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For: Läubli H, Balmelli C, Bossard M, Pfister O, Glatz K, Zippelius A. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer 2015;3:11. [PMID: 25901283 PMCID: PMC4404586 DOI: 10.1186/s40425-015-0057-1] [Citation(s) in RCA: 248] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 03/11/2015] [Indexed: 02/08/2023] Open

For:	Läubli H, Balmelli C, Bossard M, Pfister O, Glatz K, Zippelius A. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer 2015;3:11. [PMID: 25901283 PMCID: PMC4404586 DOI: 10.1186/s40425-015-0057-1] [Citation(s) in RCA: 248] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 03/11/2015] [Indexed: 02/08/2023] Open

Number

Cited by Other Article(s)

Sun J, Wu W, Wang Y, Zhang J, Qiu S, Guan Z, Shi C, Ma J, Xu Y. MLKL-Mediated Necroptosis Predominantly Contributes to Immune-Associated Myocardial Damage. Inflammation 2025:10.1007/s10753-025-02298-1. [PMID: 40195182 DOI: 10.1007/s10753-025-02298-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/31/2025] [Accepted: 04/01/2025] [Indexed: 04/09/2025]

Abstract

Activated T cells and macrophages play a critical role in immune-associated myocarditis. However, the molecular and cellular mechanisms driving cardiomyocyte damage by immune cells remain poorly understood. In this study, we co-cultured human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with activated human peripheral blood mononuclear cells (aPBMCs) to recapitulate myocardial infiltration of immune cells. Our results demonstrated that aPBMCs induced hiPSC-CMs death in a dose- and time-dependent manner. Transcriptome analysis revealed the activation of several death pathways, including pyroptosis, apoptosis and necroptosis. The time course of immunofluorescence staining of key proteins related to different death pathways demonstrated that necroptosis was the earliest activated pathway. Pharmacological blockade of necroptosis by targeting mixed lineage kinase domain-like protein (MLKL), receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein RIPK1 kinase 3 (RIPK3) protected hiPSC-CMs against injury induced by aPBMCs, while inhibitors of pyroptosis and apoptosis showed no protective effect. Moreover, MLKL knockdown in hiPSC-CMs prevented cell death due to aPBMCs challenge. Additionally, we validated the cardioprotective effects of blocking necroptosis in a mouse model of immune checkpoint inhibitors (ICIs)-related myocarditis using a combination of long-term anti-programmed cell death 1 (PD- 1) and anti-cytotoxic T-lymphocyte antigen- 4 (CTLA- 4) antibodies. ICIs led to elevation of myocardial injury markers in serum and activated immune cells infiltration. Furthermore, in vivo administration of a MLKL inhibitor prevented ICIs-induced myocardial injury. In conclusion, our findings suggested that MLKL-mediated necroptosis predominantly contributed to cardiomyocyte death resulting from activated immune cells. Suppressing necroptosis may be an effective therapeutic approach against myocardial damage in myocarditis.

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Affiliation(s)

Jinglei Sun Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China
Wenting Wu Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China Department of Clinical Pharmacy, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
Yi Wang Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China
Jiali Zhang Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China
Suhua Qiu Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China
Zhengkun Guan Department of Cardiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050010, China
Chenxia Shi Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China
Jingtao Ma Department of Cardiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050010, China
Yanfang Xu Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China.

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Huang S, Kang Y, Liu T, Xiong Y, Yang Z, Zhang Q. The role of immune checkpoints PD-1 and CTLA-4 in cardiovascular complications leading to heart failure. Front Immunol 2025;16:1561968. [PMID: 40255399 PMCID: PMC12006013 DOI: 10.3389/fimmu.2025.1561968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 02/13/2025] [Indexed: 04/22/2025] Open

Gergely TG, Drobni ZD, Sayour NV, Ferdinandy P, Varga ZV. Molecular fingerprints of cardiovascular toxicities of immune checkpoint inhibitors. Basic Res Cardiol 2025;120:187-205. [PMID: 39023770 PMCID: PMC11790702 DOI: 10.1007/s00395-024-01068-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 07/20/2024]

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by unleashing the power of the immune system against malignant cells. However, their use is associated with a spectrum of adverse effects, including cardiovascular complications, which can pose significant clinical challenges. Several mechanisms contribute to cardiovascular toxicity associated with ICIs. First, the dysregulation of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand (PD-L1), and molecular mimicry with cardiac autoantigens, leads to immune-related adverse events, including myocarditis and vasculitis. These events result from the aberrant activation of T cells against self-antigens within the myocardium or vascular endothelium. Second, the disruption of immune homeostasis by ICIs can lead to autoimmune-mediated inflammation of cardiac tissues, manifesting as cardiac dysfunction and heart failure, arrhythmias, or pericarditis. Furthermore, the upregulation of inflammatory cytokines, particularly tumor necrosis factor-alpha, interferon-γ, interleukin-1β, interleukin-6, and interleukin-17 contributes to cardiac and endothelial dysfunction, plaque destabilization, and thrombosis, exacerbating cardiovascular risk on the long term. Understanding the intricate mechanisms of cardiovascular side effects induced by ICIs is crucial for optimizing patient care and to ensure the safe and effective integration of immunotherapy into a broader range of cancer treatment protocols. The clinical implications of these mechanisms underscore the importance of vigilant monitoring and early detection of cardiovascular toxicity in patients receiving ICIs. Future use of these key pathological mediators as biomarkers may aid in prompt diagnosis of cardiotoxicity and will allow timely interventions.

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Gamero MT, Patel A, Storozynsky E. The Good (Tumor Killing) and the Bad (Cardiovascular Complications) of Immunologic Checkpoint Inhibitors. Curr Cardiol Rep 2024;26:1487-1498. [PMID: 39441327 DOI: 10.1007/s11886-024-02147-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2024] [Indexed: 10/25/2024]

Cheema PK, Iafolla MAJ, Abdel-Qadir H, Bellini AB, Chatur N, Chandok N, Comondore VR, Cunningham M, Halperin I, Hu AB, Jaskolka D, Darvish-Kazem S, Khandaker MH, Kitchlu A, Sachdeva JS, Shapera S, Woolnough NRJ, Nematollahi M. Managing Select Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors. Curr Oncol 2024;31:6356-6383. [PMID: 39451777 PMCID: PMC11506662 DOI: 10.3390/curroncol31100473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open

Affiliation(s)

Parneet K. Cheema William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
Marco A. J. Iafolla William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
Husam Abdel-Qadir Women’s College Hospital Research Institute, Toronto, ON M5S 1B2, Canada; Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, ON M5G 2N2, Canada
Andrew B. Bellini William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
Nazira Chatur Division of Gastroenterology, Faculty of Medicine, Vancouver General Hospital (Sanders), University of British Columbia, Vancouver, BC V5Z 1M9, Canada;
Natasha Chandok William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
Vikram R. Comondore William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
Morven Cunningham Toronto Centre for Liver Disease, University Health Network, Toronto, ON M5G 2C4, Canada;
Ilana Halperin Division of Endocrinology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
Anne B. Hu William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
Diana Jaskolka William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
Saeed Darvish-Kazem William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
Masud H. Khandaker William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
Abhijat Kitchlu Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON M5G 2C4, Canada;
Jasdip S. Sachdeva William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
Shane Shapera Department of Medicine, University of Toronto, Toronto, ON M5G 2N2, Canada;
Nicholas R. J. Woolnough William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
Massey Nematollahi William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)

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Yu J, Long B, Li Z, Tian X, Li D, Long J, Wang Y, Chen Y, Zhang F, Liu H, Qian C, Shan J. Central memory CD4+ T cells play a protective role against immune checkpoint inhibitor-associated myocarditis. Cardiovasc Res 2024;120:1442-1455. [PMID: 38850163 DOI: 10.1093/cvr/cvae133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 03/04/2024] [Accepted: 05/11/2024] [Indexed: 06/10/2024] Open

Abstract

AIMS

The widespread use of immune checkpoint inhibitors (ICIs) has demonstrated significant survival benefits for cancer patients and also carries the risk of immune-related adverse events. ICI-associated myocarditis is a rare and serious adverse event with a high mortality rate. Here, we explored the mechanism underlying ICI-associated myocarditis.

