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Background: Immune checkpoint inhibitors (ICIs) are associated with an increased risk of major adverse cardiovascular events (MACE). Glucagon-like peptide-1 agonists (GLP1a), initially developed for type 2 diabetes mellitus (T2DM), have shown promising results in reducing cardiovascular events. We aimed to investigate the effect of GLP1a on cardiovascular events in patients receiving ICIs., Methods: We conducted a retrospective, propensity score-matched cohort study using the TriNetX database. We identified adults with cancer and T2DM who received ICIs between April 2013 and May 2023. The primary efficacy outcome was incident MACE, defined as a composite of myocardial infarction, need for coronary revascularization, heart failure, ischemic stroke, and cardiac arrest. The secondary efficacy outcomes were the individual components of MACE as well as myocarditis and pericarditis. Safety outcomes included the occurrence of immune-related adverse events, serious adverse events related to GLP1a use, and all-cause mortality., Results: We identified 7651 patients eligible for inclusion, among which 479 received GLP1a and 7172 received non-GLP1a diabetes medications. After matching (469 patients each), baseline characteristics were well-balanced. Over a median 12-month follow-up, the GLP1a cohort had a significantly lower MACE incidence than the non-GLP1a cohort (9.0 vs. 17.1 events per 100 patient-years) with a 54 % lower risk of MACE (Hazard ratio (HR),0.46 [95 % CI: 0.32-0.67]). There were reductions in myocardial infarction or need for coronary revascularization, heart failure, and all-cause mortality, with no differences in other cardiovascular events. GLP1a use did not increase risk of adverse events, including pancreatitis, biliary disease, bowel obstruction, gastroparesis, and immune-related adverse events., Conclusion: GLP1a use in cancer patients with T2DM receiving ICIs was associated with reduced MACE and all-cause mortality without an increased risk in serious adverse events., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Neilan reported receipt of personal fees for consulting from Bristol Myers Squibb, Genentech, Roivant, Roche, and Sanofi, and receipt of grants from Bristol Myers Squibb, Abbott, and AstraZeneca. Dr Neilan is supported by a gift from A. Curt Greer and Pamela Kohlberg and from Christina and Paul Kazilionis, the Michael and Kathryn Park Endowed Chair in Cardiology, and a Hassenfeld Scholar Award and has additional grant funding from the National Institutes of Health/NHLBI (R01HL137562, K24HL150238). Dr. Reynolds is on the Advisory Board of Regeneron and SAGA Diagnostics. Dr. Reynolds has received educational fees from MedScape and CME Outfitters and research support from Bristol Myers Squibb. The remaining authors have nothing to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Current approaches to accurately identify immune-related adverse events (irAEs) in large retrospective studies are limited. Large language models (LLMs) offer a potential solution to this challenge, given their high performance in natural language comprehension tasks. Therefore, we investigated the use of an LLM to identify irAEs among hospitalized patients, comparing its performance with manual adjudication and International Classification of Disease (ICD) codes., Methods: Hospital admissions of patients receiving immune checkpoint inhibitor (ICI) therapy at a single institution from February 5, 2011, to September 5, 2023, were individually reviewed and adjudicated for the presence of irAEs. ICD codes and an LLM with retrieval-augmented generation were applied to detect frequent irAEs (ICI-induced colitis, hepatitis, and pneumonitis) and the most fatal irAE (ICI-myocarditis) from electronic health records. The performance between ICD codes and LLM was compared via sensitivity and specificity with an α = .05, relative to the gold standard of manual adjudication. External validation was performed using a data set of hospital admissions from June 1, 2018, to May 31, 2019, from a second institution., Results: Of the 7,555 admissions for patients on ICI therapy in the initial cohort, 2.0% were adjudicated to be due to ICI-colitis, 1.1% ICI-hepatitis, 0.7% ICI-pneumonitis, and 0.8% ICI-myocarditis. The LLM demonstrated higher sensitivity than ICD codes (94.7% v 68.7%), achieving significance for ICI-hepatitis ( P < .001), myocarditis ( P < .001), and pneumonitis ( P = .003) while yielding similar specificities (93.7% v 92.4%). The LLM spent an average of 9.53 seconds/chart in comparison with an estimated 15 minutes for adjudication. In the validation cohort (N = 1,270), the mean LLM sensitivity and specificity were 98.1% and 95.7%, respectively., Conclusion: LLMs are a useful tool for the detection of irAEs, outperforming ICD codes in sensitivity and adjudication in efficiency.

