Immune Checkpoint Inhibitor Cardiotoxicity

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Introduction

This executive summary outlines the key points and arguments presented by Nicolas Palaskas, M.D., M.P.H., an associate professor in the department of cardiology at MD Anderson Cancer Center and co-director for the Calf Lab there. The presentation focuses on immune checkpoint inhibitor (ICI) cardiotoxicity, specifically ICI-induced myocarditis.

Background and Significance of ICI Therapy

Immune checkpoint inhibitors represent a paradigm shift in cancer treatment. They work by unleashing T-cells to attack tumor cells by blocking checkpoint receptors that tumor cells use to evade immune surveillance. The discovery of CTLA4 and PD1 receptors and the development of inhibitors against them (e.g., ipilimumab, nivolumab) have significantly improved prognosis for patients with various malignancies, including melanoma, lung cancers, and renal cell carcinomas. These therapies are now being used in earlier stages of cancer.

ICI-Induced Cardiotoxicity

Despite their success in oncology, ICIs can cause cardiotoxicity. This cardiotoxicity is broadly divided into early cardiovascular (CV) events (within 90 days), such as myocarditis, pericarditis, and pericardial effusions, and late CV events (beyond 90 days), the immune-related nature of which is still under investigation. Dr. Palaskas' presentation primarily focuses on the toxicity of immune checkpoint inhibitors, specifically ICI-induced myocarditis.

ICI-Induced Myocarditis

• Epidemiology and Clinical Presentation: ICI-induced myocarditis is rare, with an incidence of about 1%, but it is the most fatal of the immune-related adverse events (irAEs), with mortality rates up to 50%. The symptoms are often non-specific, with fatigue being the most common. Overlap with other organ system irAEs, particularly neuromuscular involvement like myositis, myasthenia gravis, and Guillain-Barré syndrome, is common.
• Proposed Pathophysiology: The proposed mechanism involves shared antigens or molecular mimicry, where T-cells activated against tumor antigens mistakenly attack similar structures in the myocardium. Studies on fatal cases showed the same T-cell clones in the myocardium, skeletal muscle, and tumor. CD8 cytotoxic T-cells are thought to be the main drivers of this disease. Mouse models, particularly PD1 knockout haploinsufficient CTLA4 mice, recapitulate human ICI myocarditis with fulminant myocarditis, AV blocks, and similar histopathological infiltrates. Research in these mouse models identified activated CD8 T-cells expressing interferon-gamma and granzyme B as key players. Alpha-myosin heavy chain (MYH6) has been identified as a potential shared antigen. Spatial transcriptomics on human cardiac and skeletal muscle biopsies from patients with ICI toxicity showed similar infiltrates of CD8 effector T-cells and myeloid populations. Increased expression of IL-1 beta and TNF-positive myeloid cells was associated with unfavorable outcomes.
• Risk Factors: The main established risk factor is combination immune checkpoint inhibitor therapy (e.g., CTLA4 and PD1 inhibitors). There is mixed evidence for a role of prior cardiotoxic cancer therapies and pre-existing cardiovascular disease.

Diagnosis of ICI-Induced Myocarditis

Diagnosing ICI-induced myocarditis is very challenging. Various societies (ASCO, SITC, NCCN, ESC) have slightly differing diagnostic criteria. The ESC guidelines are considered the most updated, involving a pathohistologic diagnosis (based on endomyocardial biopsy) and a clinical diagnosis (troponin elevation plus major or minor criteria).

