Future Prospects for Pharmacogenomics of Immune Checkpoint Inhibitors Cardiotoxicity
Abstract
Immune checkpoint inhibitors (ICIs), including PD-1, PD-L1, and CTLA-4 inhibitors, have revolutionized cancer therapy but are associated with immune-related adverse events (IRAEs). Among these, ICI-associated cardiotoxicity is an uncommon yet serious complication, often resistant to glucocorticoid therapy, which effectively manages most IRAEs. A pharmacogenomic approach might be useful in prescribing ICIs and screening for relevant clinically measurable phenotypes such as the history of autoimmune diseases and cardiovascular disorders. This review explores the impact of genetic variations on ICI-associated cardiotoxicity, the mechanistic basis behind it, potential clinical applications, and directions of the future on how pharmacogenomics can assist oncologists in reducing the risk of cardiotoxicity. Evidence-based hypotheses on how ICI-associated cardiotoxicity occurs suggest that genetic differences might play a role in ICI response, especially regarding cardiotoxic IRAEs. Pharmacogenomic studies and multi-omics profiling might provide valuable insight regarding ICI-induced cardiotoxicity. They could be implemented to make fine-tuned clinical decisions for individual patients in the future.
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WHO. Cancer. 2022; https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed December 16, 2022.
ACS. Survival rates for pancreatic cancer. 2020; https://www.cancer.org/cancer/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html. Accessed December 16, 2022.
Tamimi AF, Juweid M. Epidemiology and Outcome of Glioblastoma. In: De Vleeschouwer S, ed. Glioblastoma. Brisbane (AU)2017.
Alberts B. Molecular Biology of the Cell. 6th ed: W.W. Norton & Company; 2015.
Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46.
Shek D, Read SA, Ahlenstiel G, Piatkov I. Pharmacogenetics of anticancer monoclonal antibodies. Cancer Drug Resist. 2019;2(1):69-81.
Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations. Front Oncol. 2018;8:86.
Lyon AR, Yousaf N, Battisti NML, Moslehi J, Larkin J. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol. 2018;19(9):e447-e458.
Castrillon JA, Eng C, Cheng F. Pharmacogenomics for immunotherapy and immune-related cardiotoxicity. Hum Mol Genet. 2020;29(R2):R186-R196.
Schadendorf D, Hodi FS, Robert C, et al. Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol. 2015;33(17):1889-1894.
Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139-148.
Liu S, Gao W, Ning Y, et al. Cardiovascular Toxicity With PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis. Front Immunol. 2022;13:908173.
Asnani A. Cardiotoxicity of Immunotherapy: Incidence, Diagnosis, and Management. Curr Oncol Rep. 2018;20(6):44.
Heinzerling L, Ott PA, Hodi FS, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer. 2016;4:50.
Upadhrasta S, Elias H, Patel K, Zheng L. Managing cardiotoxicity associated with immune checkpoint inhibitors. Chronic Dis Transl Med. 2019;5(1):6-14.
Rubio-Infante N, Ramirez-Flores YA, Castillo EC, Lozano O, Garcia-Rivas G, Torre-Amione G. Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta-analysis. Eur J Heart Fail. 2021;23(10):1739-1747.
Al-Kindi SG, Oliveira GH. Reporting of immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;392(10145):382-383.
Zito C, Manganaro R, Ciappina G, et al. Cardiotoxicity Induced by Immune Checkpoint Inhibitors: What a Cardio-Oncology Team Should Know and Do. Cancers (Basel). 2022;14(21).
Li C, Bhatti SA, Ying J. Immune Checkpoint Inhibitors-Associated Cardiotoxicity. Cancers (Basel). 2022;14(5).
Yamani N, Ahmed A, Ruiz G, Zubair A, Arif F, Mookadam F. Immune checkpoint inhibitor-induced cardiotoxicity in patients with lung cancer: a systematic review and meta-analysis. Cardiooncology. 2024;10(1):37.
Weinmann SC, Pisetsky DS. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology (Oxford). 2019;58(Suppl 7):vii59-vii67.
Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med. 2016;375(18):1749-1755.
Ji C, Roy MD, Golas J, et al. Myocarditis in Cynomolgus Monkeys Following Treatment with Immune Checkpoint Inhibitors. Clin Cancer Res. 2019;25(15):4735-4748.
Wei SC, Meijers WC, Axelrod ML, et al. A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor-Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention. Cancer Discov. 2021;11(3):614-625.
Michel L, Helfrich I, Hendgen-Cotta UB, et al. Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. Eur Heart J. 2022;43(4):316-329.
Efentakis P, Choustoulaki A, Kwiatkowski G, et al. Early microvascular coronary endothelial dysfunction precedes pembrolizumab-induced cardiotoxicity. Preventive role of high dose of atorvastatin. Basic Res Cardiol. 2024.