Immune checkpoint inhibitors are widely used anticancer therapies 1 that can cause morbid and potentially fatal immune-related adverse events such as immune-related myocarditis (irMyocarditis) 2-5 . The pathogenesis of irMyocarditis and its relationship to antitumour immunity remain poorly understood. Here we sought to define immune responses in heart, tumour and blood in patients with irMyocarditis by leveraging single-cell RNA sequencing coupled with T cell receptor (TCR) sequencing, microscopy and proteomics analyses of samples from 28 patients with irMyocarditis and 41 unaffected individuals. Analyses of 84,576 cardiac cells by single-cell RNA sequencing combined with multiplexed microscopy demonstrated increased frequencies and co-localization of cytotoxic T cells, conventional dendritic cells and inflammatory fibroblasts in irMyocarditis heart tissue. Analyses of 366,066 blood cells revealed decreased frequencies of plasmacytoid dendritic cells, conventional dendritic cells and B lineage cells but an increased frequency of other mononuclear phagocytes in irMyocarditis. Fifty-two heart-expanded TCR clones from eight patients did not recognize the putative cardiac autoantigens α-myosin, troponin I or troponin T. Additionally, TCRs enriched in heart tissue were largely nonoverlapping with those enriched in paired tumour tissue. The presence of heart-expanded TCRs in a cycling blood CD8 T cell population was associated with fatal irMyocarditis case status. Collectively, these findings highlight crucial biology driving irMyocarditis and identify putative biomarkers., Competing Interests: Competing interests: S.M.B.: consultant to Two River Consulting and Third Rock Ventures; and equity in Candid Therapeutics, Kronos Bio, 76Bio and Allogene Therapeutics. D.A.Z.: consultant to Bristol Myers Squibb, Freeline Therapeutics and Intrinsic Imaging; and research funding from Abbott Laboratories. N.P.S.: consultant to Hera Biotech. L.Z.: consultant to Bristol Myers Squibb and Merck. J.F.G.: consultant to Amgen, Arcus Biosciences, AI Proteins, AstraZeneca, Beigene, Blueprint Medicines, Bristol Myers Squibb, Genentech/Roche, EMD Serono, InterVenn Biosciences, Gilead Sciences, iTeos Therapeutics, Jounce Therapeutics, Karyopharm Therapeutics, Lilly, Loxo, Merus, Mirati Therapeutics, Pfizer, Sanofi, Silverback Therapeutics, Merck, Moderna Therapeutics, Mariana Oncology and Takeda; honorarium from Merck, Pfizer, Novartis, Pfizer and Takeda; research funding from Adaptimmune, Alexo Therapeutics, Array BioPharma, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Genentech, Jounce Therapeutics, Merck, Moderna Therapeutics, Novartis and Tesaro; has an immediate family member who is an employee with stock and other ownership interests in Ironwood Pharmaceuticals; and equity in AI Proteins. C.J.W.: equity in BionTech; research funding from Pharmacyclics; and is on the scientific advisory board of Repertoire, Adventris and Aethon Therapeutics. D.J.: grants and personal fees from Novartis, Genentech, Syros and Eisai; personal fees from Vibliome, PIC Therapeutics, Mapkure and Relay Therapeutics; and grants from Pfizer, Amgen, InventisBio, Arvinas, Takeda, Blueprint Medicines, AstraZeneca, Ribon Therapeutics and Infinity that are outside the submitted work. M.M.-K.: consultant to AstraZeneca, Pfizer, Repare, Boehringer Ingelheim, Sanofi, AbbVie and Daiichi-Sankyo; and royalties from Elsevier. G.O.: consultant to Bicycle Therapeutics. R.J.S.: consultant to Bristol Myers Squibb, Merck, Pfizer, Marengo Therapeutics, Novartis, Eisai, Iovance, OncoSec and AstraZeneca; and research funding from Merck. G.M.B.: sponsored research agreements through her institution with Olink Proteomics, Teiko Bio, InterVenn Biosciences and Palleon Pharmaceuticals; is on advisory boards for Iovance, Merck, Nektar Therapeutics, Novartis and Ankyra Therapeutics; is a consultant for Merck, InterVenn Biosciences, Iovance and Ankyra Therapeutics; and has equity in Ankyra Therapeutics. T.G.N.: consultant to Bristol Myers Squibb, Genentech, CRC Oncology, Roche, Sanofi and Parexel Imaging Pharmaceuticals; and grant funding from Astra Zeneca, Bristol Myers Squibb related to the cardiac effects of ICIs. K.L.R.: on the advisory board to SAGA Diagnostics; speaker’s fees from CMEOutfitters and Medscape; and research funding from Bristol Myers Squibb. A.-C.V.: consultant to Bristol Myers Squibb; and financial interest in 10x Genomics. 10x Genomics designs and manufactures gene sequencing technology for use in research, and such technology is being used in this research; these interests were reviewed by the Massachusetts General Hospital and Mass General Brigham in accordance with their institutional policies. All other authors (I.J.K., S.R., J.C., N.S., S.M., M.W., A.T., Y.S., K.H.X., J.B., P.S., K.S., J.T., K.M., B.Y.A., M.N., C.J.P., D.M., M.J., P.C., A.L., W.A.M., T.S., L.T.N., J.R.S. and M.F.T.) declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Immune checkpoint molecules are physiological regulators of the adaptive immune response. Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies targeting programmed cell death protein 1 or cytotoxic T lymphocyte-associated protein 4, have revolutionized cancer treatment and their clinical use is increasing. However, ICIs can cause various immune-related adverse events, including acute and chronic cardiotoxicity. Of these cardiovascular complications, ICI-induced acute fulminant myocarditis is the most studied, although emerging clinical and preclinical data are uncovering the importance of other ICI-related chronic cardiovascular complications, such as accelerated atherosclerosis and non-myocarditis-related heart failure. These complications could be more difficult to diagnose, given that they might only be present alongside other comorbidities. The occurrence of these complications suggests a potential role of immune checkpoint molecules in maintaining cardiovascular homeostasis, and disruption of physiological immune checkpoint signalling might thus lead to cardiac pathologies, including heart failure. Although inflammation is a long-known contributor to the development of heart failure, the therapeutic targeting of pro-inflammatory pathways has not been successful thus far. The increasingly recognized role of immune checkpoint molecules in the failing heart highlights their potential use as immunotherapeutic targets for heart failure. In this Review, we summarize the available data on ICI-induced cardiac dysfunction and heart failure, and discuss how immune checkpoint signalling is altered in the failing heart. Furthermore, we describe how pharmacological targeting of immune checkpoints could be used to treat heart failure., (© 2024. Springer Nature Limited.)