METHODS AND RESULTS

Using the peripheral blood of patients with ICI therapy and of ICI-treated mice with transplanted tumours, we dissect the immune cell subsets and inflammatory factors associated with myocarditis. Compared to the control group, patients with myocarditis after ICI therapy showed an increase in NK cells and myeloid cells in the peripheral blood, while T cells significantly decreased. Among T cells, there was an imbalance of CD4/CD8 ratio in the peripheral blood of myocarditis patients, with a significant decrease in central memory CD4+ T (CD4+ TCM) cells. RNA sequencing revealed that CD4+ TCM cells in myocarditis patients were immunosuppressive cell subsets, which highly express the immunosuppressive factor IL-4I1. To elucidate the potential mechanism of the decrease in CD4+ TCM cells, protein array was performed and revealed that several inflammatory factors gradually increased with the severity of myocarditis in the myocarditis group, such as IL-1B/CXCL13/CXCL9, while the myocardial protective factor IL-15 decreased. Correlation analysis indicated a positive correlation between IL-15 and CD4+ TCM cells, with high expression of IL-15 receptor IL15RA. Furthermore, in vivo studies using an anti-PDL1 antibody in a mouse tumour model indicated a reduction in CD4+ TCM cells and an increase in effector memory-expressing CD45RA CD8+ T (TEMRA) cells, alongside evidence of cardiac fibrosis. Conversely, combining anti-PDL1 antibody treatment with IL-15 led to a resurgence of CD4+ TCM cells, a reduction in CD8+ TEMRA cells, and a mitigated risk of cardiac fibrosis.

CONCLUSION

Our data highlight CD4+ TCM cells' crucial role in cardiac protection during ICI therapy. IL-15, IL-4I1, and CD4+ TCM cells can serve as therapeutic targets to reduce ICI-associated myocarditis in cancer patients.

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Affiliation(s)

Jiajun Yu School of Medicine, Chongqing University, Chongqing 400030, China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China
Bo Long Department of Cardio-Oncology, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China
Ziyong Li School of Medicine, Chongqing University, Chongqing 400030, China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China
Xiaolong Tian School of Medicine, Chongqing University, Chongqing 400030, China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China
Dairong Li Department of Medical Oncology, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China
Jianling Long Department of Cardio-Oncology, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China
Yujue Wang Department of Cardio-Oncology, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China
Yue Chen Department of Cardio-Oncology, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China
Fang Zhang Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China
Haixia Liu Department of Cardio-Oncology, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China
Cheng Qian School of Medicine, Chongqing University, Chongqing 400030, China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China
Juanjuan Shan School of Medicine, Chongqing University, Chongqing 400030, China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China

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Pan J, Zhou T, Na K, Xu K, Yan C, Song H, Han Y. Identification of hub modules and therapeutic targets associated with CD8⁺T-cells in HF and their pan-cancer analysis. Sci Rep 2024;14:18823. [PMID: 39138291 PMCID: PMC11322555 DOI: 10.1038/s41598-024-68504-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 07/24/2024] [Indexed: 08/15/2024] Open

Affiliation(s)

Jing Pan School of Life Science and Biochemistry, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016, Liaoning Province, China State Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Wenhua Road 83, Shenyang, 110016, Liaoning Province, China
Ting Zhou Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, China State Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Wenhua Road 83, Shenyang, 110016, Liaoning Province, China
Kun Na State Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Wenhua Road 83, Shenyang, 110016, Liaoning Province, China
Kai Xu State Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Wenhua Road 83, Shenyang, 110016, Liaoning Province, China
Chenghui Yan State Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Wenhua Road 83, Shenyang, 110016, Liaoning Province, China
Haixu Song State Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Wenhua Road 83, Shenyang, 110016, Liaoning Province, China.
Yaling Han School of Life Science and Biochemistry, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016, Liaoning Province, China. State Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Wenhua Road 83, Shenyang, 110016, Liaoning Province, China.

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Kirthiga Devi SS, Singh S, Joga R, Patil SY, Meghana Devi V, Chetan Dushantrao S, Dwivedi F, Kumar G, Kumar Jindal D, Singh C, Dhamija I, Grover P, Kumar S. Enhancing cancer immunotherapy: Exploring strategies to target the PD-1/PD-L1 axis and analyzing the associated patent, regulatory, and clinical trial landscape. Eur J Pharm Biopharm 2024;200:114323. [PMID: 38754524 DOI: 10.1016/j.ejpb.2024.114323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 03/10/2024] [Accepted: 05/13/2024] [Indexed: 05/18/2024]

Affiliation(s)

S S Kirthiga Devi Department of Regulatory Affairs, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India
Sidhartha Singh Department of Natural Products, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India
Ramesh Joga Department of Regulatory Affairs, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India
Sharvari Y Patil Department of Regulatory Affairs, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India
Vakalapudi Meghana Devi Department of Regulatory Affairs, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India
Sabnis Chetan Dushantrao Department of Regulatory Affairs, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India
Falguni Dwivedi School of Bioscience and Bioengineering, D Y Patil International University, Akurdi, Pune 411044, India
Gautam Kumar School of Bioscience and Bioengineering, D Y Patil International University, Akurdi, Pune 411044, India; Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani campus, Rajasthan 333031, India
Deepak Kumar Jindal Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science & Technology, Hisar, 125001, India
Charan Singh Department of Pharmaceutical Sciences, School of Sciences, Hemvati Nandan Bahuguna Garhwal University (A Central University), Srinagar, Garhwal, Uttarakhand 246174, India
Isha Dhamija Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India
Parul Grover KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad 201206, India; Department of Pharmaceutics, NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan 303121, India
Sandeep Kumar Department of Regulatory Affairs, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India; Department of Pharmaceutics, NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan 303121, India.

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Fabiani I, Chianca M, Aimo A, Emdin M, Dent S, Fedele A, Cipolla CM, Cardinale DM. Use of new and emerging cancer drugs: what the cardiologist needs to know. Eur Heart J 2024;45:1971-1987. [PMID: 38591670 DOI: 10.1093/eurheartj/ehae161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 02/28/2024] [Accepted: 03/04/2024] [Indexed: 04/10/2024] Open

He Y, Yu H, Dai S, He M, Ma L, Xu Z, Luo F, Wang L. Immune checkpoint inhibitors break whose heart? Perspectives from cardio-immuno-oncology. Genes Dis 2024;11:807-818. [PMID: 37692505 PMCID: PMC10491874 DOI: 10.1016/j.gendis.2023.01.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 01/12/2023] [Indexed: 03/30/2023] Open

Jo W, Won T, Daoud A, Čiháková D. Immune checkpoint inhibitors associated cardiovascular immune-related adverse events. Front Immunol 2024;15:1340373. [PMID: 38375475 PMCID: PMC10875074 DOI: 10.3389/fimmu.2024.1340373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 01/19/2024] [Indexed: 02/21/2024] Open