Puri P, Cortese D, Baliga S. A Time Series Analysis of Trends in Medicare Utilization and Reimbursement for Cancer Immunotherapy Drugs: 2012-2017. 2020:2020.2006.2027.20141721.
Gan L, Liu D, Ma Y, et al. Cardiotoxicity associated with immune checkpoint inhibitors: Current status and future challenges. Front Pharmacol. 2022;13:962596.
Institute B. The Genotype-Tissue Expression (GTEx) Portal - rs231775. 2024; https://www.gtexportal.org/home/snp/rs231775#eqtl-block).
Chen J, Epstein MP, Schildkraut JM, Kar SP. Mapping inherited genetic variation with opposite effects on autoimmune disease and cancer identifies candidate drug targets associated with the anti-tumor immune response. medRxiv. 2023.
Yousif LI, Tanja AA, de Boer RA, Teske AJ, Meijers WC. The role of immune checkpoints in cardiovascular disease. Front Pharmacol. 2022;13:989431.
Adhikari A, Asdaq SMB, Al Hawaj MA, et al. Anticancer Drug-Induced Cardiotoxicity: Insights and Pharmacogenetics. Pharmaceuticals (Basel). 2021;14(10).
Hoefsmit EP, Rozeman EA, Haanen J, Blank CU. Susceptible loci associated with autoimmune disease as potential biomarkers for checkpoint inhibitor-induced immune-related adverse events. ESMO Open. 2019;4(4):e000472.
Refae S, Gal J, Brest P, Milano G. Germinal immunogenetics as a predictive factor for immunotherapy. Crit Rev Oncol Hematol. 2019;141:146-152.
Chennamadhavuni A, Abushahin L, Jin N, Presley CJ, Manne A. Risk Factors and Biomarkers for Immune-Related Adverse Events: A Practical Guide to Identifying High-Risk Patients and Rechallenging Immune Checkpoint Inhibitors. Front Immunol. 2022;13:779691.
Sung C, An J, Lee S, et al. Integrative analysis of risk factors for immune-related adverse events of checkpoint blockade therapy in cancer. Nat Cancer. 2023;4(6):844-859.
Guo AJ, Deng QY, Dong P, Zhou L, Shi L. Biomarkers associated with immune-related adverse events induced by immune checkpoint inhibitors. World J Clin Oncol. 2024;15(8):1002-1020.
Udagawa C, Nakano MH, Yoshida T, et al. Association between genetic variants and the risk of nivolumab-induced immune-related adverse events. Pharmacogenomics. 2022;23(16):887-901.
Groha S, Alaiwi SA, Xu W, et al. Germline variants associated with toxicity to immune checkpoint blockade. Nat Med. 2022;28(12):2584-2591.
Taylor CA, Watson RA, Tong O, et al. IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma. Nat Med. 2022;28(12):2592-2600.
Institute B. The Genotype-Tissue Expression (GTEx) Portal - rs16906115. 2024.
PharmGKB. Ipilimumab - Variant Annotations. 2024; https://www.pharmgkb.org/chemical/PA166182718/variantAnnotation.
PharmGKB. Nivolumab - Variant Annotations. 2024; https://www.pharmgkb.org/chemical/PA166129522/variantAnnotation.
PharmGKB. Pembrolizumab - Variant Annotations. 2024; https://www.pharmgkb.org/chemical/PA166124615/variantAnnotation.
PharmGKB. Tremelimumab - Variant Annotations. 2024; https://www.pharmgkb.org/chemical/PA166293321.
PharmGKB. Durvalumab - Variant Annotations. 2024; https://www.pharmgkb.org/chemical/PA166169883.
PharmGKB. Atezolizumab - Variant Annotations. 2024; https://www.pharmgkb.org/chemical/PA166129523.
Huang YV, Waliany S, Lee D, et al. The Role of Single-Cell Profiling and Deep Immunophenotyping in Understanding
Immune Therapy Cardiotoxicity. JACC CardioOncol. 2022;4(5):629-634.
Breunis WB, Tarazona-Santos E, Chen R, Kiley M, Rosenberg SA, Chanock SJ. Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade. J Immunother. 2008;31(6):586-590.
Liu W, Li WM, Yang SS, et al. Association of HLA class II DRB1, DPA1 and DPB1 polymorphism with genetic susceptibility to idiopathic dilated cardiomyopathy in Chinese Han nationality. Autoimmunity. 2006;39(6):461-467.
Rodriguez-Perez JM, Fragoso JM, Alvarez-Leon E, et al. MHC class II genes in Mexican patients with idiopathic dilated cardiomyopathy. Exp Mol Pathol. 2007;82(1):49-52.
Lozano MD, Rubocki RJ, Wilson JE, McManus BM, Wisecarver JL. Human leukocyte antigen class II associations in patients with idiopathic dilated cardiomyopathy. Myocarditis Treatment Trial Investigators. J Card Fail. 1997;3(2):97-103.
DOI: https://doi.org/10.15416/ijcp.2024.13.1.34
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