Abstract: Immune checkpoint inhibitors (ICIs) are a form immunotherapy where the negative regulators of host immunity are targeted, thereby leveraging the own immune system. ICIs have significantly improved cancer survival in several advanced malignancies, and there are currently more than 90 different cancer indications for ICIs. Most patients develop immune-related adverse events during ICI therapy. Most are mild, but a small subset of patients will develop severe and potentially fatal immune-related adverse events. A serious cardiovascular complication of ICI therapy is myocarditis. Although the incidence of myocarditis is low, mortality rates of up to 50% have been reported. The mainstay of ICI-associated myocarditis treatment is high-dose corticosteroids. Unfortunately, half of patients with myocarditis do not show clinical improvement after corticosteroid treatment. Also, high doses of corticosteroids may adversely impact cancer outcomes. There is an evidence gap in the optimal second-line treatment strategy. Currently, there is a paradigm shift in second-line treatment taking place from empirical corticosteroid-only strategies to either intensified initial immunosuppression where corticosteroids are combined with another immunosuppressant or targeted therapies directed at the pathophysiology of ICI myocarditis. However, the available evidence to support these novel strategies is limited to observational studies and case reports. The aim of this review is to summarize the literature, guidelines, and future directions on the pharmacological treatment of ICI myocarditis., Competing Interests: The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Immune checkpoint inhibitor therapy has revolutionized the treatment of advanced malignancies in recent years. Numerous reports have detailed the myriad of possible adverse inflammatory effects of immune checkpoint therapies, including within the cardiovascular system. However, these reports have been largely limited to myocarditis. The critical role of inflammation and adaptive immunity in atherosclerosis has been well characterized in preclinical studies, and several emerging clinical studies indicate a potential role of immune checkpoint targeting therapies in the development and exacerbation of atherosclerosis. In this review, we provide an overview of the role of T-cell immunity in atherogenesis and describe the molecular effects and clinical associations of both approved and investigational immune checkpoint therapy on atherosclerosis. We also highlight the role of cholesterol metabolism in oncogenesis and discuss the implications of these associations on future treatment and monitoring of atherosclerotic cardiovascular disease in the oncologic population receiving immune checkpoint therapy., Competing Interests: Funding Support and Author Disclosures Drs Stein-Merlob and Nayeri are supported by the National Institutes of Health Cardiovascular Scientist Training Program (grant T32HL007895). Dr Sallam is supported by the American Heart Association Transformational Project Award and the National Institutes of Health grant HL149766. Dr Neilan is supported by a gift from A. Curt Greer and Pamela Kohlberg, and grants from the National Institutes of Health/National Heart, Lung, and Blood Institute grants R01HL130539, R01HL137562, and K24HL150238. Dr Yang is supported by a grant from CSL Behring. Dr Neilan has been a consultant to and received fees from Amgen, H3-Biomedicine, and AbbVie outside of the current work; has received consultant fees from Bristol Myers Squibb for a Scientific Advisory Board focused on myocarditis related to immune checkpoint inhibitors; and has received grant funding from AstraZeneca on atherosclerosis with immune checkpoint inhibitors. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Treatment with immune checkpoint inhibitors (ICIs) has been associated with an increased rate of cardiac events. There are limited data on the risk factors that predict cardiac events in patients treated with ICIs. Therefore, we created a machine learning (ML) model to predict cardiac events in this at-risk population., Methods: We leveraged the CancerLinQ database curated by the American Society of Clinical Oncology and applied an XGBoosted decision tree to predict cardiac events in patients taking programmed death receptor-1 (PD-1) or programmed death ligand-1 (PD-L1) therapy. All curated data from patients with non-small cell lung cancer, melanoma, and renal cell carcinoma, and who were prescribed PD-1/PD-L1 therapy between 2013 and 2019, were used for training, feature interpretation, and model performance evaluation. A total of 356 potential risk factors were included in the model, including elements of patient medical history, social history, vital signs, common laboratory tests, oncological history, medication history and PD-1/PD-L1-specific factors like PD-L1 tumor expression., Results: Our study population consisted of 4960 patients treated with PD-1/PD-L1 therapy, of whom 418 had a cardiac event. The following were key predictors of cardiac events: increased age, corticosteroids, laboratory abnormalities and medications suggestive of a history of heart disease, the extremes of weight, a lower baseline or on-treatment percentage of lymphocytes, and a higher percentage of neutrophils. The final model predicted cardiac events with an area under the curve-receiver operating characteristic of 0.65 (95% CI 0.58 to 0.75). Using our model, we divided patients into low-risk and high-risk subgroups. At 100 days, the cumulative incidence of cardiac events was 3.3% in the low-risk group and 6.1% in the high-risk group (p<0.001)., Conclusions: ML can be used to predict cardiac events in patients taking PD-1/PD-L1 therapy. Cardiac risk was driven by immunological factors (eg, percentage of lymphocytes), oncological factors (eg, low weight), and a cardiac history., Competing Interests: Competing interests: TGN has received advisory fees from BMS, H3 Biomedicine, Amgen, AbbVie, and Intrinsic Imaging and grant support from Astra Zeneca., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In 