Zhang H, Houadj L, Wu KY, Tran SD. Diagnosing and Managing Uveitis Associated with Immune Checkpoint Inhibitors: A Review. Diagnostics (Basel) 2024;14:336. [PMID: 38337852 PMCID: PMC10855398 DOI: 10.3390/diagnostics14030336] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 01/29/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open

Chen B, Xu A, He Y, Zhang Y, Cheng D, Fang Y, Ruan J, Dai M, Wang Y, Zhang J. The cardiac-related adverse events of PD-1/PD-L1 immunotherapy in advanced or metastatic lung cancer: a RCT-based meta-analysis. Support Care Cancer 2024;32:140. [PMID: 38294563 DOI: 10.1007/s00520-024-08344-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 01/25/2024] [Indexed: 02/01/2024]

Gul R, Shehryar M, Mahboob A, Kareem HK, Inayat A, Safi D, Kamran A. Immune Checkpoint Inhibitor-Associated Myocarditis: A Literature Review. Cureus 2024;16:e52952. [PMID: 38406102 PMCID: PMC10894055 DOI: 10.7759/cureus.52952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2024] [Indexed: 02/27/2024] Open

Abstract

Recently in the field of oncology, immune checkpoint inhibitors (ICI) are being increasingly utilized both in clinical trials and in clinical practice. It is a form of biological therapy that targets tumors by activating the immune system, which in turn eliminates proliferating cancer cells. These have numerous immune-related adverse events (irAEs), one of which is myocarditis, which has high rates of mortality. This article was a narrative review of myocarditis related to ICI use. Studies from the PubMed, Cochrane, and American Society of Clinical Oncology (ASCO) databases were used in writing this review. The databases were searched for original publications for adverse effects related to ICI use and myocarditis specifically. There are numerous published instances of cancer immunotherapy causing myocarditis. ICI therapy has numerous benefits, as it upregulates the immune system to target cancer cells, utilizing the body's own defense mechanisms to target proliferating cells. Myocarditis is a serious side effect, however. Therefore, on balance, these monotherapies are worth using. While this literature review primarily identifies cross-reaction as the main mechanism of myocarditis, there are other possible mechanisms. One proposed mechanism involves a shared antigen between the myocardial tissue and the tumor. This mechanism is called molecular mimicry, where the monoclonal antibody attacks both the myocardial tissue and the tumor cell. Management of ICI-induced myocarditis has not been studied by randomized controlled trials or prospective studies, but based on previous case reports and case series it is mostly treated with steroids initially. An ICI rechallenge after temporary discontinuation appears conceivable in many cases, especially given its therapeutic effects, but only limited data are available on the safety of a rechallenge after an irAE. The lack of RCTs regarding rechallenge with an ICI after irAE, more so specifically about myocarditis, along with the overall results and the complexity involved in such cases once again emphasize the need to make decisions on an individual basis by a multidisciplinary expert working group. At the same time, the focus should also be on publishing more data as the need will grow along with the indications for ICI therapies.

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Seňavová J, Rajmonová A, Heřman V, Jura F, Veľasová A, Hamová I, Tkachenko A, Kupcová K, Havránek O. Immune Checkpoints and Their Inhibition in T-Cell Lymphomas. Folia Biol (Praha) 2024;70:123-151. [PMID: 39644109 DOI: 10.14712/fb2024070030123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]

Miao YD, Quan WX, Tang XL, Shi WW, Li Q, Li RJ, Wang JT, Gan J, Dong X, Hao L, Luan WY, Zhang F. Uncovering the flip side of immune checkpoint inhibitors: a comprehensive review of immune-related adverse events and predictive biomarkers. Int J Biol Sci 2024;20:621-642. [PMID: 38169638 PMCID: PMC10758091 DOI: 10.7150/ijbs.89376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 11/25/2023] [Indexed: 01/05/2024] Open

Affiliation(s)

Yan-Dong Miao Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2 nd Medical College of Binzhou Medical University, Yantai 264100, China
Wu-Xia Quan Yantai Affiliated Hospital of Binzhou Medical University, The 2 nd Medical College of Binzhou Medical University, Yantai 264100, China
Xiao-Long Tang The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
Wei-Wei Shi Yantai Affiliated Hospital of Binzhou Medical University, The 2 nd Medical College of Binzhou Medical University, Yantai 264100, China
Qing Li Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2 nd Medical College of Binzhou Medical University, Yantai 264100, China
Rui Jian Li Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2 nd Medical College of Binzhou Medical University, Yantai 264100, China
Jiang-Tao Wang Department of Thyroid and Breast Surgery, Yantai Affiliated Hospital of Binzhou Medical University, The 2 nd Medical College of Binzhou Medical University, Yantai 264100, China
Jian Gan Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, The 2 nd Medical College of Binzhou Medical University, Yantai 264100, China
Xin Dong Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2 nd Medical College of Binzhou Medical University, Yantai 264100, China
Liang Hao Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2 nd Medical College of Binzhou Medical University, Yantai 264100, China
Wen-Yu Luan Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2 nd Medical College of Binzhou Medical University, Yantai 264100, China
Fang Zhang Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2 nd Medical College of Binzhou Medical University, Yantai 264100, China

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Badrigilan S, Meola A, Chang SD, Rezaeian S, Nemati H, Almasi T, Rostampour N. Stereotactic radiosurgery with immune checkpoint inhibitors for brain metastases: a meta-analysis study. Br J Neurosurg 2023;37:1533-1543. [PMID: 34979828 DOI: 10.1080/02688697.2021.2022098] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 12/20/2021] [Indexed: 11/02/2022]

Banerjee A, Narasimhulu CA, Singla DK. Immune interactions in pembrolizumab (PD-1 inhibitor) cancer therapy and cardiovascular complications. Am J Physiol Heart Circ Physiol 2023;325:H751-H767. [PMID: 37594487 PMCID: PMC10659324 DOI: 10.1152/ajpheart.00378.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/09/2023] [Accepted: 08/09/2023] [Indexed: 08/19/2023]

Horiguchi H, Kadomatsu T, Yamashita T, Yumoto S, Terada K, Sato M, Morinaga J, Miyata K, Oike Y. ANGPTL2 promotes immune checkpoint inhibitor-related murine autoimmune myocarditis. Commun Biol 2023;6:965. [PMID: 37736764 PMCID: PMC10517162 DOI: 10.1038/s42003-023-05338-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 09/08/2023] [Indexed: 09/23/2023] Open

Affiliation(s)

Haruki Horiguchi Department of Molecular Genetics, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan Department of Aging and Geriatric Medicine, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan
Tsuyoshi Kadomatsu Department of Molecular Genetics, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan. Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
Tomoya Yamashita Department of Molecular Genetics, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan
Shinsei Yumoto Department of Molecular Genetics, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan
Kazutoyo Terada Department of Molecular Genetics, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan
Michio Sato Department of Molecular Genetics, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan
Jun Morinaga Department of Molecular Genetics, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan
Keishi Miyata Department of Molecular Genetics, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan
Yuichi Oike Department of Molecular Genetics, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan. Department of Aging and Geriatric Medicine, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556, Japan. Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.

