were differentially regulated. The changes in expression were induced increased IL-17A signaling in thymus and myocarditis was prevented by pharmacological inhibition of IL-17 [51].

4.4. Timing and Clinical Presentation

Myocarditis, like other irAEs, generally occurs within the first several weeks of therapy initiation. Median time of onset appears to be 27–34 days after starting ICI (inter-quartile range: 18 to 75 days) [41,45]. However, irAEs can present with delayed onset including after cessation of therapy [52,53]. Recently, Nguyen et al. reported a case of autopsy diagnosed ICI myocarditis that developed 141 weeks after initiating ICI and 33 weeks after drug discontinuation [54]. Late occurrences of irAEs are increasingly being recognized and may be clinically distinct: late onset cases more often have heart failure whereas early cases have higher incidence of arrhythmias [46]. This delayed heart failure could reflect remodeling in the setting of smoldering inflammation and has important implications in long term monitoring as the mortality rate remains similarly high in early and late onset cases [46].The clinical presentation of ICI myocarditis is variable and could depend on the time of onset after ICI initiation. Dolladille et al. reported late onset cases (median time to onset 304 days from start of ICI) presented with HF symptoms 50% of the time vs. 5% in early onset cases (median time to onset of 14 days from start of ICI). Presentation with arrhythmias showed an opposite distribution [46]. Arrhythmias could present with tachyarrhythmia or bradyarrhythmia ranging from SVT and VT to CHB [46,55,56]. Overall, the most common presenting symptoms appear to be shortness of breath in 55–68%, palpitations in 5–33%, and chest pain in 13–28% [41,46][47]. The presence of LV systolic dysfunction appears to increase in late onset cases; one series reported 37% and 74% of early-onset and late-onset cases, respectively, had LV dysfunction explaining higher occurrence of heart failure symptoms in later presenting cases. Patients can also present with vague symptoms such as fatigue or weakness [57]. Suzuki et al found that 33% and 25% co-occurrence of myositis and myocarditis in their cohort of patients with nivolumab induced myasthenia like syndrome [58]; therefore, it is important to consider myocarditis even with non-specific symptoms. Lastly, myocarditis may be diagnosed incidentally during routine troponin surveillance in the absence of symptoms [59]. Heightened suspicion and early diagnosis are of utmost significance as the mortality is in the range of 30–50% [41,45,46][60][61].