2017, Massachusetts General Hospital implemented the Severe Immunotherapy Complications (SIC) Service, a multidisciplinary care team for patients hospitalized with immune-related adverse events (irAEs), a unique spectrum of toxicities associated with immune checkpoint inhibitors (ICIs). This study's objectives were to evaluate the intervention's (1) effect on patient outcomes and healthcare utilization, and (2) ability to collect biological samples via a central infrastructure, in order to study the mechanisms responsible for irAEs., Methods: A hospital database was used to identify patients who received ICIs for a malignancy and were hospitalized with severe irAEs, before (April 2, 2016-October 3, 2017) and after (October 3, 2017-October 24, 2018) SIC Service initiation. The primary outcome was readmission rate after index hospitalization. Secondary outcomes included length of stay (LOS) for admissions, corticosteroid and non-steroidal second-line immunosuppression use, ICI discontinuation, and inpatient mortality., Results: In the pre-SIC period, 127 of 1169 patients treated with ICIs were hospitalized for irAEs; in the post-SIC period, 122 of 1159. After SIC service initiation, reductions were observed in irAE readmission rate (14.8% post-SIC vs 25.9% pre-SIC; OR 0.46; 95% CI 0.22 to 0.95; p=0.036) and readmission LOS (median 6 days post-SIC vs 7 days pre-SIC; 95% CI -16.03 to -0.14; p=0.046). No significant pre-initiation and post-initiation differences were detected in corticosteroid use, second-line immunosuppression, ICI discontinuation, or inpatient mortality rates. The SIC Service collected 789 blood and tissue samples from 234 patients with suspected irAEs., Conclusions: This is the first study to report that establishing a highly subspecialized care team focused on irAEs is associated with improved patient outcomes and reduced healthcare utilization. Furthermore, the SIC Service successfully integrated blood and tissue collection safety into routine care., Competing Interests: Competing interests: LZ—Merck consultant. JC—consultant for BMS and Sanofi-Genzyme. DJ—scientific advisory board fee from Eisai, EMD Serono, Genentech, Ipsen, Novartis, Guardant, Petra Pharma, Mapkure, Vibliome Therapeutics, and Relay Therapeutics; institutional research funds from Novartis, Genentech, EMD Serono, Eisai, Takeda, Placon Therapeutics, Syros, Ribon Therapeutics, Infinity Pharmaceuticals, InventisBio and Amgen. GMB—sponsored research agreements with Palleon Therapeutics and Olink Proteomics; scientific advisory board for Novartis and Nektar Therapeutics; consulting for Merck. MD—consultant for Moderna, Tillotts Pharma, ORIC Pharmaceuticals, and Partner Therapeutics; research funding from Novartis and Eli Lilly; scientific advisory board for Neoleukin Therapeutics. ACG—consultant for Momenta, Alexion, UCB/Ra pharma; royalties from Oakstone Publishing; research funding from Myasthenia Gravis Foundation of America, MGNET and Project Datasphere. BDM—consultant for Sanofi, AbbVie, and Celestial Pharmaceuticals. He has also received sponsored research agreements from Boehringer-Ingelheim, Bayer, and Bristol-Myers Squib. MK—consultant for Novartis and Mymee; speaker fees for Lilly. TGN—advisory fees from Parexel, BMS, H3 Biomedicine, AbbVie, and Intrinsic Imaging; grant support from AstraZeneca. JRF—research grants from Bristol Myers Squibb and X4 Pharmaceuticals. MJM—received honarium/acted as a consultant for AstraZeneca, Nektar Therapeutics, Catalyst Pharmaceuticals, Immunai Aditya Bardia; consulting or advisory role for bioTheranostics, Genentech, Genentech/Roche (Inst), Immunomedics, Immunomedics (Inst), Innocrin Pharma (Inst), Merck, Merck (Inst), Novartis, Novartis (Inst), Pfizer, Pfizer (Inst), Radius Health (Inst), Radius Pharma, Sanofi, Spectrum Pharmaceuticals; research funding from bioTheranostics. RS—consultant/scientific advisory board member for AstraZeneca, Bristol-Myers Squibb, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, Replimune; research funding from Merck and Amgen. SB—consultant for Third Rock Consulting and Two River Consulting; equity holdings in Kronos Bio and Allogene Therapeutics. YRS—consultant for Castle Biosciences., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings., Competing Interests: Competing interests: ACG has served on an advisory board and/or consulted with Alexion, Ra Pharma/UCB and Momenta pharmaceuticals/Janssen. She has received royalties from Oakstone Publishing and research support from the Myasthenia Gravis Foundation of America, the MG Rare Disease Network and Project Data Sphere® for an irAE-N registry. She has received clinical trial support to the institution from Ra Pharma and Momenta. LBB receives salary support from Biogen, royalties from Oakstone Publishing, and research support from Project Data Sphere for an irAE-N registry. BKC reports research support from Project Data Sphere for an irAE-N registry. JH receives research support from Project Data Sphere for an irAE-N registry and from GE Healthcare. THS is an employee at the not-for-profit corporation Project DS, with a trade name of Project Data Sphere. AAA served on medical advisory boards for Alexion, Sarepta, CSL Behring, Strongbridge Pharma, Argenx, Ra Pharmaceuticals, and as a neurology consultant for Johnson & Johnson COVID-19 vaccine trials. ABW served on a medical advisory board or as a consultant with Iovance, Novartis, Shanghai Jo’Ann Medical Technology. PKB has consulted for Angiochem, Genentech-Roche, Lilly, Tesaro, Voyager Therapeutics, ElevateBio, Pfizer (Array), Pfizer, SK Life Sciences and Dantari, received grant/research support (to Massachusetts General Hospital) from Merck, BMS and Lilly and honoraria from Merck, Pfizer, Genentech-Roche and Lilly. TAC has received royalties from Wolters Kluwer. SLC serves as the Editor of the Neurology®Podcast and Neurology Minute™. She has received research and/or clinical fellowship support from the Western Institute for Veterans Research, the Siegel Rare Neuroimmune Association, the Immune Deficiency Foundation, Alexion, the Barbara Gural Steinmetz