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Suarez ZK, Finke AC, Hospedales E, Perez E, Sharifzadeh A, Foster J, Ferris A. An unusual case of checkpoint-inhibitor-induced pleuropericarditis. J Oncol Pharm Pract 2023;29:1525-1528. [PMID: 37254508 DOI: 10.1177/10781552231179369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]

Gong J, Neilan TG, Zlotoff DA. Mediators and mechanisms of immune checkpoint inhibitor-associated myocarditis: Insights from mouse and human. Immunol Rev 2023;318:70-80. [PMID: 37449556 PMCID: PMC10528547 DOI: 10.1111/imr.13240] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 06/26/2023] [Indexed: 07/18/2023]

Zheng S, Zhang H, Hu B, Zhou J, Wen L, Li M. A case of acute myocarditis induced by PD-1 inhibitor (sintilimab) in the treatment of large cell neuroendocrine carcinoma. Heliyon 2023;9:e16874. [PMID: 37342584 PMCID: PMC10277459 DOI: 10.1016/j.heliyon.2023.e16874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/30/2023] [Accepted: 05/31/2023] [Indexed: 06/23/2023] Open

Uversky VN, Redwan EM, Makis W, Rubio-Casillas A. IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein. Vaccines (Basel) 2023;11:vaccines11050991. [PMID: 37243095 DOI: 10.3390/vaccines11050991] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open

Abstract

Less than a year after the global emergence of the coronavirus SARS-CoV-2, a novel vaccine platform based on mRNA technology was introduced to the market. Globally, around 13.38 billion COVID-19 vaccine doses of diverse platforms have been administered. To date, 72.3% of the total population has been injected at least once with a COVID-19 vaccine. As the immunity provided by these vaccines rapidly wanes, their ability to prevent hospitalization and severe disease in individuals with comorbidities has recently been questioned, and increasing evidence has shown that, as with many other vaccines, they do not produce sterilizing immunity, allowing people to suffer frequent re-infections. Additionally, recent investigations have found abnormally high levels of IgG4 in people who were administered two or more injections of the mRNA vaccines. HIV, Malaria, and Pertussis vaccines have also been reported to induce higher-than-normal IgG4 synthesis. Overall, there are three critical factors determining the class switch to IgG4 antibodies: excessive antigen concentration, repeated vaccination, and the type of vaccine used. It has been suggested that an increase in IgG4 levels could have a protecting role by preventing immune over-activation, similar to that occurring during successful allergen-specific immunotherapy by inhibiting IgE-induced effects. However, emerging evidence suggests that the reported increase in IgG4 levels detected after repeated vaccination with the mRNA vaccines may not be a protective mechanism; rather, it constitutes an immune tolerance mechanism to the spike protein that could promote unopposed SARS-CoV2 infection and replication by suppressing natural antiviral responses. Increased IgG4 synthesis due to repeated mRNA vaccination with high antigen concentrations may also cause autoimmune diseases, and promote cancer growth and autoimmune myocarditis in susceptible individuals.

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Hu Y, Liu C, Jin S, Yi Z, Wang C, Pan X, Huang H. A case of subclinical immune checkpoint inhibitor-associated myocarditis in non-small cell lung cancer. BMC Pulm Med 2023;23:119. [PMID: 37060029 PMCID: PMC10103507 DOI: 10.1186/s12890-023-02417-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 04/04/2023] [Indexed: 04/16/2023] Open

Song W, Zheng Y, Dong M, Zhong L, Bazoukis G, Perone F, Li G, Ng CF, Baranchuk A, Tse G, Liu T. Electrocardiographic Features of Immune Checkpoint Inhibitor-Associated Myocarditis. Curr Probl Cardiol 2023;48:101478. [PMID: 36336121 DOI: 10.1016/j.cpcardiol.2022.101478] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 10/26/2022] [Indexed: 11/06/2022]

Affiliation(s)

Wenhua Song Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
Yi Zheng Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
Mei Dong Department of Cardiology, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai Shandong, China
Lin Zhong Department of Cardiology, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai Shandong, China
George Bazoukis Department of Cardiology, Larnaca General Hospital, Larnaca, Cyprus; Department of Basic and Clinical Sciences, University of Nicosia Medical School, 2414, Nicosia, Cyprus
Francesco Perone Cardiac Rehabilitation Unit, Rehabilitation Clinic "Villa delle Magnolie", Castel Morrone, Caserta, Italy
Guangping Li Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
Chi Fai Ng SH Ho Urology Centre, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
Adrian Baranchuk Division of Cardiology, Kingston Health Science, Center, Queen's University, Kingston, Ontario, Canada
Gary Tse Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China; Epidemiology Research Unit, Cardiovascular Analytics Group, Hong Kong, China; Kent and Medway Medical School, University of Kent and Canterbury Christ Church University, Canterbury, Kent, UK; School of Nursing and Health Studies, Hong Kong, Metropolitan University, Hong Kong, China.
Tong Liu Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China.

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Boutros A, Bottini A, Rossi G, Tanda ET, Spagnolo F, Barletta G, Croce E, Fava P, Parisi A, De Rosa F, Palla M, Marconcini R, Ferrari M, Grandis M, Spallarossa P, Sarocchi M, Arboscello E, Del Mastro L, Lambertini M, Pronzato P, Genova C. Neuromuscular and cardiac adverse events associated with immune checkpoint inhibitors: pooled analysis of individual cases from multiple institutions and literature. ESMO Open 2023;8:100791. [PMID: 36791639 PMCID: PMC9958259 DOI: 10.1016/j.esmoop.2023.100791] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/12/2022] [Accepted: 01/04/2023] [Indexed: 02/15/2023] Open

Abstract

BACKGROUND

Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple tumors, due to improved efficacy, quality of life, and safety. While most immune-related adverse events (irAEs) are mild and easily managed, in rare cases such events may be life-threatening, especially those affecting the neuromuscular and cardiac system. The management of neuromuscular/cardiac irAEs is not clear due to the lack of consistent data. Therefore, we carried out a pooled analysis of collected cases from selected Italian centers and individual data from published case reports and case series, in order to improve our understanding of these irAEs.

PATIENTS AND METHODS

We collected retrospective data from patients treated in six Italian centers with ICIs (programmed cell death protein 1 or programmed death-ligand 1 and/or cytotoxic T-lymphocyte antigen 4 inhibitor) for any solid tumor who experienced neuromuscular and/or cardiovascular toxicity. Then, we carried out a search of case reports and series of neuromuscular/cardiac irAEs from ICIs with any solid tumor.

RESULTS

This analysis includes cases from Italian institutions (n = 18) and the case reports identified in our systematic literature search (n = 120), for a total of 138 patients. Among these patients, 50 (36.2%) had complete resolution of their neuromuscular/cardiac irAEs, in 21 (15.2%) cases there was a clinical improvement with mild sequelae, and 53 (38.4%) patients died as a result of the irAEs. Factors significantly associated with worse outcomes were early irAE onset, within the first two cycles of ICI (Fisher P < 0.0001), clinical manifestation of both myositis and myocarditis when compared with patients who developed only myositis or myocarditis (chi-square P = 0.0045), and the development of arrhythmia (Fisher P = 0.0070).

CONCLUSIONS

To the best of our knowledge, this is the largest collection of individual cases of immune-related myocarditis/myositis. Early irAE onset, concurrent development of myositis and myocarditis, as well as occurrence of arrhythmias are associated with worse outcomes and should encourage an aggressive immunomodulatory treatment.

