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Immunotherapy is a type of novel cancer therapy that leverages the body’s own immune system to target cancer cells. In this episode, we focused on the most common type of immunotherapy: immune checkpoint inhibitors or ICIs. ICIs are monoclonal antibodies targeting immune “checkpoints” or brakes to enhance T-cell recognition against tumors. ICI has become a pillar in cancer care, with over 100 approvals and 5,000 ongoing trials. ICIs can lead to non-specific activation of the immune system, causing off-target adverse events such as cardiotoxicities. ICI-related myocarditis, though less common, can be fatal in 30% of cases. Clinical manifestations vary but can include chest pain, dyspnea, palpitations, heart failure symptoms, and arrhythmias. Diagnosis involves echocardiography, cardiac MRI, and endomyocardial biopsy. Treatment includes high-dose corticosteroids with potential additional immunosuppressants. Baseline EKG and troponin are recommended before ICI initiation, but routine surveillance is not advised. Subclinical myocarditis is a challenge, with unclear management implications. So let’s dive in and learn about cardiotoxicity of novel immunotherapies with Drs. Giselle Suero (series co-chair), Evelyn Song (episode FIT lead), Daniel Ambinder (CardioNerds co-founder), and Tomas Neilan (faculty expert). Audio editing by CardioNerds Academy Intern, Dr. Maryam Barkhordarian.

This episode is supported by a grant from Pfizer Inc.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan. 

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls and Quotes – Cardiotoxicity of Novel Immunotherapies

1. Immune checkpoint inhibitors (ICI) play a crucial role in current oncology treatment by enhancing T-cell recognition against tumors.
2. ICI-related cardiac immune-related adverse events (iRAEs) include myocarditis, heart failure, stress-cardiomyopathy, conduction abnormalities, venous thrombosis, pericardial disease, vasculitis, and atherosclerotic-related events.
3. ICI myocarditis can be fatal; thus, prompt recognition and treatment is crucial.
4. Management includes cessation of the ICI and treatment with corticosteroids and potentially other immunosuppressants. Close monitoring and collaboration with cardiology and oncology are crucial.
5. Rechallenging patients with immunotherapies after developing an iRAE is controversial and requires careful consideration of risks and benefits, typically with the involvement of a multidisciplinary team.

Show notes – Cardiotoxicity of Novel Immunotherapies

What are immune checkpoint inhibitors (ICIs)?

• ICIs are monoclonal antibodies used to enhance the body’s immune response against cancer cells. Currently, there are four main classes of FDA-approved ICIs: monoclonal antibodies blocking cytotoxic T lymphocyte antigen-4 (CTLA-4), programed cell death protein-1 (PD-1), lymphocyte-activation gene 3 (LAG3), and programmed cell death ligand-1 (PD-L1).
• ICIs can lead to non-specific activation of the immune system, potentially causing off-target adverse events in various organs, including the heart, leading to myocarditis.   
• The mechanisms of cardiac iRAEs are not fully understood, but they are believed to involve T-cell activation against cardiac antigens, which leads to inflammation and tissue damage. 

What are the cardiotoxicities related to ICI therapies?

• ICI-related cardiac immune-related adverse events (iRAEs) include myocarditis, heart failure, stress-cardiomyopathy, conduction abnormalities, venous thrombosis, pericardial disease, vasculitis, and atherosclerotic-related events.
• ICI-related myocarditis is considered rare compared to other systemic IRAEs. While the incidence rate of ICI-myocarditis is around 0.7-2.0%, it can be fatal in 30% of cases.
• Clinical manifestations vary but can include chest pain, dyspnea, palpitations, heart failure symptoms, and arrhythmias. Severe cases of ICI myocarditis can present as cardiogenic shock or complete heart block (a fulminant myocarditis picture).
• The timing of adverse events is typically within the first three months of starting immunotherapy, with the majority occurring early on; however, some cases may present after three months.
• Increased clinical suspicion is key for early recognition and prompt diagnosis and treatment.

What is the general approach to the diagnosis of ICI-myocarditis?

