1
|
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.
Collapse
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.
| |
Collapse
|
2
|
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
Abstract
Immune checkpoints, such as PD-1 and CTLA-4, are crucial regulators of immune responses, acting as gatekeepers to balance immunity against foreign antigens and self-tolerance. These checkpoints play a key role in maintaining cardiac homeostasis by preventing immune-mediated damage to critical organs like the heart. In this study, we explored the involvement of PD-1 and CTLA-4 in cardiovascular complications, particularly atherosclerosis and myocarditis, which can lead to heart failure. We conducted a comprehensive analysis using animal models and clinical data to assess the effects of immune checkpoint inhibition on cardiac function. Our findings indicate that disruption of PD-1 and CTLA-4 pathways exacerbates myocardial inflammation, accelerates atherosclerotic plaque formation, and promotes the development of heart failure. Additionally, we observed that immune checkpoint inhibition in these models led to increased infiltration of T lymphocytes, higher levels of pro-inflammatory cytokines, and enhanced tissue damage. These results suggest that PD-1 and CTLA-4 are critical in preserving cardiac health, and their inhibition can result in severe cardiovascular toxicity. Our study emphasizes the need for careful monitoring of cardiovascular health in patients undergoing immune checkpoint inhibitor therapies.
Collapse
Affiliation(s)
- Shoulian Huang
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Cardiology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Yu Kang
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ting Liu
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yan Xiong
- Institute of Cardiovascular Diseases & Department of Cardiology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zixuan Yang
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qing Zhang
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| |
Collapse
|
3
|
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.
Collapse
Affiliation(s)
- Tamás G Gergely
- Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary
| | - Zsófia D Drobni
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Nabil V Sayour
- Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary
| | - Péter Ferdinandy
- Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - Zoltán V Varga
- Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
- HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary.
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary.
| |
Collapse
|
4
|
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]
Abstract
PURPOSE OF REVIEW This review details the significant advancement in knowledge of Immune-checkpoint inhibitor (ICI) and its potential deleterious cardiac immune-related adverse effects (irAE). We explore their mechanisms on the cardiac tissue, providing guidance on risk factors, clinical presentations, diagnostic strategies along with treatment. RECENT FINDINGS Recent findings have provided insights of cardiac irAEs that exist beyond the previously well-known ICI-induced myocarditis. We have a better understanding of the wide variety of cardiac irAEs pathologies both early and late onset. Moreover, there is more data on mechanisms of cardiotoxicity and patient and therapy-related risk factors, supporting closer routine cardiac monitoring with biomarkers and imaging for prevention and early detection. Diagnosing cardiac irAEs is a challenge given its broad clinical presentation. A high-level of suspicion in addition to early work-up is crucial to prevent serious cardiac events. A multi-disciplinary team including Cardiologists and Oncologists is essential for closely monitor patients' cardiac status on ICI therapy. There is a need of updated guidelines to establish clear recommendations in patients on ICIs.
Collapse
Affiliation(s)
- Maria T Gamero
- Department of Medicine, Division of Cardiovascular Disease, Jefferson Heart Institute, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
| | - Avish Patel
- Department of Medicine, Division of Cardiovascular Disease, Jefferson Heart Institute, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Eugene Storozynsky
- Department of Medicine, Division of Cardiovascular Disease, Jefferson Heart Institute, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| |
Collapse
|
5
|
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
Abstract
The increased use of immune checkpoint inhibitors (ICIs) across cancer programs has created the need for standardized monitoring and management of immune-related adverse events (irAEs). Delayed recognition without appropriate treatment can have serious and life-threatening consequences. The management of irAEs presents a unique set of challenges that must be addressed at a multidisciplinary level. Although various national and international guidelines and working groups provide high-level recommendations for the management of irAEs, practical guidance is lacking. Furthermore, timely collaboration between specialists requires institutional protocols that enable the early recognition, assessment, and treatment of irAEs. Such protocols should be developed by institution specialists and include algorithms for all healthcare providers involved in the care of patients treated with ICIs. At William Osler Health System in Brampton, Ontario, practical step-by-step multidisciplinary treatment approaches with recommendations for the management of irAEs were developed in collaboration with experts across Canada. Here, we provide an in-depth description of the approaches, outlining baseline investigations prior to the initiation of ICIs, as well as the monitoring and management of irAEs based on symptoms, severity, and involved organ systems. We encourage other centres to adapt and modify our approaches according to their specific needs and requirements.
Collapse
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.)
| |
Collapse
|
6
|
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.
Collapse
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
| |
Collapse
|
7
|
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
Abstract
Heart failure (HF) is a terminal condition of multiple cardiovascular disorders. Cancer is a deadly disease worldwide. The relationship between HF and cancer remains poorly understood. The Gene Expression Omnibus database was used to download the RNA sequencing data of 356 patients with hypertrophic cardiomyopathy-induced HF and non-HF. A co-expression network was established through the weighted correlation network analysis (WGCNA) to identify hub genes of HF and cancer. Cox risk analysis was performed to predict the prognostic risks of HF hub genes in pan-cancer. HF was linked to immune response pathway by the analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). A positive correlation was observed between the expression levels of 4 hub genes and the infiltration of CD8+T-cells in pan-cancer. 4 hub genes were identified as beneficial prognostic factors in several cancers. Western blotting and real-time polymerase chain reaction validated the high expression of GZMM, NKG7, and ZAP70 in both mice and patients with HF compared to control groups. Our study highlights the shared immune pathogenesis of HF and cancer and provides valuable insights for developing novel therapeutic strategies, offering new opportunities for improving the management and treatment outcomes of both HF and cancer.
Collapse
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.
| |
Collapse
|
8
|
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]
Abstract
Cancer treatment modalities and their progression is guided by the specifics of cancer, including its type and site of localization. Surgery, radiation, and chemotherapy are the most often used conventional treatments. Conversely, emerging treatment techniques include immunotherapy, hormone therapy, anti-angiogenic therapy, dendritic cell-based immunotherapy, and stem cell therapy. Immune checkpoint inhibitors' anticancer properties have drawn considerable attention in recent studies in the cancer research domain. Programmed Cell Death Protein-1 (PD-1) and its ligand (PD-L1) checkpoint pathway are key regulators of the interactions between activated T-cells and cancer cells, protecting the latter from immune destruction. When the ligand PD-L1 attaches to the receptor PD-1, T-cells are prevented from destroying cells that contain PD-L1, including cancer cells. The PD-1/PD-L1 checkpoint inhibitors block them, boosting the immune response and strengthening the body's defenses against tumors. Recent years have seen incredible progress and tremendous advancement in developing anticancer therapies using PD-1/PD-L1 targeting antibodies. While immune-related adverse effects and low response rates significantly limit these therapies, there is a need for research on methods that raise their efficacy and lower their toxicity. This review discusses various recent innovative nanomedicine strategies such as PLGA nanoparticles, carbon nanotubes and drug loaded liposomes to treat cancer targeting PD-1/PD-L1 axis. The biological implications of PD-1/PD-L1 in cancer treatment and the fundamentals of nanotechnology, focusing on the novel strategies used in nanomedicine, are widely discussed along with the corresponding guidelines, clinical trial status, and the patent landscape of such formulations.
Collapse
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.
| |
Collapse
|
9
|
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
Abstract
The last decade has witnessed a paradigm shift in cancer therapy, from non-specific cytotoxic chemotherapies to agents targeting specific molecular mechanisms. Nonetheless, cardiovascular toxicity of cancer therapies remains an important concern. This is particularly relevant given the significant improvement in survival of solid and haematological cancers achieved in the last decades. Cardio-oncology is a subspecialty of medicine focusing on the identification and prevention of cancer therapy-related cardiovascular toxicity (CTR-CVT). This review will examine the new definition of CTR-CVT and guiding principles for baseline cardiovascular assessment and risk stratification before cancer therapy, providing take-home messages for non-specialized cardiologists.