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Affiliation(s)

A Boutros Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genoa, Genova, Italy.
A Bottini Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genoa, Genova, Italy
G Rossi Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
E T Tanda Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy
F Spagnolo Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Surgical Sciences and Integrated Diagnostics (DISC), Plastic Surgery Division, University of Genova, Genoa, Italy
G Barletta Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy
E Croce Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy
P Fava Department of Medical Sciences, Dermatologic Clinic, University of Turin, Torino, Italy
A Parisi Department of Life, Health & Environmental Sciences, University of L'Aquila, L'Aquila, Italy
F De Rosa IRCCS Istituto Romagnolo per lo Studio dei Tumori 'Dino Amadori', Meldola (FC), Italy
M Palla Department of Skin Cancers, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy
R Marconcini Azienda Ospedaliero Universitaria Pisana, Medical Oncology Unit, Pisa, Italy
M Ferrari Azienda Ospedaliero Universitaria Pisana, Medical Oncology Unit, Pisa, Italy
M Grandis Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences (DINOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy
P Spallarossa Cardiovascular Disease Unit, Ospedale Policlinico San Martino IRCCS, Genova, Italy
M Sarocchi Cardiovascular Disease Unit, Ospedale Policlinico San Martino IRCCS, Genova, Italy
E Arboscello Emergency Department, IRCCS Ospedale Policlinico San Martino, Genova, Italy
L Del Mastro Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genoa, Genova, Italy; Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
M Lambertini Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genoa, Genova, Italy; Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
P Pronzato Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy
C Genova Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genoa, Genova, Italy; Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy

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Lee SM, Lee S, Cho HW, Min KJ, Hong JH, Song JY, Lee JK, Lee NW. Application of Immune Checkpoint Inhibitors in Gynecological Cancers: What Do Gynecologists Need to Know before Using Immune Checkpoint Inhibitors? Int J Mol Sci 2023;24:974. [PMID: 36674491 PMCID: PMC9865129 DOI: 10.3390/ijms24020974] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/30/2022] [Accepted: 12/30/2022] [Indexed: 01/06/2023] Open

Madanat L, Gupta R, Weber P, Kumar N, Chandra R, Ahaneku H, Bansal Y, Anderson J, Bilolikar A, Jaiyesimi I. Cardiotoxicity of Biological Therapies in Cancer Patients: An In-depth Review. Curr Cardiol Rev 2023;19:e310522205428. [PMID: 35642110 PMCID: PMC10280990 DOI: 10.2174/1573403x18666220531094800] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/14/2022] [Accepted: 04/14/2022] [Indexed: 11/22/2022] Open

Denaro N, Garrone O, Morelli A, Pellegrino B, Merlano MC, Vacca D, Pearce J, Farci D, Musolino A, Scartozzi M, Tommasi C, Solinas C. A narrative review of the principal glucocorticoids employed in cancer. Semin Oncol 2022;49:429-438. [PMID: 36737303 DOI: 10.1053/j.seminoncol.2023.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 01/29/2023]

Duarte T, Costa C, Gonçalves S, Raposo L, Ferreira A, Albuquerque C, Vau N, Caria R. A case of lymphocytic myocarditis in a patient treated with an immune checkpoint inhibitor, a recent class of chemotherapy agents. Rev Port Cardiol 2022;41:1047-1051. [PMID: 36257498 DOI: 10.1016/j.repc.2019.03.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/07/2018] [Accepted: 03/31/2019] [Indexed: 11/06/2022] Open

Abstract

Chemotherapy-associated cardiotoxicity is a common adverse event. Immune checkpoint inhibitors (ICI) - a new class of monoclonal antibodies - have revolutionized the management of various diseases. Their use is expected to increase in the near future and their cardiac side effects have been increasingly recognized. CLINICAL CASE: We describe a case of a 67-year-old female patient with urothelial carcinoma undergoing treatment with pembrolizumab who presented to the emergency department with progressive fatigue, retrosternal pain and palpitations for three days. On admission she was diagnosed with acute heart failure (HF). The electrocardiogram revealed a right bundle branch block and ventricular bigeminy. Blood tests showed elevated troponin I, while transthoracic echocardiography revealed severe left ventricular dysfunction. Coronary angiography excluded coronary artery disease. Cardiac magnetic resonance revealed moderate left ventricular dysfunction and late gadolinium enhancement typical of myocarditis. Endomyocardial biopsy confirmed the diagnosis of lymphocytic myocarditis. In the first 48h of hospitalization, she developed transient complete AV block. Corticoid and HF therapy were initiated, leading to symptom improvement and disappearance of the rhythm disturbances. She was discharged on the 12th day, maintaining moderate LV dysfunction, which improved only mildly at a subsequent outpatient assessment. She died suddenly 35 days after discharge. CONCLUSION: Lymphocytic myocarditis is a serious cardiac side effect of ICI therapy. Pembrolizumab is increasingly used, so it is important to be aware of its effects, in order to perform an early diagnosis and provide adequate treatment. Corticosteroid therapy seems to be crucial in preventing disease progression and enabling ventricular remodeling.

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Torrente M, Blanco M, Franco F, Garitaonaindia Y, Calvo V, Collazo-Lorduy A, Gutiérrez L, Sánchez JC, González-del-Alba A, Hernández R, Méndez M, Cantos B, Núñez B, Sousa PAC, Provencio M. Assessing the risk of cardiovascular events in patients receiving immune checkpoint inhibitors. Front Cardiovasc Med 2022;9:1062858. [PMID: 36531707 PMCID: PMC9751318 DOI: 10.3389/fcvm.2022.1062858] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/08/2022] [Indexed: 11/10/2023] Open

Efentakis P, Andreadou I, Iliodromitis KE, Triposkiadis F, Ferdinandy P, Schulz R, Iliodromitis EK. Myocardial Protection and Current Cancer Therapy: Two Opposite Targets with Inevitable Cost. Int J Mol Sci 2022;23:14121. [PMID: 36430599 PMCID: PMC9696420 DOI: 10.3390/ijms232214121] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/10/2022] [Accepted: 11/12/2022] [Indexed: 11/17/2022] Open

Won T, Kalinoski HM, Wood MK, Hughes DM, Jaime CM, Delgado P, Talor MV, Lasrado N, Reddy J, Čiháková D. Cardiac myosin-specific autoimmune T cells contribute to immune-checkpoint-inhibitor-associated myocarditis. Cell Rep 2022;41:111611. [PMID: 36351411 PMCID: PMC11108585 DOI: 10.1016/j.celrep.2022.111611] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 08/15/2022] [Accepted: 10/14/2022] [Indexed: 11/09/2022] Open

The prognostic value of global myocardium strain by CMR-feature tracking in immune checkpoint inhibitor-associated myocarditis. Eur Radiol 2022;32:7657-7667. [PMID: 35567603 DOI: 10.1007/s00330-022-08844-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 01/03/2023]

Abstract

OBJECTIVES

Immune checkpoint inhibitor (ICI)-associated myocarditis is a potentially fatal complication. Sparse published researches evaluated the prognostic value of cardiovascular magnetic resonance feature tracking (CMR-FT) for ICI-associated myocarditis.

METHODS

In the single-center retrospective study, 52 patients with ICI-associated myocarditis and CMR were included from August 2018 to July 2021. The ICI-associated myocarditis was diagnosed by using the clinical criteria of the European Society of Cardiology guidelines. Major adverse cardiovascular events (MACE) were comprised of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block.

RESULTS

During a median follow-up of 171 days, 14 (27%) patients developed MACE. For patients with MACE, the global circumferential strain (GCS), global radial strain (GRS), global longitudinal strain (GLS), and left ventricular ejection fraction (LVEF) were significantly worse and native T1 values and late gadolinium enhancement (LGE) extent were significantly increased, compared with patients without MACE (p < 0.05). The GLS remained the independent factor associated with a higher risk of MACE (hazard ratio (HR): 2.115; 95% confidence interval (CI): 1.379-3.246; p = 0.001) when adjusting for LVEF, LGE extent, age, sex, body mass index, steroid treatment, and prior cardiotoxic chemotherapy or radiation. After adjustment for LVEF, the GLS remained the independent risk factor associated with a higher rate of MACE among patients with a preserved LVEF (HR: 1.358; 95% CI: 1.007-1.830; p = 0.045).

CONCLUSIONS

GLS could provide independent prognostic value over GCS, GRS, traditional CMR features, and clinical features in patients with ICI-associated myocarditis.