• Diagnosis is based on clinical history and presentation, elevated troponin, and imaging findings. Echocardiography (with global longitudinal strain) and cardiac MRI (with T1 and T2 mapping as per the modified Lake Louise Criteria) are key diagnostic tools. If cardiac MRI is not diagnostic but suspicion remains high, an endomyocardial biopsy is the next diagnostic step.
• Baseline cardiac tests, such as ECG and troponin, are important before initiating ICIs in every patient to serve as a reference standard for comparison in case of troponin elevation during therapy. However, routine surveillance of asymptomatic patients on ICIs is not recommended.

How do endomyocardial biopsy findings for ICI-myocarditis compare to other types of autoimmune-mediated conditions such as transplant rejection?

• ICI-myocarditis is pathologically almost identical to transplant rejection; therefore, a similar grading system used for transplant rejection is applied to ICI-myocarditis to determine the severity and provide guidance on the intensity of immunosuppression.

What are the treatment strategies for ICI-myocarditis?

• In general, all patients with suspected ICI-myocarditis should have their immunotherapy held temporarily until the diagnosis is confirmed. Next, patients should be typically admitted to an inpatient unit with telemetry capabilities, given the risk of progression to complete heart block and cardiogenic shock.
• High-dose corticosteroids are the first-line pharmacological treatment, but the optimal dose varies between guidelines. An approach for severe life-threatening cases based on the NCCN and SITC guideline recommendations is a pulse of high-dose corticosteroids (consider 1000 mg methylprednisolone IV daily for 3–5 days until troponin normalizes) followed by a taper of 1–2 mg/kg methylprednisolone or oral prednisone for 4–6 weeks.
• For patients who do not respond to high-dose corticosteroids, additional immunosuppressive therapies can be considered, including intravenous immunoglobulin (IVIG), mycophenolate mofetil, anti-thymocyte globulin (ATG), alemtuzumab (monoclonal antibody to CD52), abatacept (CTLA-4 agonist), or plasmapheresis. This is an area where more data is needed to support guidelines for patient treatment. Currently, there are ongoing studies in this area, such as a phase 3 clinical of Abatacept for immune checkpoint inhibitor-associated myocarditis (ATRIUM, NCT053359280)
• High doses of corticosteroids used to treat ICI-associated myocarditis may adversely impact cancer outcomes. Further research is needed to understand the impact of cardiac toxicities and immunosuppressive treatments on cancer outcomes

Can patients be re-treated after an episode of ICI myocarditis?

• Patients who develop ICI-associated adverse events, including myocarditis, may have a second chance and be rechallenged with ICIs after resolution of the adverse event, but this decision should be made carefully considering the risks and benefits.

References – Cardiotoxicity of Novel Immunotherapies

• Zhang L, Reynolds KL, Lyon AR, Palaskas N, Neilan TG. The Evolving Immunotherapy Landscape and the Epidemiology, Diagnosis, and Management of Cardiotoxicity: JACC: CardioOncology Primer. JACC CardioOncology. 2021;3(1):35-47. doi:10.1016/J.JACCAO.2020.11.012

• Drobni ZD, Alvi RM, Taron J, et al. Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque. Circulation. 2020;142(24):2299-2311. doi:10.1161/CIRCULATIONAHA.120.049981

• Stein-Merlob AF, Rothberg M V., Holman P, Yang EH. Immunotherapy-Associated Cardiotoxicity of Immune Checkpoint Inhibitors and Chimeric Antigen Receptor T Cell Therapy: Diagnostic and Management Challenges and Strategies. Curr Cardiol Rep. 2021;23(3):1-11. doi:10.1007/s11886-021-01440-3

• Suero-Abreu GA, Zanni MV, Neilan TG. Atherosclerosis With Immune Checkpoint Inhibitor Therapy: Evidence, Diagnosis, and Management: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2022 Dec 20;4(5):598-615. doi: 10.1016/j.jaccao.2022.11.011. PMID: 36636438; PMCID: PMC9830225.