Foundation, and the Sumaira Foundation for NMO. She has served on an advisory board and/or consulted with Alexion, Genentech, VielaBio, Guidepoint, Clarion Healthcare Consulting, ExpertConnect (majority fees paid to University of Utah). JC has received consulting fees from Sanofi-Genzyme and BMS. JD is a consultant for Blue Earth Diagnostics, Magnolia, Gamaka Bio, and Unum Therapeutics. JD has received research support from Beacon Biosignals, Boehringer Ingelheim, Brystol-Myers Squibb, Eli Lilly, Medimmune, Acerta Pharma, Orbus Therapeutics, and Novartis Pharmaceuticals. JD has received royalties from Wolters Kluwer for serving as an author for UpToDate. MD has research funding from Novartis and Eli Lilly, has served as a consultant for Roche-Genentech, Tillotts Pharma, ORIC Pharmaceuticals, Partner Therapeutics, and Moderna, and is a member of the Scientific Advisory Board for Neoleukin Therapeutics. CTD has served on advisory boards for Argenx and Dysimmune Diseases Foundation. He has received royalties from Oakstone Publishing. He has received grant support from NINDS/NeuroNext. DD has served on an advisory board and/or consulted for UCB, Astellas and Immunovant pharmaceuticals. All compensation for the consulting activities is paid to Mayo Clinic. He has patents pending for KLHL11 and LUZP4 as markers of neurological autoimmunity and germ cell tumors. JG has received research to UCSF support from Genentech/Roche for a clinical trial, performed consulting for Biogen, and received personal compensation for medical-legal consulting. JTG has served as a consultant in past 12 months for Immunovant, Alexion, Momenta, Ra Pharma, Grifols, Jacobus, Cabaletta, Regeneron, Argenx, Signant, UCB, Toleranzia and Piedmont Pharmaceuticals. He receives industry grant support from UCB pharma for a fellowship training grant. Full disclosure statement available at: https://dcri.org/about-us/conflict-of-interest/. DBJ has served on advisory boards for Array Biopharma, BMS, Catalyst Biopharma, Iovance, Jansen, Merck, Novartis, and Oncosec, and has received research funding from BMS and Incyte. VCJ is a site investigator in myasthenia gravis research trials sponsored by PCORI and by Alexion Pharmaceuticals. RK receives research funding from Alexion Pharmaceuticals. NK reports no relevant disclosures. NRL is a consultant and has received honoraria from Bayer, Seattle Genetics, Sanofi, Fortress Biotech, Silverback Therapeutics and SYNOX Therapeutics. JL reports no disclosures. AM reports no disclosures. MM-L reports no relevant disclosures. MJM has served on an advisory board and/or consulted with AstraZeneca Pharmaceuticals, Nektar Therapeutics, Catalyst Pharmaceuticals and Immunai. JN has received research funding from Merck and AstraZeneca; served as a consultant/advisory board member with Merck, AstraZeneca, BMS, Pfizer, Takeda, Roche/Genentech, Daiichi/Sankyo and has received honoraria from Merck, AstraZeneca, BMS, Pfizer, Takeda, Roche/Genentech. TGN reports acting as a consultant for Parexel, Bristol Myers-Squibb, H3 Biomedicine, AbbVie, and Intrinsic Imaging unrelated to the current research. TGN reports grant funding from AstraZeneca unrelated to current research. DR has been an advisor or consultant with AbbVie; Advantagene; Agenus; Agios; Amgen; Bayer; Boston Biomedical; Boehringer Ingelheim; Bristol-Myers Squibb; Celldex; Deciphera; DelMar; EMD Serono; Genenta; Genentech/Roche; Imvax; Inovio; Kintara; Kiyatec; Medicenna Biopharma; Merck; Merck KGaA; Monteris; Neuvogen; Novartis; Novocure; Oncorus; Oxigene; Regeneron; Stemline; Sumitono Dainippon Pharma; Taiho Oncology. Research support to his institution has been provided by Acerta Phamaceuticals; Agenus; Celldex; EMD Serono; Incyte; Inovio; Omniox; Tragara. KMR has served on an advisory board and/or consulted with Merck, BMS, and Eisai. BDS has served on an advisory board and/or consulted with Janssen, Kite/Gilead, and Celgene/BMS. RS has served on an advisory board and/or consulted with AstraZeneca, Bristol-Myers Squib, Eisai, Iovance, Merck, Novartis, Oncosec, Pfizer, and Replimune. He has received research funding from Merck. NW has served on an advisory board with Seattle Genetics, received royalties from Wolters Kluwer and research support from Merck. KW reports no disclosures. LZ has been a consultant for Merck. WCL is an employee of the not-for-profit corporation Project DS, with a trade name of Project Data Sphere. KLR has received personal compensation from Teladoc research support from Project Data Sphere for a irAE-N registry., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There are limited data on the occurrence, associations and outcomes of pericardial effusions and pericarditis on or after treatment with immune checkpoint inhibitors (ICIs)., Methods: This was a retrospective study at a single academic center that compared 2842 consecutive patients who received ICIs with 2699 age- and cancer-type matched patients with metastatic disease who did not receive ICI. A pericardial event was defined as a composite outcome of pericarditis and new or worsening moderate or large pericardial effusion. The endpoints were obtained through chart review and were blindly adjudicated. To identify risk factors associated with a pericardial event, we compared patients who developed an event on an ICI with patients treated with an ICI who did not develop a pericardial event. Cox proportional-hazard model and logistical regression analysis were performed to study the association between ICI use and pericardial disease as well as pericardial disease and mortality. An additional 6-week landmark analysis was performed to account for lead-time bias., Results: There were 42 pericardial events in the patients treated with ICI (n=2842) over 193 days (IQR: 64-411), yielding an incidence rate of 1.57 events per 100 person-years. There was a more than fourfold increase in risk of pericarditis or a pericardial effusion among patients on an ICI compared with controls not treated with ICI after adjusting for potential confounders (HR 4.37, 95% CI 2.09 to 9.14, p<0.001). Patients who developed