• Troponins: While troponin elevation is a key diagnostic criterion, it can be non-specific. Troponin I is generally preferred over troponin T due to less likelihood of elevation from skeletal muscle injury, which is common in ICI toxicity with overlapping myositis. However, troponin T still has prognostic value. Surveillance with troponins in all patients starting ICIs has a low positive predictive value due to the rarity of myocarditis. MD Anderson is conducting a randomized controlled trial comparing troponin surveillance with standard of care.
• Electrocardiogram (ECG): ECG findings are non-specific but can include increased heart rate, QRS duration, PVCs, bundle branch blocks, and repolarization abnormalities. Increased PR interval (AV block) is a concerning finding. Notably, complete heart block in ICI myocarditis can be reversible with immunosuppressive therapy.
• Echocardiography: Unlike viral myocarditis where low ejection fraction (EF) is common, most patients with ICI myocarditis present with normal EF. However, these patients still have a similar risk of major adverse cardiovascular events as those with low EF. Global longitudinal strain (GLS) on echocardiography has shown promise as an independent predictor of outcomes.
• Cardiac Magnetic Resonance (CMR): CMR is the best non-invasive tool for diagnosing myocarditis but has limitations in ICI myocarditis. The modified Lake Louise criteria, highly sensitive and specific for non-ICI myocarditis, have lower sensitivity and specificity (around 50%) in ICI myocarditis. Late gadolinium enhancement (LGE) in the septal wall and elevated T1 times have been associated with worse prognosis.
• Positron Emission Tomography (PET): Current commercially available PET tracers like FDG have significant logistical and diagnostic limitations in ICI myocarditis due to dietary restrictions and interference from steroid treatment. Novel PET tracers targeting CD8 T-cells show promise as they have no baseline uptake in the myocardium and do not require extensive dietary preparation.
• Endomyocardial Biopsy: Endomyocardial biopsy is often necessary for a definitive diagnosis, especially given the limitations of non-invasive imaging. It requires experienced centers and pathologists familiar with the histopathological findings of ICI myocarditis, which can resemble viral myocarditis and transplant rejection. The Dallas criteria (inflammatory infiltrate and myocyte necrosis) are used, but patchy involvement necessitates multiple samples (at least five) to avoid sampling error. Some patients may present with inflammatory infiltrate without myocyte necrosis (Grade 1A/B). These cases may represent immune surveillance and might not require aggressive immunosuppression. Pericapillary C4D deposition suggests a role for antibody-mediated immunity in addition to the T-cell driven process.

Management of ICI-Induced Myocarditis

• First-line treatment is high-dose corticosteroids (e.g., methylprednisolone 500-1000 mg IV daily for 3-5 days). This recommendation is based on registry data showing improved cardiovascular outcomes with high-dose steroids. However, lower doses may be considered in certain situations, such as overlap with myasthenia gravis.
• For patients not responsive to steroids or with fulminant cases, other immunomodulatory therapies are considered, including mycophenolate, anti-thymocyte globulin, and TNF-alpha inhibitors (with caution in patients with heart failure).
• There is a trend towards earlier initiation of non-steroidal immunomodulatory therapy.
• Abatacept, a CTLA4 agonist, has shown promising results in mouse models and early human studies (historical controls) in combination with ruxolitinib (JAK inhibitor) and steroids, demonstrating significantly reduced mortality. Two randomized controlled trials are currently underway to evaluate the efficacy of abatacept in ICI myocarditis.
• Management requires a multidisciplinary team involving cardiologists and oncologists.
• It is crucial to consider cancer outcomes alongside cardiovascular outcomes, as treating myocarditis should not compromise the efficacy of cancer therapy. Rechallenge with ICIs after myocarditis can be attempted in some cases, but recurrence rates are around 50%, and there are no clear predictors of safe rechallenge.

Examples Provided

• Mouse Model: The PD1 knockout haploinsufficient CTLA4 mouse model developed at MD Anderson that mimics human ICI myocarditis, including EKG changes and histopathology.
• Clinical Studies:
  • Hanzoo's troponin surveillance protocol at Stanford: Showed a low positive predictive value for troponin elevation in detecting myocarditis.
  • MD Anderson's randomized controlled trial: Comparing troponin surveillance versus standard of care in patients on ICIs.
  • Registry study on steroid dosing: Demonstrated improved outcomes with high-dose steroids in ICI myocarditis.
  • Tom Neland's (MGH) phase three randomized controlled trial: Comparing steroids plus abatacept versus steroids plus placebo in ICI myocarditis.
  • Joey Lee Sullum's (Sorbonne) randomized controlled trial: Evaluating different dosing regimens of abatacept in ICI myocarditis.
  • Joey Lee Sullum's retrospective study on FDG PET: Showed limitations of FDG PET in diagnosing ICI myocarditis.
• Clinical Observations:
  • Reversal of complete heart block with immunosuppressive therapy in ICI myocarditis patients at MD Anderson.
  • Most ICI myocarditis patients presenting with normal left ventricular ejection fraction.
  • Cases of inflammatory infiltrate without myocyte necrosis (Grade 1A/B) that did not develop adverse cardiac events without specific myocarditis treatment.
  • Observation of C4D deposition in endomyocardial biopsies, suggesting a role for humoral immunity.

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