Collapse
Affiliation(s)
- Iacopo Fabiani
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy
| | - Michela Chianca
- Interdisciplinary Center for Health Science, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Alberto Aimo
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy
- Interdisciplinary Center for Health Science, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Michele Emdin
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy
- Interdisciplinary Center for Health Science, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Susan Dent
- Duke Cancer Institute, Duke University, Durham, NC, USA
| | - Antonella Fedele
- Cardioncology Unit, Cardioncology and Second Opinion Division, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
| | - Carlo Maria Cipolla
- Cardioncology Unit, Cardioncology and Second Opinion Division, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
| | - Daniela Maria Cardinale
- Cardioncology Unit, Cardioncology and Second Opinion Division, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
| |
Collapse
|
10
|
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
Abstract
Immune checkpoint inhibitors (ICIs) are monoclonal antibody antagonists, which can block cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1/ligand-1 (PD-1/PD-L1) pathways, and other molecules exploited by tumor cells to evade T cell-mediated immune response. ICIs have transformed the treatment landscape for various cancers due to their amazing efficacy. Many anti-tumor therapies, including targeted therapy, radiotherapy, and chemotherapy, combine ICIs to make the treatment more effective. However, the off-target immune activation caused by ICIs may lead to a broad spectrum of immune-related adverse events (irAEs) affecting multiple organ systems. Among irAEs, cardiotoxicity induced by ICIs, uncommon but fatal, has greatly offset survival benefits from ICIs, which is heartbreaking for both patients and clinicians. Consequently, such cardiotoxicity requires special vigilance, and it has become a common challenge both for patients and clinicians. This article reviewed the clinical manifestations and influence of cardiotoxicity from the view of patients and clinicians, elaborated on the underlying mechanisms in conjunction with animal studies, and then attempted to propose management strategies from a cardio-immuno-oncology multidisciplinary perspective.
Collapse
Affiliation(s)
- Yingying He
- Oncology Department, Deyang People's Hospital, Deyang, Sichuan 618000, China
- Department of Medical Oncology, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China
| | - Hui Yu
- Cardiovascular Department, Mianyang Central Hospital, Mianyang, Sichuan 621000, China
| | - Shuang Dai
- Department of Medical Oncology, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China
| | - Miao He
- Oncology Department, Deyang People's Hospital, Deyang, Sichuan 618000, China
- Department of Medical Oncology, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China
| | - Ling Ma
- Department of Rheumatology and Immunology, Deyang People's Hospital, Deyang, Sichuan 618000, China
| | - Zihan Xu
- Department of Medical Oncology, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China
| | - Feng Luo
- Department of Medical Oncology, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China
| | - Li Wang
- Department of Medical Oncology, Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China
| |
Collapse
|
11
|
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
Abstract
Immune checkpoint inhibitors (ICIs) are specialized monoclonal antibodies (mAbs) that target immune checkpoints and their ligands, counteracting cancer cell-induced T-cell suppression. Approved ICIs like cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), its ligand PD-L1, and lymphocyte activation gene-3 (LAG-3) have improved cancer patient outcomes by enhancing anti-tumor responses. However, some patients are unresponsive, and others experience immune-related adverse events (irAEs), affecting organs like the lung, liver, intestine, skin and now the cardiovascular system. These cardiac irAEs include conditions like myocarditis, atherosclerosis, pericarditis, arrhythmias, and cardiomyopathy. Ongoing clinical trials investigate promising alternative co-inhibitory receptor targets, including T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). This review delves into the mechanisms of approved ICIs (CTLA-4, PD-1, PD-L1, and LAG-3) and upcoming options like Tim-3 and TIGIT. It explores the use of ICIs in cancer treatment, supported by both preclinical and clinical data. Additionally, it examines the mechanisms behind cardiac toxic irAEs, focusing on ICI-associated myocarditis and atherosclerosis. These insights are vital as ICIs continue to revolutionize cancer therapy, offering hope to patients, while also necessitating careful monitoring and management of potential side effects, including emerging cardiac complications.
Collapse
Affiliation(s)
- Wonyoung Jo
- Department of Biomedical Engineering, Johns Hopkins University, Whiting School of Engineering, Baltimore, MD, United States
| | - Taejoon Won
- Department of Pathobiology, University of Illinois Urbana-Champaign, College of Veterinary Medicine, Urbana, IL, United States
| | - Abdel Daoud
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, United States
| | - Daniela Čiháková
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, United States
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
| |
Collapse
|
12
|
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
Abstract
This review aims to provide an understanding of the diagnostic and therapeutic challenges of uveitis associated with immune checkpoint inhibitors (ICI). In the wake of these molecules being increasingly employed as a treatment against different cancers, cases of uveitis post-ICI therapy have also been increasingly reported in the literature, warranting an extensive exploration of the clinical presentations, risk factors, and pathophysiological mechanisms of ICI-induced uveitis. This review further provides an understanding of the association between ICIs and uveitis, and assesses the efficacy of current diagnostic tools, underscoring the need for advanced techniques to enable early detection and accurate assessment. Further, it investigates the therapeutic strategies for ICI-related uveitis, weighing the benefits and limitations of existing treatment regimens, and discussing current challenges and emerging therapies in the context of their potential efficacy and side effects. Through an overview of the short-term and long-term outcomes, this article suggests recommendations and emphasizes the importance of multidisciplinary collaboration between ophthalmologists and oncologists. Finally, the review highlights promising avenues for future research and development in the field, potentially informing transformative approaches in the ocular assessment of patients under immunotherapy and the management of uveitis following ICI therapy.
Collapse
Affiliation(s)
- Huixin Zhang
- Faculty of Medicine, Laval University, Quebec, QC G1V 0A6, Canada;
| | - Lysa Houadj
- Faculty of Medicine, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada;
| | - Kevin Y. Wu
- Department of Surgery, Division of Ophthalmology, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada
| | - Simon D. Tran
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada
| |
Collapse
|
13
|
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]
Abstract
BACKGROUND This study aims to investigate the effect of PD-1/PD-L1 immunotherapy on cardiac-related adverse events in patients with advanced or metastatic lung cancer. METHODS We conducted a detailed search in PubMed, Web of Science, Cochran, and Embase for articles on the application of immunotherapy for lung cancer and report cardiac-related adverse events with respect to myocardial ischemia, pericardial effusion, myocarditis, and electrophysiology. The dichotomous variables were assessed by relative risk (RR) and 95% confidence intervals (CI). RESULTS A total of 7132 subjects were included in 12 phase III randomized controlled trials (RCTs). The results showed that under the fixed effects model, the probability of cardiac-related adverse events in pericardial effusion was higher in the experimental group than in the control group (RR 2.30, 95% CI 1.01-5.21, P = 0.05). Under the random effects model, there was no statistical difference between the two groups (RR 2.03, 95% CI 0.81-5.12, P = 0.13). No statistical difference is observed between the experimental group and the control group (under the fixed effects model and the random effects model) for other cardiac-related adverse events, including myocarditis, acute coronary syndrome, myocardial infarction, acute myocardial infarction, myocardial ischemia, unstable angina, ventricular tachycardia, supraventricular tachycardia, tachycardia, bradycardia, atrial flutter, atrial fibrillation, cardiac failure, cardiac arrest, cardiopulmonary failure, acute heart failure, cardiac arrest (all P > 0.05). CONCLUSIONS PD-1/PD-L1 immunotherapy in advanced or metastatic lung cancer is generally safe for cardiac-related adverse events.