KEY POINTS

• The global circumferential strain (GCS), global radial strain (GRS), and global longitudinal strain (GLS) by cardiovascular magnetic resonance feature tracking were significantly impaired in patients with an immune checkpoint inhibitor (ICI)-associated myocarditis. • GLS was still significantly impaired in patients with preserved left ventricular ejection fraction. • The worse GLS was an independent risk factor over GCS, GRS, traditional CMR features, and clinical features for predicting major adverse cardiovascular events in patients with ICI-associated myocarditis.

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Zhao SH, Yun H, Chen CZ, Chen YY, Lin JY, Zeng MS, Liu TS, Pan CZ, Jin H. Applying quantitative CMR parameters for detecting myocardial lesion in immune checkpoint inhibitors-associated myocarditis. Eur J Radiol 2022;156:110558. [PMID: 36265221 DOI: 10.1016/j.ejrad.2022.110558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/20/2022] [Accepted: 10/10/2022] [Indexed: 11/21/2022]

Abstract

PURPOSE

Sparse researches evaluated the quantitative cardiovascular magnetic resonance (CMR) parameters for immune checkpoint inhibitors (ICI)-associated myocarditis. We aimed to apply quantitative CMR mappings and late gadolinium enhancement (LGE) extent for detecting ICI-associated myocarditis.

METHOD

The retrospective study included patients with ICI-associated myocarditis and CMR examination from August 2018 to August 2021 in our hospital. ICI-associated myocarditis was clinically diagnosed based on the clinical criteria by European Society of Cardiology guidelines. The multiparametric CMR images including T2 mapping and black blood T2-weighted images were used to evaluate myocardial edema. The myocardial edema ratio (ER) ≥ 2.0 was applied for determining myocardial edema on T2-weighted images.

RESULTS

56 patients with ICI-associated myocarditis were included. The global T2 value and native T1 value of patients with ICI-associated myocarditis were significantly higher than the reference ranges in our hospital (p < 0.05). The rate of elevated global T2 value (92%) was significantly higher than those of abnormal native T1 value (73%), ER (52%) and LGE presence (68%) in patients with ICI-associated myocarditis (p < 0.05). The LGE extent and left ventricular ejection fraction of patients with ICI-associated myocarditis were 10.38 ± 9.64% and 56.42 ± 8.54%, respectively. LGE extent inversely correlated with left ventricular ejection fraction (r = -0.38, p = 0.004) but positively correlated with native T1 value (r = 0.28, p < 0.04) and extracellular volume (r = 0.50, p = 0.001).

CONCLUSIONS

T2 mapping could detect higher rate of patients with ICI-associated myocarditis than native T1 mapping, ER and LGE presence. LGE extent inversely correlated with left ventricular ejection fraction but positively correlated with native T1 value and extracellular volume in patients with ICI-associated myocarditis.

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Affiliation(s)

Shi-Hai Zhao Department of Radiology, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, Shanghai, China; Department of Medical Imaging, Shanghai Medical School, Fudan University, Shanghai, China; Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
Hong Yun Department of Radiology, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, Shanghai, China; Department of Medical Imaging, Shanghai Medical School, Fudan University, Shanghai, China; Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
Cai-Zhong Chen Department of Radiology, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, Shanghai, China; Department of Medical Imaging, Shanghai Medical School, Fudan University, Shanghai, China; Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
Yin-Yin Chen Department of Radiology, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, Shanghai, China; Department of Medical Imaging, Shanghai Medical School, Fudan University, Shanghai, China; Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
Jin-Yi Lin Department of Cardiology, Zhongshan Hospital, Fudan University and Shanghai Institute of Cardiovascular Diseases, Shanghai, China
Meng-Su Zeng Department of Radiology, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, Shanghai, China; Department of Medical Imaging, Shanghai Medical School, Fudan University, Shanghai, China; Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
Tian-Shu Liu Department of Medical Oncology, Zhongshan Hospital of Fudan University, Shanghai, China; Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
Cui-Zhen Pan Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai, China.
Hang Jin Department of Radiology, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, Shanghai, China; Department of Medical Imaging, Shanghai Medical School, Fudan University, Shanghai, China; Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China

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Ganesh S, Zhong P, Zhou X. Cardiotoxicity induced by immune checkpoint inhibitor: The complete insight into mechanisms, monitoring, diagnosis, and treatment. Front Cardiovasc Med 2022;9:997660. [PMID: 36204564 PMCID: PMC9530557 DOI: 10.3389/fcvm.2022.997660] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/05/2022] [Indexed: 11/17/2022] Open

Ruperti-Repilado FJ, van der Stouwe JG, Haaf P, Mueller C, Läubli H, Pfister O, Rothschild SI, Kuster GM. Case report of elevation of high-sensitivity cardiac troponin T in the absence of cardiac involvement in immune checkpoint inhibitor-associated myositis. Eur Heart J Case Rep 2022;6:ytac353. [PMID: 36090458 PMCID: PMC9449681 DOI: 10.1093/ehjcr/ytac353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/22/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022]

Abstract

Background

Immune checkpoint inhibitors (ICIs) have markedly improved outcome in various types of cancer. ICI-associated myocarditis is one of the most severe immune-related adverse events. In particular, high concentrations of cardiac troponin T (cTnT) are associated with a high risk of death and early detection and vigorous therapy with high-dose steroids may improve survival. However, chronic skeletal muscle disorders have been suggested as a non-cardiac source of elevated high-sensitivity cardiac troponin T (hs-cTnT) concentrations.

Case summary

Here, we present the case of a 72-year-old patient with metastatic melanoma treated with nivolumab and ipilimumab, who developed symptomatic myositis [creatine kinase (CK) max. 3113 U/L]. Due to substantially elevated concentrations of hs-cTnT (max. 1128 ng/L, normal <14 ng/L, Elecsys), the patient was referred to the cardio-oncology unit for evaluation of concomitant myocarditis. The patient did not report any cardiac symptoms and there were no clinical signs of congestion or rhythm abnormalities. Concentrations of NT-proBNP were within the normal range. Echocardiography showed normal cardiac dimensions and normal systolic and diastolic function. Cardiac magnetic resonance imaging confirmed these findings and also showed no evidence of acute or post-inflammatory myocardial tissue changes. Absence of relevant cardiomyocyte injury was supported by determination of normal levels of cardiac troponin I concentrations and made endomyocardial biopsy in this severely ill patient unnecessary.

Discussion

Our observation documents ICI-induced myositis as an alternative non-cardiac cause of hs-cTnT elevation. A global cardiologic approach employing clinical and cardiac magnetic resonance imaging data as well as NT-proBNP and cardiac troponin I helps to identify false positive hs-TnT elevation under ICI therapy.

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Myocarditis Induced by Immunotherapy in Metastatic Melanoma—Review of Literature and Current Guidelines. J Clin Med 2022;11:jcm11175182. [PMID: 36079112 PMCID: PMC9457343 DOI: 10.3390/jcm11175182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open

Yun CO, Hong J, Yoon AR. Current clinical landscape of oncolytic viruses as novel cancer immunotherapeutic and recent preclinical advancements. Front Immunol 2022;13:953410. [PMID: 36091031 PMCID: PMC9458317 DOI: 10.3389/fimmu.2022.953410] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/03/2022] [Indexed: 12/12/2022] Open

Stefanovic F, Gomez-Caminero A, Jacobs DM, Subramanian P, Puzanov I, Chilbert MR, Feuerstein SG, Yatsynovich Y, Switzer B, Schentag JJ. Neural Net Modeling of Checkpoint Inhibitor Related Myocarditis and Steroid Response. CLINICAL PHARMACOLOGY : ADVANCES AND APPLICATIONS 2022;14:69-90. [PMID: 35975122 PMCID: PMC9376002 DOI: 10.2147/cpaa.s369008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 08/02/2022] [Indexed: 02/02/2023]

Abstract

Background

Serious but rare side effects associated with immunotherapy pose a difficult problem for regulators and practitioners. Immune checkpoint inhibitors (ICIs) have come into widespread use in oncology in recent years and are associated with rare cardiotoxicity, including potentially fatal myocarditis. To date, no comprehensive model of myocarditis progression and outcomes integrating time-series based laboratory and clinical signals has been constructed. In this paper, we describe a time-series neural net (NN) model of ICI-related myocarditis derived using supervised machine learning.