4.5. Diagnosis

The Society of Immunotherapy in Cancer (SITC), European Society of Medical Oncology (ESMO), and the recent European Society of Cardiology (ESC) guidelines recommend obtaining baseline basic cardiac biomarkers such as troponin I, BNP, ECG [57] [62][49] prior to ICI start to develop an accurate baseline for comparison, whereas American Society of Clinical oncology (ASCO) guidelines do not; stating “there is no clear evidence regarding the efficacy or value of routine ECGs or troponin measurements in patients receiving checkpoint inhibitor therapy” [63]. We believe obtaining a baseline level of cardiac biomarkers is important for future diagnostic evaluation. ESC Guidelines also recommend obtaining a baseline echocardiogram in high-risk patients as defined under the section on risk factors. As for diagnostic tests, Mahmood et al. reported troponin was the most sensitive biomarker of myocarditis, followed by ECG abnormalities in a cohort of 35 cases, with sensitivity of 94% and 89%, respectively [41]. In a cohort of 101 myocarditis patients, Awadalla et al. reported 98% had elevated troponin. Though BNP is likely non-specific, the incidence of elevated BNP was significantly higher in myocarditis compared with controls who received ICI without myocarditis [64]. On the contrary, troponin was elevated only in 63% of early-onset and 50% of late-onset myocarditis in a separate cohort of 37 cases [46]. Similarly, ECG abnormalities were also lower at 50% and 55% in the cohorts of Dolladille et al. [46] and Zhang et al. [47], respectively. Notably, 50–60% of patients had a normal left ventricular ejection fraction (LVEF) both by echocardiogram and by MRI [41,47]. The ECHO modality of global longitudinal strain has long been utilized as a sensitive marker of cardiotoxicity in patients receiving cardiotoxic chemotherapy or targeted therapy [49]. Awadalla et al. investigated the utility of strain in 101 ICI myocarditis cases [64]. They saw a mean 14.1 ± 2.8% decrease in strain in myocarditis cases from pre-ICI ECHO to that done during ICI myocarditis, a decrease not observed in age, sex and cancer type matched controls. The significant decrease in strain was present in both decreased-LVEF and preserved-LVEF cases and predicted major adverse cardiovascular events (MACE) in both groups. Cardiac MRI is the gold standard for non-invasive tissue characterization in cases of myocarditis [65]. Zhang et al. investigated its diagnostic value in 103 myocarditis patients in 56 of whom, myocarditis diagnosis was confirmed by endomyocardial biopsy, and by ESC diagnostic criteria in the rest [47][66]. Late gadolinium enhancement (LGE) was present in 48% of cases, with similar rates in both preserved LVEF and reduced LVEF groups. LGE had varying patterns, most commonly midmyocardial (49%), subepicardial (27%) and diffuse (18%) enhancement. Of note, when MRI was performed after four days of admission, its sensitivity increased to 72% compared with 22% when done within the first four days of admission [47]. Moreover, LGE presence did not predict occurrence of major adverse cardiac events of cardiogenic shock, cardiac arrest, or complete heart block. Thus, neither normal LVEF nor absence of LGE rule out ICI myocarditis, a condition for which timely treatment is of paramount importance. Regardless, a repeat MRI in a few days can increase the diagnostic yield in uncertain clinical cases. Recently, Thavendiranathan et al. reported the results of MRI parametric mapping in 31 biopsy proven ICI myocarditis patients. Presence of non-ischemic myocardial injury by abnormal T1 mapping, myocardial extracellular volume fraction (ECV) or LGE was present in all patients and 63% had myocardial edema by T2 mapping or T2 weighted images [67]. Another non-invasive diagnostic tool, PET-CT, has a limited role in diagnosing ICI myocarditis. A recent study by Ederhy et al. showed that ¹⁸F-fluorodeoxyglucose PET/CT was positive only in 2 of 21 (9.5%) of patients with definite myocarditis [68,69]. Molecular PET imaging merits future attention. In a recent small study, PET-CT with ⁶⁸Ga-DOTATOC (radio-tagged somatostatin analogue) was shown to be a sensitive diagnostic method for ICI myocarditis [70]. Endomyocardial biopsy is indicated in patients presenting with acute cardiogenic shock in the absence of coronary artery disease [71]. It is also frequently considered in suspected cases of myocarditis in the absence of hemodynamic instability. Even though endomyocardial biopsy has been considered the gold standard for diagnosis of myocarditis and has a relatively low complication rate of about ~1% [71], its sensitivity in ICI myocarditis is limited due to the patchy nature of the disease [72][73]. Nevertheless, it should be considered when hemodynamic instability or non-MRI compatible implants preclude performing non-invasive testing. To summarize the diagnostic modalities with the most comprehensive and up-to-date guidelines on the subject, the ESC Guidelines [49], echocardiogram and cardiac-MRI (CMR) with parametric mapping are recommended in all patients with suspected ICI myocarditis. Although it has lower sensitivity, cardiac-PET may be considered if CMR is not available or contraindicated, and endomyocardial biopsy (EMB) should be considered in cases where the diagnosis is suspected but not confirmed non-invasively. The field most commonly follows the consensus criteria initially developed by Bonaca et al. to adjudicate the probability of ICI myocarditis [68]. This set of criteria was also presented by the ESC in their 2022 Guidelines (Figure 2)[49].

Figure 2.

Diagnostic Criteria for ICI Myocarditis Adapted from Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology [48]

4.6. Co-occurring irAEs

Other irAEs frequently accompany myocarditis. Pharmacovigilance studies have reported that one-half to two-thirds of patients with ICI-myocarditis have accompanying irAEs [45,64]. Of the accompanying irAEs, most common was myositis in 25%, followed by pneumonitis in 11–29%, then colitis in 7–10%. Interestingly, myasthenia gravis was reported 11% of the time concurrently with myocarditis [45]. In another study looking at 62 myositis cases in VigiBase, 16% presented with myocarditis and 16% with myasthenia gravis-like symptoms, whereas both myocarditis and myasthenia gravis–like symptoms occurred in 3.3% of those with myositis [74]. Myositis can accompany myocarditis or precede it. Myositis mainly presents as weakness of the proximal extremities as commonly encountered in other autoimmune myopathies. It can involve the diaphragm resulting in respiratory complications and can also present as myasthenia gravis. In a recent study, Aldrich et al. reported that more than half of ICI myocarditis patients had accompanying myasthenia graves or myocarditis. These patients tended to have worse prognosis with 79% of them developing respiratory failure [75]. The common occurrence of distinct myotoxic phenotypes points to a shared antigen between skeletal and cardiac muscle and should prompt work up for myocarditis [50]. It is notable that endocrine and skin irAEs, the most common irAEs in general, do not commonly co-occur with myocarditis (co-occurrence 5% and 2–6%, respectively).