Collapse
Affiliation(s)
- Bangsheng Chen
- Emergency Medical Center, Ningbo Yinzhou No. 2 Hospital, Ningbo, Zhejiang, China
| | - Anyi Xu
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yujing He
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yueming Zhang
- Intensive Care Unit, Hospital of Zhejiang People's Armed Police, Hangzhou, Zhejiang, China
| | - Dongying Cheng
- Community Department, Ningbo Yinzhou No. 3 Hospital, Ningbo, Zhejiang, China
| | - Yingying Fang
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jiale Ruan
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Min Dai
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yu Wang
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jie Zhang
- Emergency Department, Zhuji People's Hospital, No.9, Jianmin Road, Taozhu Street, Shaoxing, 311899, Zhejiang, China.
| |
Collapse
|
14
|
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.
Collapse
Affiliation(s)
- Rohail Gul
- Internal Medicine, Shifa Tameer-E-Millat University Shifa College of Medicine, Islamabad, PAK
| | | | - Anber Mahboob
- Internal Medicine, Sharif Medical and Dental College, Lahore, PAK
| | - Hira K Kareem
- Internal Medicine, King Edward Medical University, Lahore, PAK
| | - Arslan Inayat
- Internal Medicine, HSHS St. Marys Hospital, Decatur, USA
| | - Danish Safi
- Hematology and Medical Oncology, West Virginia University School of Medicine, Morgantown, USA
| | - Amir Kamran
- Hematology and Medical Oncology, Charleston Area Medical Center, Charleston, USA
| |
Collapse
|
15
|
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]
Abstract
T-cell lymphomas (TCLs) are a rare and heterogeneous subgroup of non-Hodgkin lymphomas (NHLs), forming only 10 % of all NHL cases in Western countries. Resulting from their low incidence and heterogeneity, the current treatment outcome is generally unfavorable, with limited availability of novel therapeutic approaches. Therefore, the recent success of immune checkpoint inhibitors (ICIs) in cancer treatment motivated their clinical investigation in TCLs as well. Multiple studies showed promising results; however, cases of TCL hyperprogression following ICI treatment and secondary T-cell-derived malignancies associated with ICI treatment of other cancer types were also reported. In our review, we first briefly summarize classification of T-cell-derived malignancies, general anti-tumor immune response, immune evasion, and immune checkpoint signaling. Next, we provide an overview of immune checkpoint molecule deregulation in TCLs, summarize available studies of ICIs in TCLs, and review the above-mentioned safety concerns associa-ted with ICI treatment and T-cell-derived malignancies. Despite initial promising results, further studies are necessary to define the most suitable clinical applications and ICI therapeutic combinations with other novel treatment approaches within TCL treatment. ICIs, and their combinations, might hopefully bring the long awaited improvement for the treatment of T-cell-derived malignancies.
Collapse
Affiliation(s)
- Jana Seňavová
- 1st Department of Medicine - Department of Haematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Anežka Rajmonová
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Václav Heřman
- 1st Department of Medicine - Department of Haematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Filip Jura
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Adriana Veľasová
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Iva Hamová
- 1st Department of Medicine - Department of Haematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Anton Tkachenko
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Kristýna Kupcová
- 1st Department of Medicine - Department of Haematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Ondřej Havránek
- 1st Department of Medicine - Department of Haematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic.
| |
Collapse
|
16
|
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
Abstract
Immune checkpoint inhibitors (ICIs) have generated considerable excitement as a novel class of immunotherapeutic agents due to their remarkable efficacy in treating various types of cancer. However, the widespread use of ICIs has brought about a number of safety concerns, especially the development of immune-related adverse events (irAEs). These serious complications could result in treatment discontinuation and even life-threatening consequences, making it critical to identify high-risk groups and predictive markers of irAEs before initiating therapy. To this end, the current article examines several potential predictive markers of irAEs in important organs affected by ICIs. While retrospective studies have yielded some promising results, limitations such as small sample sizes, variable patient populations, and specific cancer types and ICIs studied make it difficult to generalize the findings. Therefore, prospective cohort studies and real-world investigations are needed to validate the potential of different biomarkers in predicting irAEs risk. Overall, identifying predictive markers of irAEs is a crucial step towards improving patient safety and enhancing the management of irAEs. With ongoing research efforts, it is hoped that more accurate and reliable biomarkers will be identified and incorporated into clinical practice to guide treatment decisions and prevent the development of irAEs in susceptible patients.
Collapse
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
| |
Collapse
|
17
|
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]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are an emerging tool in the treatment of brain metastases (BMs), Stereotactic radiosurgery (SRS), traditionally used for BMs, elicits an immune brain response and can act synergistically with ICIs. We aim to investigate the efficacy of ICI administered with SRS and determine the impact of timing on BM response. METHODS A systematical search was performed to identify potential studies concerning BMs managed with SRS alone or with SRS + ICI with relative timing administration (ICI concurrent with SRS, ICI nonconcurrent with SRS, SRS before ICI, SRS after ICI). The overall survival (OS), 12-month OS, local progression-free survival (LPFS), 12-month local brain control (LBC), distant progression-free survival (DPFS), 12-month distant brain control (DBC), and adverse events (intracranial hemorrhage, radionecrosis) were analyzed using the random-effects model. RESULTS A total of 16 retrospective studies with 1356 BM patients were included. Compared to nonconcurrent therapy, concurrent therapy revealed a significantly longer OS (HR= 1.43; p = 0.008) and 12-months LBC (HR = 1.91; p = 0.04), a similar 12-months DBC (HR = 1.12; p = 0.547) and higher complication rate (R = 0.77; p = 0.346). Concurrent therapy leads to a significantly higher OS compared to ICI before SRS (HR = 2.55; p = 0.0003). CONCLUSION The combination of SRS with ICI improves patients' clinical and radiological outcomes. The effectiveness of the combination is subject to the identification of an optimal therapeutic window.
Collapse
Affiliation(s)
- Samireh Badrigilan
- Department of Medical Physics, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Antonio Meola
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Steven D Chang
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Shahab Rezaeian
- Research Center for Environmental Determinants of Health (RCEDH), Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hossein Nemati
- Department of Epidemiology, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Tinoosh Almasi
- Department of Medical Physics, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nima Rostampour
- Department of Medical Physics, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| |
Collapse
|
18
|
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]
Abstract
The use of immunotherapies like pembrolizumab (PEM) is increasingly common for the management of numerous cancer types. The use of PEM to bolster T-cell response against tumor growth is well documented. However, the interactions PEM has on other immune cells to facilitate tumor regression and clearance is unknown and warrants further investigation. In this review, we present literature findings that have reported the interactions of PEM in stimulating innate and adaptive immune cells, which enhance cytotoxic phenotypes. This triggers secretion of cytokines and chemokines, which have both beneficial and detrimental effects. We also describe how this leads to the development of rare but underreported occurrence of PEM-induced immune-related cardiovascular complications that arise suddenly and progress rapidly to debilitating and fatal consequences. This review encourages further research and investigation of PEM-induced cardiovascular complications and other immune cell interactions in patients with cancer. As PEM therapy in treating cancer types is expanding, we expect that this review will inform health care professionals of diverse specializations of medicine like dermatology (melanoma skin cancers), ophthalmology (eye cancers), and pathology (hematological malignancies) about PEM-induced cardiac complications.