pericardial disease while on an ICI had a trend for increased all-cause mortality compared with patients who did not develop a pericardial event (HR 1.53, 95% CI 0.99 to 2.36, p=0.05). When comparing those who developed pericardial disease after ICI treatment with those who did not, a higher dose of corticosteroid pre-ICI (>0.7 mg/kg prednisone) was associated with increased risk of pericardial disease (HR 2.56, 95% CI 1.00 to 6.57, p=0.049)., Conclusions: ICI use was associated with an increased risk of development of pericardial disease among patients with cancer and a pericardial event on an ICI was associated with a trend towards increase in mortality., Competing Interests: Competing interests: TGN has been a consultant to and received fees from Intrinsic Imaging, H3-Biomedicine, Amgen, Roche, and AbbVie, outside of the current work. TGN also reports consultant fees from Bristol Myers Squibb for a Scientific Advisory Board focused on myocarditis related to immune checkpoint inhibitors and grant funding from AstraZeneca. RS has been a consultant to Asana, Bristol Myers Squibb, Merck, Replimune; and received research funding from Amgen and Merck, all outside of the current work. KLR has received research funding from Project Datasphere. AN receives research support from Amgen and is a consultant for Takeda Oncology, AstraZeneca and Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited., Objectives: This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis., Methods: In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block., Results: Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across all patients, mean z-scores for T1 and T2 values were 2.9 ± 1.9 (p < 0.001) and 2.2 ± 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1 (1,079.0 ± 55.5 ms vs. 1,000.3 ± 22.1 ms; p < 0.001) and T2 (56.2 ± 4.9 ms vs. 49.8 ± 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91 (95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE., Conclusions: The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis., Competing Interests: Funding Support and Author Disclosures Dr. Thavendiranathan was supported, in part, through the Canadian Institutes of Health Research New Investigator Award (FRN 147814) and a Canada Research Chair in Cardio-Oncology. This work is supported by the New York Academy of Medicine's Glorney-Raisbeck Award to Dr. Mahmood. Dr. Sullivan was supported, in part, through the National Institutes of Health (NIH)/National Cancer Institute (RO1CA229851, UH2CA207355, RO1CA193970). Dr. C.L. Chen, and Dr. D. Gupta were supported, in part, through the NIH/National Cancer Institute P30CA008748. Dr. Neilan was supported, in part, through the Kohlberg Foundation, the NIH/National Heart, Lung, and Blood Institute (RO1HL130539, RO1HL137562, and K24HL150238), and the NIH/Harvard Center for AIDS Research (P30 AI060354). Dr. Thavendiranathan has received Speakers Bureau fees from Amgen, Takeda, and BI. Dr. Mahmood has received consulting fees from OMR Globus, Alpha Detail, and Opinion Research Team. Dr. Nohria has received research grant support from Amgen; and has served a consultant for Takeda Oncology. Dr. Heinzerling has received consulting, advisory board, and speaker fees from MSD, BMS, Roche, Novartis, Amgen, and Curevac. Dr. Sullivan has served as a consultant for Merck and Novartis. Dr. Groarke has received research support from Amgen. Dr. Neilan has received advisory fees from Parexel, BMS, H3 Biomedicine, AbbVie, and Intrinsic Imaging. Dr. Neilan has received grant support from AstraZeneca. Dr. Wintersperger has received research support and speaker honoraria from Siemens Healthineers (the University Health Network has a master research agreement with Siemens Healthineers); and is an inventor of the IG fitting method owned by the University Health Network (US10314548B2). Dr. Yang has received research funding from CSL Behring. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis., Methods: From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested., Results: Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39)., Conclusions: The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification., Competing Interests: Competing interests: SSM has received consultancy fees from OMR Globus, Alpha Detail, and Opinion Research Team. RS has been a consultant to Merck and Novartis. LH has received consultancy, advisory board, and speaker fees from MSD, BMS, Roche, Novartis, Amgen, and Curevac. LZu has been a consultant to Merck. JG has received research support from Amgen. AN has received research support from Amgen and has been a consultant for Takeda Oncology and AstraZeneca. TGN has received advisory fees from Parexel, AbbVie, H3-Biomedicine, Aprea Therapeutics, BMS, and Intrinsic Imaging. TGN has received grant funding from AstraZeneca., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Immune checkpoint inhibitors (ICIs) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events., Methods: The study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls matched by age, a history of cardiovascular events, and cancer type. In a second design, a case-crossover analysis was performed with an at-risk period defined as the 2-year period after and the control period as the 2-year period before treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization, and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. In addition, in an imaging substudy (n=40), the rate of atherosclerotic plaque progression was compared from before to after the ICI was started. All study measures and outcomes were blindly adjudicated., Results: In the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (hazard ratio, 3.3 [95% CI, 2.0-5.5]; P <0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at 2 years (adjusted hazard ratio, 4.8 [95% CI, 3.5-6.5]; P <0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/y before 6.7%/y after). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids., Conclusions: Cardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk before, during, and after treatment should be considered among patients on an ICI.