4.7. Other CV irAEs

Pharmacovigilance studies have also suggested that ICIs are associated with other cardiovascular adverse events besides myocarditis (Reporting Odds Ratios (ROR) for myocarditis 11.2, pericardial disease 3.8, supraventricular arrhythmias 1.7, vasculitis 1.6, where the confidence intervals of all of these excluded the null value). Amongst these cardiovascular irAEs, only myocarditis had increased ROR for combination therapy compared with monotherapy [45]. It is important to note that these data are from registries, and these CV irAEs could be occurring secondary to myocarditis. There have also been case reports of ICI induced pericardial effusion, acute coronary syndrome, and takotsubo like syndrome [76][77–81].

4.8. Treatment

The first step in treatment in all suspected ICI myocarditis cases interruption of ICI treatment while diagnostic work-up is underway. This is endorsed by all society guidelines. Corticosteroids are the first line treatment for irAEs including myocarditis [57]. ESC and ESMO Guidelines recommend immediate initiation of high dose corticosteroids (methylprednisolone 500–1000 mg IV daily) for the first 3–5 days or until clinical improvement starting from when the diagnosis is considered likely. Clinical improvement is defined as troponin reduction by >50% from its peak level within 24–72 hours and resolution of ventricular dysfunction, AV block, and arrhythmias resolved. Switching to oral prednisolone is recommended after clinical improvement, starting at 1 mg/kg up to 80 mg/day and tapering it 10 mg per week under biomarker and clinical surveillance [49][62]. SITC and ASCO both recommend high-dose corticosteroids (1 mg/kg methylprednisolone IV or 2 mg/kg prednisone) in cases of confirmed myocarditis (and in those with high clinical suspicion) until resolution or significant improvement of symptoms followed by tapering for at least 4–5 weeks [82][63]. It is important to note that even though early initiation of high dose steroids has the highest recommendation (Class I) by all society guidelines, the strength of evidence beyond this recommendation is low and based on expert consensus of opinion and a case series by Zhang et al. These investigators reported a 67% decreased adjusted risk of adverse events in patients who received more than 500 mg/day methylprednisolone compared with those who had less than 60 mg/day. Moreover, patients who received corticosteroids within 24 hours had a hazard ratio of 0.3 for MACE compared with those who received steroids after 24 hours of presentation [60]. In cases where clinical and biomarker improvement with steroids is not observed, additional therapies with anecdotal evidence of efficacy could be utilized. These include tocilizumab (an IL-6 inhibitor), alemtuzumab (a CD52 antibody), anti-thymocyte immunoglobulin, and mycophenolate mofetil [83,84][85,86]. Recently abatacept, a soluble fusion protein containing the human CTLA-4 extracellular domain and Fc portion of IgG antibody was reported as an efficacious treatment option [87]. Abatacept competes with CD28 in binding to CD80/86, and thus limits costimulatory signals upstream of CTLA-4 and PD-(L)1 [88]. Salem et al. reported an impressive mortality reduction to 3.4% in Grade ≥ 3 ICI myocarditis (Table 2) patients who were treated with a combination of low dose steroids, abatacept titrated to CD86 receptor occupancy, and ruxolitinib, a JAK1/JAK2 inhibitor which shows rapid synergistic effects with abatacept by decreasing CD86 expression on APCs and impairs T-cell activation [87].

Table 2.

Common Terminology Criteria for Adverse Events Myocarditis (Version 5, 2017)

Grade 1 Myocarditis	N/A
Grade 2 Myocarditis	Symptoms with moderate activity or exertion
Grade 3 Myocarditis	Severe with symptoms at rest or with minimal activity or exertion; intervention indicated; new onset of symptoms
Grade 4 Myocarditis	Life-threatening consequences: urgent intervention indicated (e.g., continuous IV therapy or mechanical hemodynamic support)
Grade 5 Myocarditis	Death

4.9. Rechallenge

The decision to rechallenge requires a multidisciplinary discussion. Since each case is unique in terms of irAE presentation, alternative cancer treatment options, indication for therapy (metastatic vs. (neo)adjuvant), a treatment plan should be devised specific to the patient’s needs by the treating cardiologist and oncologist. There is sparse evidence in the literature on rechallenge. An examination of VigiBase found a 28.8% recurrence rate of the same irAE after rechallenging with the same ICI; however, myocarditis was underrepresented with three cases who received rechallenge without recurrence of myocarditis [89]. In a NSCLC cohort of 38 patients who were rechallenged after stopping treatment due to irAEs, 48% patients had no subsequent irAEs, 26% had recurrence of the initial irAE, and 26% had a new irAE; the recurrence of irAE did not differ between those who had the same combination and those switched to monotherapy [90]. All recurrent irAEs in this cohort were mild (grade 1–2) and did not include myocarditis. The data on myocarditis and ICI rechallenge is scarce. Hasson et al. reported a case series of three patients with myocarditis who were rechallenged with ICI with concomitant low dose steroids and weekly troponin follow-up. Two patients who initially had ≤ grade 2 myocarditis were successfully rechallenged without recurrence of symptoms. The third patient who had grade 3 myocarditis had reappearance of symptoms upon rechallenge and therapy was stopped after the first cycle of reintroduction [91]. Similarly, another patient with grade 3 myocarditis was rechallenged after resolution of symptoms with steroids, however his myocarditis also recurred after reintroduction [92]. The decision to restart ICI treatment in patients who developed myocarditis is difficult and depends on the availability of alternative treatments, feasibility of frequent monitoring, the overall status of the cancer, and the rapidity of onset of myocarditis after treatment initiation. The initial severity of myocarditis also plays an important role in deciding whom to rechallenge.