Methods

We extracted and modeled data from electronic medical records of ICI-treated patients who had an elevation in their troponin. All data collection was performed using an electronic case report form, with approximately 300 variables collected on as many occasions as available, yielding 6000 data elements per patient over their clinical course. Key variables were scored 0-5 and sequential assessments were used to construct the model. The NN model was developed in MatLab and applied to analyze the time course and outcomes of treatments.

Results

We identified 23 patients who had troponin elevations related to their ICI therapy, 15 of whom had ICI-related myocarditis, while the remaining 8 patients on ICIs had other causes for troponin elevation, such as myocardial infarction. Our model showed that troponin was the most predictive biomarker of myocarditis, in line with prior studies. Our model also identified early and aggressive use of steroid treatment as a major determinant of survival for cases of grade 3 or 4 ICI-related myocarditis.

Conclusion

Our study shows that a supervised learning NN can be used to model rare events such as ICI-related myocarditis and thus provide clinical insight into drivers of progression and treatment outcomes. These findings direct attention to early detection biomarkers and clinical symptoms as the best means of implementing early and potentially life-saving steroid treatment.

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Pan W, Yin L, Guo Y, Pan D, Huang H. Case Report: Good cardiac tolerance to Toripalimab in a CVD patient with oral melanoma. Front Pharmacol 2022;13:890546. [PMID: 35979233 PMCID: PMC9376878 DOI: 10.3389/fphar.2022.890546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 06/28/2022] [Indexed: 11/20/2022] Open

Sun G, Liu H, Shi X, Tan P, Tang W, Chen X, Sun G, Yang W, Kong X, Zheng Z, Cao H, Shao G. Treatment of patients with cancer using PD‑1/PD‑L1 antibodies: Adverse effects and management strategies (Review). Int J Oncol 2022;60:74. [PMID: 35485291 PMCID: PMC9084612 DOI: 10.3892/ijo.2022.5364] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 03/14/2022] [Indexed: 12/12/2022] Open

Affiliation(s)

Guangshun Sun Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
Hanyuan Liu Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
Xuesong Shi Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
Pengyu Tan Department of Food Science and Engineering, Nanjing Xiaozhuang University, Nanjing, Jiangsu 211166, P.R. China
Weiwei Tang Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 215005, P.R. China
Xin Chen Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
Guoqiang Sun Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
Weijun Yang Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
Xiangyi Kong Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 215005, P.R. China
Zhiying Zheng Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 215005, P.R. China
Hongyong Cao Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
Guoqiang Shao Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China

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Tonry C, Russel-Hallinan A, McCune C, Collier P, Harbinson M, Dixon L, Watson CJ. Circulating biomarkers for management of cancer therapeutics related cardiac dysfunction. Cardiovasc Res 2022;119:710-728. [PMID: 35640873 PMCID: PMC10153425 DOI: 10.1093/cvr/cvac087] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 05/09/2022] [Accepted: 05/15/2022] [Indexed: 11/14/2022] Open

Chen X, Jiang A, Zhang R, Fu X, Liu N, Shi C, Wang J, Zheng X, Tian T, Liang X, Ruan Z, Yao Y. Immune Checkpoint Inhibitor-Associated Cardiotoxicity in Solid Tumors: Real-World Incidence, Risk Factors, and Prognostic Analysis. Front Cardiovasc Med 2022;9:882167. [PMID: 35669482 PMCID: PMC9163804 DOI: 10.3389/fcvm.2022.882167] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/20/2022] [Indexed: 11/13/2022] Open

Abstract BackgroundImmune checkpoint inhibitors (ICIs) have achieved acknowledged progress in cancer therapy. However, ICI-associated cardiotoxicity as one of the most severe adverse events is potentially life-threatening, with limited real-world studies reporting its predictive factors and prognosis. This study aimed to investigate the real-world incidence, risk factors, and prognosis of ICI-related cardiotoxicity in patients with advanced solid tumors.MethodsElectronic medical records from patients with advanced solid tumors receiving ICIs in the First Affiliated Hospital of Xi’an Jiaotong University were retrospectively reviewed. All patients were divided into the cardiotoxicity group and control group, with logistic regression analysis being implemented to identify potential risk factors of ICI-related cardiotoxicity. Furthermore, survival analysis was also performed to investigate the prognosis of patients with ICI-related cardiotoxicity.ResultsA total of 1,047 participants were enrolled in this retrospective study. The incidence of ICI-related cardiotoxicity in our hospital is 7.0%, while grade 3 and above cardiotoxicity was 2.4%. The logistic regression analysis revealed that diabetes mellitus [odds ratio (OR):1.96, 95% confidence Interval (CI): 1.05–3.65, p = 0.034] was an independent risk factor, whereas baseline lymphocyte/monocyte ratio (LMR) (OR: 0.59, 95% CI: 0.36–0.97, p = 0.037) was the protective factor of ICI-related cardiotoxicity. Survival analysis indicated that severe cardiotoxicity (≥grade 3) was significantly correlated with bleak overall survival (OS) than mild cardiotoxicity (≤grade 2) (8.3 months vs. not reached, p = 0.001). Patients with ICI-related overlap syndrome had poorer overall survival than patients with mere cardiotoxicity (9.4 vs. 24.7 months, p = 0.033). However, the occurrence of ICI-related cardiotoxicity was not significantly associated with the OS of overall population with solid tumors. Subgroup analysis showed that lung cancer and PD-L1 usage were significantly correlated with a higher incidence of severe cases.ConclusionImmune checkpoint inhibitor-related cardiotoxicity is more common in the real-world setting than the previously published studies. Diabetes mellitus and baseline LMR are the potential predictive biomarkers of ICI-related cardiotoxicity. Although ICI-related cardiotoxicity is not correlated with the prognosis of these patients in our cohort, a systematic and comprehensive baseline examination and evaluation should be performed to avoid its occurrence. Collapse

Dong H, Qi Y, Kong X, Wang Z, Fang Y, Wang J. PD-1/PD-L1 Inhibitor-Associated Myocarditis: Epidemiology, Characteristics, Diagnosis, Treatment, and Potential Mechanism. Front Pharmacol 2022;13:835510. [PMID: 35517794 PMCID: PMC9062035 DOI: 10.3389/fphar.2022.835510] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/14/2022] [Indexed: 12/19/2022] Open

Kersting D, Settelmeier S, Mavroeidi IA, Herrmann K, Seifert R, Rischpler C. Shining Damaged Hearts: Immunotherapy-Related Cardiotoxicity in the Spotlight of Nuclear Cardiology. Int J Mol Sci 2022;23:3802. [PMID: 35409161 PMCID: PMC8998973 DOI: 10.3390/ijms23073802] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/20/2022] [Accepted: 03/25/2022] [Indexed: 11/30/2022] Open

Zhou J, Lee S, Lakhani I, Yang L, Liu T, Zhang Y, Xia Y, Wong WT, Bao KKH, Wong ICK, Tse G, Zhang Q. Adverse Cardiovascular Complications following prescription of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors: a propensity-score matched Cohort Study with competing risk analysis. CARDIO-ONCOLOGY (LONDON, ENGLAND) 2022;8:5. [PMID: 35300724 PMCID: PMC8928662 DOI: 10.1186/s40959-021-00128-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 12/20/2021] [Indexed: 12/18/2022]

Abstract

BACKGROUND

Programmed death-1 (PD-1) and programmed death- ligand 1 (PD-L1) inhibitors, such as pembrolizumab, nivolumab and atezolizumab, are major classes of immune checkpoint inhibitors that are increasingly used for cancer treatment. However, their use is associated with adverse cardiovascular events. We examined the incidence of new-onset cardiac complications in patients receiving PD-1 or PD-L1 inhibitors.