Collapse
Affiliation(s)
- Abha Banerjee
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States
| | - Chandrakala Aluganti Narasimhulu
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States
| | - Dinender K Singla
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States
| |
Collapse
|
19
|
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
Abstract
Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy advances rapidly in the clinic. Despite their therapeutic benefits, ICIs can cause clinically significant immune-related adverse events (irAEs), including myocarditis. However, the cellular and molecular mechanisms regulating irAE remain unclear. Here, we investigate the function of Angiopoietin-like protein 2 (ANGPTL2), a potential inflammatory mediator, in a mouse model of ICI-related autoimmune myocarditis. ANGPTL2 deficiency attenuates autoimmune inflammation in these mice, an outcome associated with decreased numbers of T cells and macrophages. We also show that cardiac fibroblasts express abundant ANGPTL2. Importantly, cardiac myofibroblast-derived ANGPTL2 enhances expression of chemoattractants via the NF-κB pathway, accelerating T cell recruitment into heart tissues. Our findings suggest an immunostimulatory function for ANGPTL2 in the context of ICI-related autoimmune inflammation and highlight the pathophysiological significance of ANGPTL2-mediated cardiac myofibroblast/immune cell crosstalk in enhancing autoimmune responses. These findings overall provide insight into mechanisms regulating irAEs.
Collapse
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.
| |
Collapse
|
20
|
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]
Abstract
INTRODUCTION Pembrolizumab is an immune checkpoint inhibitor that promotes effector T-cell functions on malignant cells by binding to programmed cell death protein 1 (PD-1). Pembrolizumab is well tolerated in most cases with an adverse event profile consisting mainly of pruritus, fatigue, and anorexia. Cardiotoxicity comprises 1% of the total adverse events. CASE REPORT We present a case of a 64-year-old female with non-small cell lung cancer (NSCLC) who developed pleuropericarditis following pembrolizumab therapy. MANAGEMENT & OUTCOME The patient was successfully managed with colchicine, furosemide, and timely initiation of methylprednisolone with the improvement of her symptoms. The decision to discontinue pembrolizumab was made, and six months after this intervention, the patient has remained asymptomatic. DISCUSSION Clinicians should recognize these potential immune-mediated adverse effects to provide effective and timely management and optimize patient care.
Collapse
Affiliation(s)
- Zoilo K Suarez
- Internal Medicine Department, Florida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, FL, USA
| | - Ana C Finke
- Internal Medicine Department, Universidad Iberoamericana, Santo Domingo, Dominican Republic
| | - Emilio Hospedales
- Internal Medicine Department, Florida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, FL, USA
| | - Ernesto Perez
- Internal Medicine Department, Kendall Regional Medical Center, Kendall, FL, USA
| | - Arya Sharifzadeh
- Internal Medicine Department, Florida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, FL, USA
| | - Jennifer Foster
- Internal Medicine Department, Florida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, FL, USA
| | - Allison Ferris
- Internal Medicine Department, Florida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, FL, USA
| |
Collapse
|
21
|
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]
Abstract
The broad application of immune checkpoint inhibitors (ICIs) has led to significant gains in cancer outcomes. By abrogating inhibitory signals, ICIs promote T cell targeting of cancer cells but can frequently trigger autoimmune manifestations, termed immune-related adverse events (irAEs), affecting essentially any organ system. Among cardiovascular irAEs, immune-related myocarditis (irMyocarditis) is the most described and carries the highest morbidity. The currently recommended treatment for irMyocarditis is potent immunosuppression with corticosteroids and other agents, but this has limited evidence basis. The cellular pathophysiology of irMyocarditis remains poorly understood, though mouse models and human data have both implicated effector CD8+ T cells, some of which are specific for the cardiomyocyte protein α-myosin. While the driving molecular signals and transcriptional programs are not well defined, the involvement of chemokine receptors such as CCR5 and CXCR3 has been proposed. Fundamental questions regarding why only approximately 1% of ICI recipients develop irMyocarditis and why irMyocarditis carries a much worse prognosis than other forms of lymphocytic myocarditis remain unanswered. Further work in both murine systems and with human samples are needed to identify better tools for diagnosis, risk-stratification, and treatment.
Collapse
Affiliation(s)
- Jingyi Gong
- Cardio-Oncology Program, Division of Cardiology, Massachusetts General Hospital, Boston, MA
| | - Tomas G. Neilan
- Cardio-Oncology Program, Division of Cardiology, Massachusetts General Hospital, Boston, MA
- Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology, Massachusetts General Hospital, Boston, MA
| | - Daniel A. Zlotoff
- Cardio-Oncology Program, Division of Cardiology, Massachusetts General Hospital, Boston, MA
| |
Collapse
|
22
|
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
Abstract
The combination of Sintilimab with pemetrexed/platinum has become the first-line treatment for non-squamous non-small-cell lung carcinoma (NSCLC). Here, we report a patient with metastatic large cell neuroendocrine carcinoma (LCNEC) treated with Sintilimab for five cycles who developed shortness of breath after activity. The level of creatine kinase (CK), creatine kinase-MB (CK-MB) and cardiac troponin T (cTnT) were significantly increased. The cardiac MR suggested that heart function was slightly decreased. Considering that the patient did not take any illicit drugs, without history of autoimmune disease, coronary heart disease, arrhythmia, or chronic heart failure, we diagnosed the patient with Sintilimab-induced myocarditis. The symptoms alleviated after rapid use of glucocorticoids. Myocarditis is a rare immune-related adverse events (irAEs), especially myocarditis induced by programmed cell death receptor-1 (PD-1) inhibitor in the treatment of LCNEC.
Collapse
|
23
|
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.
Collapse
Affiliation(s)
- Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Elrashdy M Redwan
- Biological Science Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
- Therapeutic and Protective Proteins Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab, Alexandria 21934, Egypt
| | - William Makis
- Cross Cancer Institute, Alberta Health Services, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
| | - Alberto Rubio-Casillas
- Autlan Regional Hospital, Health Secretariat, Autlan 48900, Jalisco, Mexico
- Biology Laboratory, Autlan Regional Preparatory School, University of Guadalajara, Autlan 48900, Jalisco, Mexico
| |
Collapse
|
24
|
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
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have been widely used in the treatment of cancer. Moreover, immune-related adverse events (irAEs) have become a new clinical challenge. ICI-associated myocarditis is a rare but fatal condition among diverse organ injuries, and early recognition and effective interventions are critical for patients. CASE PRESENTATION In this report, we present the case of a healthy 60-year-old male who was diagnosed with lung squamous cell carcinomas following chemotherapy and received ICIs. The patient presented with asymptomatic cardiac biomarker elevation followed by immune-related myocarditis. Fortunately, the patient achieved a good clinical result after receiving high-dose steroids. The treatment with ICIs was discontinued because of recurrent increases in troponin T. CONCLUSION ICI-mediated associated myocarditis is an uncommon but potentially life-threatening adverse event. The current data suggest that clinicians need to be cautious about reinitiation in low-grade patients; however, further study of the diagnosis and treatment is necessary.