5. Expert Opinion

ICIs brought impressive advances in cancer survival; however, uncommon cases of cardiotoxicity come with high morbidity and mortality. While vigilance have increased amongst cardiology and oncology communities, further understanding of risk factors, surveillance methods and development of reliable diagnostic modalities are needed. We follow a strict initial risk assessment and surveillance regimen comprised of baseline ECG, BNP and troponin evaluation prior to start of therapy and then before each dose for the following three cycles and thereafter every 3 months. We also perform a baseline echocardiogram in every patient who is considered to be more than intermediate risk per the American College of Cardiology/American heart Association pooled cohort equation. Any suspected myocarditis patient gets admitted to the inpatient service immediately for expedited diagnostic work-up and monitoring. At our centers we are lucky to have the capacity for CMR with parametric mapping which we utilize as initial imaging modality. If this is not feasible due to contraindications, we default to echocardiogram and endomyocardial biopsy. We initiate steroids early at a high dose as recommended by all society guidelines. We have utilized abatacept successfully in two cases of steroid-refractory myocarditis. In selection of cases for re-challenge, we consider those with low levels of troponin elevation, no malignant arrhythmia, heart failure, LV dysfunction for rechallenge under close surveillance with troponin, serial ECGs, and mobile cardiac telemetry.

Admittedly, the field needs more evidence-based approaches to risk stratification so that therapy can be tailored towards less cardiotoxic alternatives. Data from animal models are unlikely to provide conclusive evidence since these do not fully capture the complexity of the human immune system. Multicenter registries are in place to provide clinical data and biospecimens for future -omics research. These registries would also provide us with clues on the best strategy to treat steroid resistant cases. Society guidelines recommend steroids as first line therapy based on evidence from the transplant literature, however we still lack mechanism driven treatment approaches. Moreover, we do not yet know if targeted inhibition of the culprit immune system should be preferred over the very high dose steroids in treatment of cardiotoxicities so as to not affect the overall cancer survival. There is an ongoing study (ATRIUM Trial: NCT05335928) that will provide an answer on this for abatacept. We need trials on other emerging therapies such as JAK1/JAK2 inhibitors or IL-17 inhibitors. Finally, we do not have clear evidence on long term consequences of acute cardiac irAEs which points to the need to develop well designed and funded prospective registries.

Figure 1.

Schematic of T-cell activation and exhaustion Naïve T-cells are primed through a two-signal process. The first signal requires antigen binding to the T-cell receptor (TCR) and the second signal is provided by the binding of activated antigen presenting cell (APC) ligands CD80 and 86 (also called B7–1 and B7–2) to CD28 on the T-cell. However, when the stimulation becomes chronic, the antigen-specific T-cells become exhausted and functionally unresponsive via upregulation of immune checkpoints CTLA-4 and PD-1. In the tumor tissue, cytotoxic T-cell function occurs when the TCR re-encounters the antigen for which it was primed. However, chronic stimulation induces expression of PD-1 on the exhausted T-cell. Many cancer cells express PD-L1. Engagement of PD-1 and PD-L1 results in suppression of the effector T-cell activity. Immune checkpoint inhibitors are monoclonal antibodies which attenuate these negative regulators of activation. Mφ: Macrophage; MHC: Major histocompatibility complex; _exTcell: Exhausted T-cell; Ca: Cancer cell.

Article Highlights:

• Although it is rare, myocarditis is the most fatal complication of ICI therapy with a mortality of 40%.

• It is essential to identify high-risk patients and provide close surveillance. These patients include those with baseline CV disease, those receiving combination ICI therapy or other cardiotoxic therapies concurrently, and those with prior cancer therapy related cardiotoxicity.

• If you suspect ICI myocarditis, admit the patient to a closely monitored bed. Hold ICIs. Keep in mind that the patient may have both acute coronary syndrome and myocarditis. Keep in mind that myositis, myasthenia gravis, and myocarditis can co-occur.

• Initiate the diagnostic work-up with biomarkers, parametric CMR or endomyocardial biopsy. Start high-dose steroids when the diagnosis is considered likely.

• In cases where clinical and biomarker improvement with steroids is not observed, consider additional immunosupressive therapies.