Background Myocarditis attributable to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune-related adverse event. Limited data have suggested an association between baseline and on-treatment absolute lymphocyte count (ALC) and neutrophil/lymphocyte ratio (NLR) and the development of other immune-related adverse events; there are no data characterizing the role of ALC and NLR in ICI-associated myocarditis. Methods and Results This was a case control study of 55 patients with ICI myocarditis and 55 controls without any post-ICI immune-related adverse events. We leveraged clinical testing, where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events was also tested. In cases, there was a statistically significant decrease in ALC with myocarditis from baseline (1.6 thousands per cubic milliliter (K/μL); interquartile range, 1.1-1.9 K/μL) to admission (1.1 K/μL; interquartile range, 0.7-1.3 K/μL; P <0.001). Similarly, there was an increase in NLR from baseline (3.5; interquartile range, 2.3-5.4) to admission (6.6; interquartile range, 4.5-14.1; P <0.001). There was no statistically significant change in controls. In follow-up, there were 20 events; larger decreases in ALC (44.6% versus 18.2%; P <0.001) or increases in NLR (156.5% versus 65.1%; P =0.019) were associated with major adverse cardiac events. Conclusions A reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR was associated with subsequent major adverse cardiac events.

Aims: Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented., Methods and Results: From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE., Conclusion: These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Summary: 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. [ABSTRACT FROM AUTHOR]

Over the last decade or so, there has been a paradigm shift in the oncologic care of patients with a range of solid tumour and haematologic malignancies, away from traditional cytotoxic chemotherapy and towards personalized cancer treatments, using both targeted therapy and immunotherapy. This shift has contributed to the remarkable and sustained increase in the number of cancer survivors and the longevity of patients with a cancer diagnosis. This review will focus on the cardiovascular effects of immune checkpoint inhibitors and will present a background on immune checkpoint inhibition for cancer, the epidemiology, potential mechanisms, the potential insights into cardiovascular biology, and a diagnostic and therapeutic approach to potential cases. Our understanding of the cardiovascular effects of immune checkpoint inhibitors needs to improve. However, the evolution necessarily needs to be rapid. Initial observations noted that immune checkpoint inhibitor therapy can lead to a fulminant myocarditis. Recent reports have expanded the effect of immune checkpoint inhibitor therapy on the cardiovascular system to include an increase in cardiac dysfunction without myocarditis, arrhythmias, venous thromboembolic disease, accelerated atherosclerosis, and atherosclerosis-related cardiovascular events. The association between immune checkpoint inhibitor therapy and an increase in these cardiovascular events is not only limited to events occurring within the first few weeks after starting therapy but can also include events that occur months to years after therapy. The latter observation is especially of relevance in those treated with adjuvant or neoadjuvant therapy. There needs to be a shift from recognition of an increase in cardiovascular events to currently approved immune checkpoint inhibitor therapies to understanding the mechanisms that lead to adverse cardiovascular effects, understanding who is at risk, and understanding what we can do about it. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have been associated with neurological immune related adverse events (irAE-N) and patients with ICI toxicity may present with neurological or ocular symptoms. Furthermore, patients on ICI may initially present to oncology or neurology. We report a case series of 3 patients treated with ICIs presenting with diplopia or ptosis, found to have concurrent myocarditis in addition to immune-related myopathy (irMyopathy) or myasthenia gravis (irMG). None of the patients described cardiac symptoms, underscoring the importance of screening for myocarditis in patients presenting with diplopia and/or other neuromuscular symptoms which may suggest either irMyopathy or irMG. [ABSTRACT FROM AUTHOR]

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The article informs about critical role of the immune system in cardiovascular biology with immune checkpoint inhibitors and cardiovascular events among patients with cancer. Topics include improved outcomes among patients with predominantly solid tumour malignancies; and cytotoxic T-lymphocyte antigen 4 with programmed cell death 1 (PD-1) pathways, to evade T-cell-mediated targeting and destruction in clinical trials.