Collapse
Affiliation(s)
- Yue Hu
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
| | - Cuixia Liu
- Department of Respiratory and Critical Care Medicine, Songyang people's Hospital of Zhejiang, Lishui, 323499, Zhejiang, China
| | - Shaojun Jin
- Department of emergency, Zhuji people's Hospital of Zhejiang, Zhuji, 311800, Zhejiang, China
| | - Zihan Yi
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Chao Wang
- Department of Radiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Xiaohong Pan
- Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Huaqiong Huang
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
| |
Collapse
|
25
|
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]
Abstract
Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events including myocarditis, whilst improving cancer-related outcomes. There is thus a clinical need to identify electrocardiographic manifestations of ICI-related myocarditis to guide clinical management. PubMed was searched for clinical studies and case reports describing electrocardiographic changes in patients with ICI-related myocarditis. A total of 6 clinical studies and 79 case reports were included. This revealed a range of presentations for patients on ICIs, including supraventricular arrhythmias, ventricular arrhythmias and heart block, and new changes of ST-T segment unrelated to coronary artery disease, ST-segment elevation or depression and T-wave abnormalities. Several patients showed low voltages in multiple leads and new onset Q-wave development. Patients with ICI-related myocarditis may develop new arrhythmia and ST-T changes, and infrequently low voltages in multiple leads.
Collapse
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.
| |
Collapse
|
26
|
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.
Collapse
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
| |
Collapse
|
27
|
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
Abstract
Standard treatments for gynecological cancers include surgery, chemotherapy, and radiation therapy. However, there are limitations associated with the chemotherapeutic drugs used to treat advanced and recurrent gynecological cancers, and it is difficult to identify additional treatments. Therefore, immune checkpoint inhibitor (ICI) therapy products, including PD-1/PD-L1 inhibitors and CTLA-4 inhibitors, are in the spotlight as alternatives for the treatment of advanced gynecological cancers. Although the ICI monotherapy response rate in gynecological cancers is lower than that in melanoma or non-small cell lung cancer, the response rates are approximately 13-52%, 7-22%, and 4-17% for endometrial, ovarian, and cervical cancers, respectively. Several studies are being conducted to compare the outcomes of combining ICI therapy with chemotherapy, radiation therapy, and antiangiogenesis agents. Therefore, it is critical to determine the mechanism underlying ICI therapy-mediated anti-tumor activity and its application in gynecological cancers. Additionally, understanding the possible immune-related adverse events induced post-immunotherapy, as well as the appropriate management of diagnosis and treatment, are necessary to create a quality environment for immunotherapy in patients with gynecological cancers. Therefore, in this review, we summarize the ICI mechanisms, ICIs applied to gynecological cancers, and appropriate diagnosis and treatment of immune-related side effects to help gynecologists treat gynecological cancers using immunotherapy.
Collapse
Affiliation(s)
- Seon-Mi Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Koreadae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Sanghoon Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Koreadae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Hyun-Woong Cho
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 148, Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea
| | - Kyung-Jin Min
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 123, Jeokgeum-ro, Danwon-gu, Ansan-si 15355, Gyeonggi-do, Republic of Korea
| | - Jin-Hwa Hong
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 148, Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea
| | - Jae-Yun Song
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Koreadae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Jae-Kwan Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 148, Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea
| | - Nak-Woo Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 123, Jeokgeum-ro, Danwon-gu, Ansan-si 15355, Gyeonggi-do, Republic of Korea
| |
Collapse
|
28
|
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
Abstract
Cardiotoxicity from chemotherapy regimens has been long reported. However, the understanding of cardiac side effects of biological therapies is rapidly evolving. With cancer patients achieving higher life expectancy due to the use of personalized medicine and novel targeted anticancer agents, the occurrence of cardiotoxicity is becoming more significant. Novel biological therapies include anti-HER2 antibodies, tyrosine kinase inhibitors, bruton kinase inhibitors, antivascular endothelial growth factors, proteasome inhibitors, immunomodulator drugs, and immune checkpoint inhibitors. Potential cardiovascular toxicities linked to these anticancer agents include hypertension, arrhythmias, QT prolongation, myocardial ischemia and infarction, left ventricular dysfunction, congestive heart failure, and thromboembolism. Cardiac biomarkers, electrocardiography, echocardiography and magnetic resonance imaging are common diagnostic modalities used for early detection of these complications and timely intervention. This review discusses the various types of cardiotoxicities caused by novel anticancer biologic agents, their molecular and pathophysiological mechanisms, risk factors, and diagnostic and management strategies that can be used to prevent, minimize, and treat them.
Collapse
Affiliation(s)
- Luai Madanat
- Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan
| | - Ruby Gupta
- Department of Hematology and Medical Oncology, William Beaumont Hospital, Royal Oak, Michigan
| | - Paul Weber
- College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan
| | - Navneet Kumar
- Department of Cardiovascular Disease, St. Joseph Mercy Oakland Hospital, Pontiac, Michigan
| | - Rohit Chandra
- Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan
| | - Hycienth Ahaneku
- Department of Hematology and Medical Oncology, William Beaumont Hospital, Royal Oak, Michigan
| | - Yatharth Bansal
- Department of Internal Medicine, University of Detroit Mercy, Detroit, Michigan
| | - Joseph Anderson
- Department of Hematology and Medical Oncology, William Beaumont Hospital, Royal Oak, Michigan
| | - Abhay Bilolikar
- Department of Cardiovascular Disease, William Beaumont Hospital, Royal Oak, Michigan
| | - Ishmael Jaiyesimi
- Department of Hematology and Medical Oncology, William Beaumont Hospital, Royal Oak, Michigan
| |
Collapse
|
29
|
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]
Abstract
Glucocorticoids (GCs) are a pharmacological class of drugs widely used in oncology in both supportive and palliative settings. GCs differentially impact organs with immediate and long-term effects; with suppressive effect on the immune system anchoring their use to manage the toxicities of immune checkpoint inhibitors (ICIs). In addition, GCs are often used in the management of symptoms related to cancer or chemotherapy and as adjuvants in the treatment of pain in the management of other. In the palliative setting, GCs, especially administered subcutaneously can be to assist in the control of nausea, dyspnea, asthenia, and anorexia-cachexia syndrome. In this narrative review, we aim to summarize the role of GCs in the different settings (curative, supportive, and palliative) to help clinicians use these important drugs in their daily clinical practice with cancer patients.
Collapse
Affiliation(s)
- Nerina Denaro
- Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Ornella Garrone
- Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | | | - Benedetta Pellegrino
- Medical Oncology and Breast Unit, University Hospital of Parma, Italy; Department of Medicine and Surgery, University of Parma, Italy
| | | | - Denise Vacca
- Palliative Care Unit, Ospedale Sirai, Carbonia, ASSL Carbonia, Italy
| | - Josie Pearce
- Harvard Premedical Program, Harvard University, Cambridge, MA, USA
| | - Daniele Farci
- Medical Oncology, Nuova Casa di Cura, Decimomannu, Cagliari, Italy
| | - Antonino Musolino
- Medical Oncology and Breast Unit, University Hospital of Parma, Italy; Department of Medicine and Surgery, University of Parma, Italy
| | - Mario Scartozzi
- Medical Oncology, AOU Cagliari, Policlinico di Monserrato, Cagliari, Italy
| | - Chiara Tommasi
- Medical Oncology and Breast Unit, University Hospital of Parma, Italy; Department of Medicine and Surgery, University of Parma, Italy.
| | - Cinzia Solinas
- Medical Oncology, AOU Cagliari, Policlinico di Monserrato, Cagliari, Italy
| |
Collapse
|
30
|
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.