METHODS

Patients receiving PD-1 or PD-L1 inhibitors since their launch up to 31st December 2019 at publicly funded hospitals of Hong Kong, China, without pre-existing cardiac complications were included. The primary outcome was a composite of incident heart failure, acute myocardial infarction, atrial fibrillation, or atrial flutter with the last follow-up date of 31st December 2020. Propensity score matching between PD-L1 inhibitor use and PD-1 inhibitor use with a 1:2 ratio for patient demographics, past comorbidities and non-PD-1/PD-L1 medications was performed with nearest neighbour search strategy (0.1 caliper). Univariable and multivariable Cox regression analysis models were conducted. Competing risks models and multiple propensity matching approaches were considered for sensitivity analysis.

RESULTS

A total of 1959 patients were included. Over a median follow-up of 247 days (interquartile range [IQR]: 72-506), 320 (incidence rate [IR]: 16.31%) patients met the primary outcome after PD-1/PD-L1 treatment: 244 (IR: 12.57%) with heart failure, 38 (IR: 1.93%) with acute myocardial infarction, 54 (IR: 2.75%) with atrial fibrillation, 6 (IR: 0.31%) with atrial flutter. Compared with PD-1 inhibitor treatment, PD-L1 inhibitor treatment was significantly associated with lower risks of the composite outcome both before (hazard ratio [HR]: 0.32, 95% CI: [0.18-0.59], P value=0.0002) and after matching (HR: 0.34, 95% CI: [0.18-0.65], P value=0.001), and lower all-cause mortality risks before matching (HR: 0.77, 95% CI: [0.64-0.93], P value=0.0078) and after matching (HR: 0.80, 95% CI: [0.65-1.00], P value=0.0463). Patients who developed cardiac complications had shorter average readmission intervals and a higher number of hospitalizations after treatment with PD-1/PD-L1 inhibitors in both the unmatched and matched cohorts (P value<0.0001). Multivariable Cox regression models, competing risk analysis with cause-specific and subdistribution hazard models, and multiple propensity approaches confirmed these observations.

CONCLUSIONS

Compared with PD-1 treatment, PD-L1 treatment was significantly associated with lower risk of new onset cardiac complications and all-cause mortality both before and after propensity score matching.

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Affiliation(s)

Jiandong Zhou Nuffield Department of Medicine, University of Oxford, Oxford, UK Cardio-Oncology Research Unit, Cardiovascular Analytics Group, UK Collaboration, Hong Kong, China
Sharen Lee Cardio-Oncology Research Unit, Cardiovascular Analytics Group, UK Collaboration, Hong Kong, China
Ishan Lakhani Cardio-Oncology Research Unit, Cardiovascular Analytics Group, UK Collaboration, Hong Kong, China
Lei Yang Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, 300211, Tianjin, China
Tong Liu Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, 300211, Tianjin, China
Yuhui Zhang Heart Failure Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Yunlong Xia Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
Wing Tak Wong School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China
Kelvin King Hei Bao Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
Ian Chi Kei Wong Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong, China
Gary Tse Cardio-Oncology Research Unit, Cardiovascular Analytics Group, UK Collaboration, Hong Kong, China. Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, 300211, Tianjin, China. Kent and Medway Medical School, Canterbury, UK.
Qingpeng Zhang Nuffield Department of Medicine, University of Oxford, Oxford, UK. School of Data Science, City University of Hong Kong, Hong Kong, China.

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Brumberger ZL, Branch ME, Klein MW, Seals A, Shapiro MD, Vasu S. Cardiotoxicity risk factors with immune checkpoint inhibitors. CARDIO-ONCOLOGY (LONDON, ENGLAND) 2022;8:3. [PMID: 35277208 PMCID: PMC8915459 DOI: 10.1186/s40959-022-00130-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 02/21/2022] [Indexed: 12/18/2022]

Abstract

Background

Checkpoint-inhibitor immunotherapies have had a profound effect in the treatment of cancer by inhibiting down-regulation of T-cell response to malignancy. The cardiotoxic potential of these agents was first described in murine models and, more recently, in numerous clinical case reports of pericarditis, myocarditis, pericardial effusion, cardiomyopathy, and new arrhythmias. The objective of our study was to determine the frequency of and associated risk factors for cardiotoxic events in patients treated with immune checkpoint inhibitors.

Methods

Medical records of patients who underwent immunotherapy with durvalumab, ipilimumab, nivolumab, and pembrolizumab at Wake Forest Baptist Health were reviewed. We collected retrospective data regarding sex, cancer type, age, and cardiovascular disease risk factors and medications. We aimed to identify new diagnoses of heart failure, atrial fibrillation, ventricular fibrillation/tachycardia, myocarditis, and pericarditis after therapy onset. To assess the relationship between CVD risk factors and the number of cardiac events, a multivariate model was applied using generalized linear regression. Incidence rate ratios were calculated for every covariate along with the adjusted P-value. We applied a multivariate model using logistic regression to assess the relationship between CVD risk factors and mortality. Odds ratios were calculated for every covariate along with the adjusted P-value. Adjusted P-values were calculated using multivariable regression adjusting for other covariates.

Results

Review of 538 medical records revealed the following events: 3 ventricular fibrillation/tachycardia, 12 pericarditis, 11 atrial fibrillation with rapid ventricular rate, 0 myocarditis, 8 heart failure. Significant risk factors included female gender, African American race, and tobacco use with IRR 3.34 (95% CI 1.421, 7.849; P = 0.006), IRR 3.39 (95% CI 1.141, 10.055; P = 0.028), and IRR 4.21 (95% CI 1.289, 13.763; P = 0.017) respectively.

Conclusions

Our study revealed 34 significant events, most frequent being pericarditis (2.2%) and atrial fibrillation (2.0%) with strongest risk factors being female gender, African American race, and tobacco use. Patients who meet this demographic, particularly those with planned pembrolizumab treatment, may benefit from early referral to a cardio-oncologist. Further investigation is warranted on the relationship between CTLA-4 and PD-L1 expression and cardiac adverse events with ICIs, particularly for these subpopulations.

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Mu J, Deng H, Lyu C, Yuan J, Li Q, Wang J, Jiang Y, Deng Q, Shen J. Efficacy of programmed cell death 1 inhibitor maintenance therapy after combined treatment with programmed cell death 1 inhibitors and anti-CD19-CAR T cells in patients with relapsed/refractory diffuse large B-cell lymphoma and high tumor burden. Hematol Oncol 2022;41:275-284. [PMID: 35195933 DOI: 10.1002/hon.2981] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/17/2022] [Accepted: 02/19/2022] [Indexed: 11/08/2022]

Afrin H, Salazar CJ, Kazi M, Ahamad SR, Alharbi M, Nurunnabi M. Methods of screening, monitoring and management of cardiac toxicity induced by chemotherapeutics. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.01.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]