Preclinical studies indicate that the concurrent use of inhibitors of the renin–angiotensin–aldosterone system (RAAS) may improve outcomes in broad groups of patients with cancer. There are limited data on the association between the use of RAAS inhibitors and outcomes among patients treated with immune checkpoint inhibitors (ICIs). We performed a retrospective study of all patients treated with an ICI in a single academic network. Of 10,903 patients, 5910 were on any anti-hypertensive medication. Of those on anti-hypertensive therapy, 3426 were prescribed a RAAS inhibitor during ICI treatment, and 2484 were prescribed other anti-hypertensive medications. The primary outcome was overall survival in the entire cohort and in sub-groups by cancer types. Thoracic cancer (34%) and melanoma (16%) were the most common types of cancer. Those prescribed a RAAS inhibitor were older, more frequently male, and had more cardiovascular risk factors. In a Cox proportional hazard model, the concurrent use of RAAS inhibitors was associated with better overall survival (hazard ratio (HR):0.92, [95% Confidence Interval (CI):0.85–0.99], P =.032). Patients with gastrointestinal (HR:0.82, [95% CI: 0.67–1.01], P =.057) and genitourinary cancer (HR:0.81, [95% CI:0.64–1.01], P =.067) had a non-statistically significant better overall survival. In this large retrospective study, patients with hypertension who were concomitantly taking a RAAS inhibitor during ICI therapy had better overall survival. This benefit was primarily noted among patients with gastrointestinal and genitourinary cancers. Prospective randomized trials are warranted to further evaluate and specify the benefit of RAAS inhibitors in patients with cancer who receive ICI therapy. • We evaluated the effect of RAAS inhibitors among 5910 patients with cancer on an ICI. • Patients taking a RAAS inhibitor during ICI therapy had better overall survival. • The effect of RAAS inhibitors was similar among patients on an ACE inhibitor and an ARB. • The benefit was not noted among patients with melanoma and lung cancer. • Benefit was principally seen in patients with gastrointestinal and genitourinary cancers. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are widely used cancer treatments. There are limited data on the risk for developing venous thromboembolism (VTE) among patients on an ICI. This was a retrospective study of 2854 patients who received ICIs at a single academic centre. VTE events, defined as a composite of deep vein thrombosis or pulmonary embolism, were identified by individual chart review and blindly adjudicated using standard imaging criteria. A self-controlled risk-interval design was applied with an 'at-risk period' defined as the two-year period after and the 'control period', defined as the two-year before treatment. The hazard ratio (HR) was calculated using a fixed-effect proportional hazards model. Of the 2854 patients, 1640 (57.5%) were men; the mean age was 64 ± 13 years. The risk for VTE was 7.4% at 6 months and 13.8% at 1 year after starting an ICI. The rate of VTE was > 4-fold higher after starting an ICI (HR 4.98, 95% CI 3.65–8.59, p < 0.001). There was a 5.7-fold higher risk for deep vein thrombosis (HR 5.70, 95% CI 3.79–8.59, p < 0.001) and a 4.75-fold higher risk for pulmonary embolism (HR 4.75, 95% CI 3.20–7.10, p < 0.001). Comparing patients with and without a VTE event, a history of melanoma and older age predicted lower risk of VTE, while a higher Khorana risk score, history of hypertension and history of VTE predicted higher risk. The rate of VTE among patients on an ICI is high and increases after starting an ICI. • Rate of venous thromboembolism (VTE) increases after starting an immune checkpoint inhibitor (ICI). • Patients with a higher Khorana score are more likely to develop VTE with an ICI. • Compared to lung cancer, patients with melanoma have a lower risk of VTE on an ICI. • Anticoagulation can attenuate the increase in the risk of VTE with ICI use. • Clinical suspicion for VTE in patients receiving ICIs should be increased. [ABSTRACT FROM AUTHOR]

Immunotherapies such as immune checkpoint inhibitors (ICI) are effective in multiple tumor entities but induce a plethora of side effects. Comprehensive real-world analyses are essential to identify new signals, characterize diagnostic features, enable risk assessment, determine pathomechanisms, assess effectiveness of side effect management and compare tumor outcomes. The international online 'Side-Effect Registry Immuno-Oncology´ (SERIO; www.serio-registry.org) collects rare, complex, and severe immunotherapy-induced side effects across all tumor entities with a strong focus on ICI-induced immune-related adverse events (irAE). The relational database management system (RDMS) contains structured data on patient and tumor characteristics, type of immunotherapy, treatment of side effects, and outcome of tumor and irAE. Data are captured within 25 organ modules including new modules for immune effector cell-associated neurotoxicity syndrome (ICANS) for CAR-T-cell therapies and cytokine release syndrome (CRS) for bispecific antibodies. Information on biological samples is gathered. A total of 1398 irAE cases have been documented by 58 centers from 13 countries in patients with 17 tumor types. IrAEs were induced by nine different immunotherapies including tebentafusp and CAR-T cell therapies, and resulted, among others, in neurological (7.6%), pulmonary (4.0%), and cardiac toxicities (2.9%). 50.0% of all irAEs were graded severe or life-threatening and 23.0% of patients received second-line therapy for steroid-refractory or steroid-dependent irAE. SERIO has contributed to 44 original publications on topics ranging from irMyocarditis to irEncephalitis to long-term persistent sequelae of immunotherapy. A reliable evidence base is crucial for decision-making in rare, complex or therapy-refractory irAE. SERIO can help optimize side effect management and thereby reduce morbidity and mortality induced by immunotherapy. • Growing number of challenging immune-related adverse events (irAE) • Real-world international database - Side Effect Registry Immuno-Oncology (SERIO) • 1330 rare, complex, and therapy-refractory irAE cases from 58 centers worldwide • 44 original publications ranging from irMyocarditis to life-threatening irAEs • To optimize irAE management and reduce immunotherapy-induced morbidity and mortality [ABSTRACT FROM AUTHOR]