Collapse
Affiliation(s)
- Tatiana Duarte
- Cardiology Department, Hospital de S. Bernardo, Centro Hospitalar de Setúbal, Setúbal, Portugal.
| | - Cátia Costa
- Cardiology Department, Hospital de S. Bernardo, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | - Sara Gonçalves
- Cardiology Department, Hospital de S. Bernardo, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | - Luís Raposo
- Hospital de Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal
| | - António Ferreira
- Hospital de Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal
| | | | - Nuno Vau
- Fundação Champalimaud, Lisbon, Portugal
| | - Rui Caria
- Cardiology Department, Hospital de S. Bernardo, Centro Hospitalar de Setúbal, Setúbal, Portugal
| |
Collapse
|
31
|
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
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, despite their excellent therapeutic effect, these medications typically result in a broad spectrum of toxicity reactions. Immune-related cardiotoxicity is uncommon but can be potentially fatal, and its true incidence is underestimated in clinical trials. The aim of this study is to assess the incidence and identify risk factors for developing a cardiac event in patients treated with ICIs. METHODS We conducted a single-institution retrospective study, including patients treated with ICIs in our center. The main outcomes were cardiac events (CE) and cardiovascular death. RESULTS A total of 378 patients were analyzed. The incidence of CE was 16.7%, during a median follow-up of 50.5 months. The multivariable analysis showed that age, a history of arrhythmia or ischemic heart disease, and prior immune-related adverse events were significantly associated with CE. CONCLUSION CE during ICI treatment are more common than currently appreciated. A complete initial cardiovascular evaluation is recommended, especially in high-risk patients, being necessary a multidisciplinary approach of a specialized cardio-oncology team.
Collapse
Affiliation(s)
- María Torrente
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
- Faculty of Health Sciences, Francisco de Vitoria University, Madrid, Spain
| | - Mariola Blanco
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Fabio Franco
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Yago Garitaonaindia
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Virginia Calvo
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Ana Collazo-Lorduy
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Lourdes Gutiérrez
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Juan Cristóbal Sánchez
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | | | - Roberto Hernández
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Miriam Méndez
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Blanca Cantos
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Beatriz Núñez
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| | - Pedro A. C. Sousa
- Department of Electrical Engineering, NOVA School of Science and Technology, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Mariano Provencio
- Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
| |
Collapse
|
32
|
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
Abstract
Myocardial protection against ischemia/reperfusion injury (IRI) is mediated by various ligands, activating different cellular signaling cascades. These include classical cytosolic mediators such as cyclic-GMP (c-GMP), various kinases such as Phosphatydilinositol-3- (PI3K), Protein Kinase B (Akt), Mitogen-Activated-Protein- (MAPK) and AMP-activated (AMPK) kinases, transcription factors such as signal transducer and activator of transcription 3 (STAT3) and bioactive molecules such as vascular endothelial growth factor (VEGF). Most of the aforementioned signaling molecules constitute targets of anticancer therapy; as they are also involved in carcinogenesis, most of the current anti-neoplastic drugs lead to concomitant weakening or even complete abrogation of myocardial cell tolerance to ischemic or oxidative stress. Furthermore, many anti-neoplastic drugs may directly induce cardiotoxicity via their pharmacological effects, or indirectly via their cardiovascular side effects. The combination of direct drug cardiotoxicity, indirect cardiovascular side effects and neutralization of the cardioprotective defense mechanisms of the heart by prolonged cancer treatment may induce long-term ventricular dysfunction, or even clinically manifested heart failure. We present a narrative review of three therapeutic interventions, namely VEGF, proteasome and Immune Checkpoint inhibitors, having opposing effects on the same intracellular signal cascades thereby affecting the heart. Moreover, we herein comment on the current guidelines for managing cardiotoxicity in the clinical setting and on the role of cardiovascular confounders in cardiotoxicity.
Collapse
Affiliation(s)
- Panagiotis Efentakis
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece
| | - Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece
| | | | | | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
- Pharmahungary Group, 6722 Szeged, Hungary
| | - Rainer Schulz
- Institute of Physiology, Justus Liebig University Giessen, 35390 Giessen, Germany
| | | |
Collapse
|
33
|
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
Abstract
Immune checkpoint inhibitors (ICIs) are an effective therapy for various cancers; however, they can induce immune-related adverse events (irAEs) as a side effect. Myocarditis is an uncommon, but fatal, irAE caused after ICI treatments. Currently, the mechanism of ICI-associated myocarditis is unclear. Here, we show the development of myocarditis in A/J mice induced by anti-PD-1 monoclonal antibody (mAb) administration alone without tumor cell inoculation, immunization, or viral infection. Mice with myocarditis have increased cardiac infiltration, elevated cardiac troponin levels, and arrhythmia. Anti-PD-1 mAb treatment also causes irAEs in other organs. Autoimmune T cells recognizing cardiac myosin are activated and increased in mice with myocarditis. Notably, cardiac myosin-specific T cells are present in naive mice, showing a phenotype of antigen-experienced T cells. Collectively, we establish a clinically relevant mouse model for ICI-associated myocarditis and find a contribution of cardiac myosin-specific T cells to ICI-associated myocarditis development and pathogenesis.
Collapse
Affiliation(s)
- Taejoon Won
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Hannah M Kalinoski
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Megan K Wood
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - David M Hughes
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA
| | - Camille M Jaime
- Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Paul Delgado
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Monica V Talor
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ninaad Lasrado
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jay Reddy
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Daniela Čiháková
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
| |
Collapse
|
34
|
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.
Collapse
|
35
|
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.
Collapse
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
| |
Collapse
|
36
|
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
Abstract
Immune checkpoint inhibitors (ICIs) have been taking cancer research by storm as they provide valuable therapeutic benefits to cancer patients in terms of immunotherapy. Melanoma and non-small cell lung cancer (NSCLC) are among the most prevalent cancer varieties that were utilized in ICI trials with many other cancer types being involved too. Despite impressive clinical benefits of overall response rate (ORR), progression-free survival (PFS), etc., ICIs are also accompanied by various immune-related adverse events (irAEs). Amongst the irAEs, cardiotoxicity bags a crucial role. It is of paramount importance that ICI-induced cardiotoxicity should be studied in detail due to its high mortality rate although the prevalence rate is low. Patients with ICI cardiotoxicity can have a greatly enhanced life quality despite adverse reactions from ICI therapy if diagnosed early and treated in time. As such, this review serves to provide a complete insight into the predisposing factors, mechanism, diagnostic methods and treatment plans revolving around ICI-induced cardiotoxicity.
Collapse
|
37
|
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.
Collapse
Affiliation(s)
- Francisco Javier Ruperti-Repilado
- Department Circulation, Thorax, Transplantation, Clinic of Cardiology, University Hospital Basel , Petersgraben 4, 4031 Basel , Switzerland
| | - Jan Gerrit van der Stouwe
- Department of Acute Medicine, Clinic of Internal Medicine, University Hospital Basel , Petersgraben 4, 4031 Basel , Switzerland
| | - Philip Haaf
- Department Circulation, Thorax, Transplantation, Clinic of Cardiology, University Hospital Basel , Petersgraben 4, 4031 Basel , Switzerland
| | - Christian Mueller
- Department Circulation, Thorax, Transplantation, Clinic of Cardiology, University Hospital Basel , Petersgraben 4, 4031 Basel , Switzerland
- Cardiovascular Research Institute Basel (CRIB), University Hospital Basel , Spitalstrasse 2, 4056 Basel , Switzerland
| | - Heinz Läubli
- Department of Theragnostic, Division of Medical Oncology, University Hospital Basel , Petersgraben 4, 4031 Basel , Switzerland
- Department of Biomedicine, University Hospital and University of Basel , 4031 Basel , Switzerland
| | - Otmar Pfister
- Department Circulation, Thorax, Transplantation, Clinic of Cardiology, University Hospital Basel , Petersgraben 4, 4031 Basel , Switzerland
- Department of Biomedicine, University Hospital and University of Basel , 4031 Basel , Switzerland
| | - Sacha I Rothschild
- Department of Theragnostic, Division of Medical Oncology, University Hospital Basel , Petersgraben 4, 4031 Basel , Switzerland
- Department of Biomedicine, University Hospital and University of Basel , 4031 Basel , Switzerland
| | - Gabriela M Kuster
- Department Circulation, Thorax, Transplantation, Clinic of Cardiology, University Hospital Basel , Petersgraben 4, 4031 Basel , Switzerland
- Department of Biomedicine, University Hospital and University of Basel , 4031 Basel , Switzerland
| |
Collapse
|
38
|
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
Abstract
Immunotherapy is a widely used treatment modality in oncology. Immune checkpoint inhibitors, as a part of immunotherapy, caused a revolution in oncology, especially in melanoma therapy, due to the significant prolongation of patients’ overall survival. These drugs act by activation of inhibited immune responses of T lymphocytes against cancer cells. The mechanism responsible for the therapy’s high efficacy is also involved in immune tolerance of the patient’s own tissues. The administration of ICI therapy to a patient can cause severe immune reactions against non-neoplastic cells. Among them, cardiotoxicity seems most important due to the high mortality rate. In this article, we present the history of a 79 year-old patient diagnosed with melanoma who died due to myocarditis induced by ICI therapy, despite the fast administration of recommended immunosuppressive therapy, as an illustration of possible adverse events of ICI. Additionally, we summarize the mechanism, risk factors, biomarkers, and clinical data from currently published guidelines and studies about ICI-related myocarditis. The fast recognition of this fatal adverse effect of therapy may accelerate the rapid introduction of treatment and improve patients’ outcomes.
Collapse
|
39
|
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
Abstract
Oncolytic viruses (OVs) have been gaining attention in the pharmaceutical industry as a novel immunotherapeutic and therapeutic adjuvant due to their ability to induce and boost antitumor immunity through multiple mechanisms. First, intrinsic mechanisms of OVs that enable exploitation of the host immune system (e.g., evading immune detection) can nullify the immune escape mechanism of tumors. Second, many types of OVs have been shown to cause direct lysis of tumor cells, resulting in an induction of tumor-specific T cell response mediated by release of tumor-associated antigens and danger signal molecules. Third, armed OV-expressing immune stimulatory therapeutic genes could be highly expressed in tumor tissues to further improve antitumor immunity. Last, these OVs can inflame cold tumors and their microenvironment to be more immunologically favorable for other immunotherapeutics. Due to these unique characteristics, OVs have been tested as an adjuvant of choice in a variety of therapeutics. In light of these promising attributes of OVs in the immune-oncology field, the present review will examine OVs in clinical development and discuss various strategies that are being explored in preclinical stages for the next generation of OVs that are optimized for immunotherapy applications.
Collapse
Affiliation(s)
- Chae-Ok Yun
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, South Korea
- Institute of Nano Science and Technology (INST), Hanyang University, Seoul, South Korea
- Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, South Korea
- GeneMedicine CO., Ltd., Seoul, South Korea
| | | | - A-Rum Yoon
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, South Korea
- Institute of Nano Science and Technology (INST), Hanyang University, Seoul, South Korea
- Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, South Korea
| |
Collapse
|
40
|
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.
Collapse
Affiliation(s)
- Filip Stefanovic
- Department of Biomedical Engineering, University at Buffalo School of Engineering and Applied Sciences, Buffalo, NY, USA,CPL Associates LLC, Buffalo, NY, USA
| | - Andres Gomez-Caminero
- Worldwide Health Economic and Outcomes Research, Bristol Myers Squibb, Princeton, NJ, USA
| | - David M Jacobs
- CPL Associates LLC, Buffalo, NY, USA,Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA
| | | | - Igor Puzanov
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA,Department of Medicine, University at Buffalo Jacobs School of Medicine, Buffalo, NY, USA
| | - Maya R Chilbert
- Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA
| | - Steven G Feuerstein
- Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA
| | - Yan Yatsynovich
- Department of Medicine, University at Buffalo Jacobs School of Medicine, Buffalo, NY, USA,Kettering Medical Center, Kettering, OH, USA
| | - Benjamin Switzer
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Jerome J Schentag
- CPL Associates LLC, Buffalo, NY, USA,Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA,Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA,Correspondence: Jerome J Schentag, CPL Associates LLC, 73 High St. Suite 310, Buffalo, NY, 14203, USA, Tel +1 716-867-0550, Fax +1 716-633-3331, Email
| |
Collapse
|
41
|
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
Abstract
Primary oral melanoma is extremely rare, and the prognosis is very poor. With the development of immunotherapy, melanoma’s treatment landscape changed dramatically. Toripalimab, a recombinant programmed death receptor 1 (PD-1) monoclonal antibody, has been approved as second-line therapy for metastatic melanoma. However, the cardiac toxicity of Toripalimab is seldom reported. This article describes the application of Toripalimab on a patient who suffered from primary oral melanoma accompanied with arrhythmic mitral valve prolapse (AMVP). Case Summary: A 55-year-old Chinese female was diagnosed with BRAF wild-type oral malignant melanoma by excisional biopsy and genetic test. The melanoma quickly progressed after complete tumor resection. Combined therapy after surgical resection was applied to control the progression of melanoma. Due to this patient’s basic cardiovascular situation, sacubitril–valsartan, spironolactone, and bisoprolol were used to maintain cardiac function. After five antitumor treatment courses, we re-evaluated the patient systemically from the symptom, physical examination, and auxiliary examination. The result showed that the patient who received Toripalimab combined with chemotherapy and radiotherapy did not present severe side effects on the cardiovascular system. The cardiac function remained well. Conclusions: This case provided evidence of Toripalimab combined with chemotherapy on melanoma patients with complex cardiovascular diseases. Toripalimab demonstrated a manageable safety profile and durable clinical response. In addition, the standard CHF treatment plays a vital role in the protection of cardiac function. In a cancer patient with complex cardiovascular diseases, standard prophylactic CHF treatment should be applied at an early stage.
Collapse
Affiliation(s)
- Wei Pan
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Li Yin
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Yadi Guo
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Dachao Pan
- Oncology Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Hui Huang
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
- *Correspondence: Hui Huang,
| |
Collapse
|
42
|
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
Abstract
In 2020, there were an estimated 19.3 million new cancer cases and close to 10 million cancer deaths worldwide. Cancer remains one of the leading causes of death. In recent years, with the continuous improvement of our understanding of tumor immunotherapy, immunotherapeutics, such as immune checkpoint inhibitors, have gradually become a hot spot for tumor treatment. Amongst these, programmed cell death protein 1/programmed cell death protein ligand 1 (PD‑1/PD‑L1) related inhibitors, such as nivolumab and pembrolizumab, atezolizumab, avelumab and durvalumab have been shown to exhibit a high level of efficacy in several types of tumors. It has been confirmed that these inhibitors play an important role in the anti‑tumor process, significantly improving the survival rate of patients and delaying the progress of the underlying cancer. However, its method of therapeutic interference and potential for damaging the immune system has caused concern regarding its suitability. As these adverse effects are caused by an immune response to endogenous tissues, they are designated as immune‑related adverse events (irAEs). In this review, the typical irAEs reported in recent years and the management strategies adopted are highlighted, to serve as a reference in assessing the clinical response to these adverse reactions.
Collapse
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
| |
Collapse
|
43
|
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
Abstract
Cancer therapeutics related cardiac dysfunction (CTRCD) has emerged as a major cause of morbidity and mortality in cancer survivors. Effective clinical management of CTRCD is impeded by a lack of sensitive diagnostic and prognostic strategies. Circulating molecular markers could potentially address this need as they are often indicative of cardiac stress before cardiac damage can be detected clinically. A growing understanding of the underlying physiological mechanisms for CTRCD has inspired research efforts to identify novel pathophysiologically-relevant biomarkers that may also guide development of cardio-protective therapeutic approaches. The purpose of this review is to evaluate current circulating biomarkers of cardiac stress and their potential role in diagnosis and management of CTRCD. We also discuss some emerging avenues for CTRCD-focused biomarker investigations.
Collapse
Affiliation(s)
- Claire Tonry
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Northern Ireland, United Kingdom
| | - Adam Russel-Hallinan
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Northern Ireland, United Kingdom
| | - Claire McCune
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Northern Ireland, United Kingdom
| | | | | | | | - Chris J Watson
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Northern Ireland, United Kingdom
| |
Collapse
|
44
|
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
|
45
|
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
Abstract
Immune checkpoint inhibitors (ICIs) induce T-cell activation against cancer cells, and due to their anti-tumor function in multiple cancers, ICIs have been considered an important option for oncotherapy. PD-1/PD-L1 inhibitors are now widely used as ICIs for many types of cancers in clinical practices. Myocarditis induced by anti-PD-1/PD-L1 agents is uncommon but shows potentially fatal toxicity. In this review, we attempted to conclude the incidence, characteristics, diagnosis, and treatments, as well as illustrate the potential pathogenesis from the perspectives of T-lymphocyte infiltration, disturbance of regulatory T cells, cytokines, macrophage-mediated inflammatory response, and synergistic effect of PD-1/PD-L1 and CTLA4.
Collapse
Affiliation(s)
- Hao Dong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yihang Qi
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhongzhao Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yi Fang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jing Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| |
Collapse
|
46
|
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
Abstract
The emerging use of immunotherapies in cancer treatment increases the risk of immunotherapy-related cardiotoxicity. In contrast to conventional chemotherapy, these novel therapies have expanded the forms and presentations of cardiovascular damage to a broad spectrum from asymptomatic changes to fulminant short- and long-term complications in terms of cardiomyopathy, arrythmia, and vascular disease. In cancer patients and, particularly, cancer patients undergoing (immune-)therapy, cardio-oncological monitoring is a complex interplay between pretherapeutic risk assessment, identification of impending cardiotoxicity, and post-therapeutic surveillance. For these purposes, the cardio-oncologist can revert to a broad spectrum of nuclear cardiological diagnostic workup. The most promising commonly used nuclear medicine imaging techniques in relation to immunotherapy will be discussed in this review article with a special focus on the continuous development of highly specific molecular markers and steadily improving methods of image generation. The review closes with an outlook on possible new developments of molecular imaging and advanced image evaluation techniques in this exciting and increasingly growing field of immunotherapy-related cardiotoxicity.
Collapse
Affiliation(s)
- David Kersting
- Department of Nuclear Medicine, University Hospital Essen, West German Cancer Center (WTZ), University of Duisburg-Essen, 45147 Essen, Germany; (K.H.); (R.S.); (C.R.)
- German Cancer Consortium (DKTK, Partner Site Essen/Düsseldorf), 45147 Essen, Germany;
| | - Stephan Settelmeier
- Department of Cardiology and Vascular Medicine, University Hospital Essen, West German Heart and Vascular Center, University of Duisburg-Essen, 45147 Essen, Germany;
| | - Ilektra-Antonia Mavroeidi
- German Cancer Consortium (DKTK, Partner Site Essen/Düsseldorf), 45147 Essen, Germany;
- Clinic for Internal Medicine (Tumor Research), University Hospital Essen, West German Cancer Center (WTZ), University of Duisburg-Essen, 45147 Essen, Germany
| | - Ken Herrmann
- Department of Nuclear Medicine, University Hospital Essen, West German Cancer Center (WTZ), University of Duisburg-Essen, 45147 Essen, Germany; (K.H.); (R.S.); (C.R.)
- German Cancer Consortium (DKTK, Partner Site Essen/Düsseldorf), 45147 Essen, Germany;
| | - Robert Seifert
- Department of Nuclear Medicine, University Hospital Essen, West German Cancer Center (WTZ), University of Duisburg-Essen, 45147 Essen, Germany; (K.H.); (R.S.); (C.R.)
- German Cancer Consortium (DKTK, Partner Site Essen/Düsseldorf), 45147 Essen, Germany;
| | - Christoph Rischpler
- Department of Nuclear Medicine, University Hospital Essen, West German Cancer Center (WTZ), University of Duisburg-Essen, 45147 Essen, Germany; (K.H.); (R.S.); (C.R.)
- German Cancer Consortium (DKTK, Partner Site Essen/Düsseldorf), 45147 Essen, Germany;
| |
Collapse
|
47
|
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.
Collapse
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
| | | | - 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.
| |
Collapse
|
48
|
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.
Collapse
Affiliation(s)
- Zachary L Brumberger
- Department of Internal Medicine, Wake Forest University School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA
| | - Mary E Branch
- Department of Internal Medicine, Section On Cardiovascular Medicine, Wake Forest University School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA
| | - Max W Klein
- Department of Internal Medicine, Wake Forest University School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
| | - Austin Seals
- Department of Internal Medicine, Section On Cardiovascular Medicine, Wake Forest University School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA
| | - Michael D Shapiro
- Department of Internal Medicine, Section On Cardiovascular Medicine, Wake Forest University School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA
| | - Sujethra Vasu
- Department of Internal Medicine, Section On Cardiovascular Medicine, Wake Forest University School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA
| |
Collapse
|
49
|
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]
Abstract
We studied the efficacy and safety of the combined treatment with programmed cell death 1 (PD-1) inhibitors and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and subsequent PD-1 inhibitor maintenance treatment in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and high tumor burden. Forty-four R/R DLBCL patients with high tumor burden were enrolled in this study. The experimental group of 26 patients received combined therapy with PD-1 inhibitors and anti-CD19-CAR T cells, while the control group of 18 patients received anti-CD19-CAR T-cell therapy alone. The objective response rate (ORR) was 65.39% and 61.11% in the combination and control groups, respectively. The PD-1 inhibitor maintenance therapy was selected for patients who achieved complete response (CR) or partial response (PR) in the combination therapy group. Progression-free survival (PFS) and overall survival (OS) rates in the combination group were higher than those in the control group 3 and 12 months after CAR T-cell infusion. There was no significant difference in the grade of cytokine release syndrome (CRS) or immune effector cell associated neurotoxic syndrome (ICANS) between the two groups. In the maintenance therapy group, only eight patients experienced grade 1 Common Terminology Criteria for Adverse Events (CTCAE) and three grade 2 CTCAE. Overall, we found that the ORR was not affected by the combination therapy with PD-1 inhibitors and anti-CD19-CAR T cells. However, patients who had achieved the ORR might benefit from PD-1 inhibitor maintenance therapy after combination therapy without increased side effects.Trial registration: The patients were enrolled in a clinical trial ofChiCTR-ONN-16009862 and ChiCTR1800019622. This article is protected by copyright. All rights reserved.
Collapse
Affiliation(s)
- Juan Mu
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Haobin Deng
- The first central clinical college of tianjin medical university, Tianjin, China
| | - Cuicui Lyu
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Jijun Yuan
- Shanghai Genbase Biotechnology Co., Ltd. Shanghai, 201203, China
| | - Qing Li
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Jia Wang
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Yanyu Jiang
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Qi Deng
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Jichun Shen
- Department of Hematology, Characteristic Medical Center of Chinese People's Armed Police Force, Tianjin, China
| |
Collapse
|
50
|
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]
|