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ImportanceImmune checkpoint inhibitors (ICIs) improve outcomes in a wide range of cancers; however, serious adverse effects, including cardiovascular adverse effects (CVAEs), can occur.ObjectiveTo determine the incidence of CVAEs and analyze data on the management of myocarditis in patients exposed to ICIs.Data SourcesPubMed, Embase, and Cochrane Central Register of Controlled Trials from inception were searched on April 4, 2023.Study SelectionTwo separate studies were performed. Key inclusion criteria for study 1 were phases 1 to 4 trials involving adults with malignant neoplasms treated with an ICI and toxicity data; for study 2, publications (case reports and retrospective analyses) on clinical manifestations and treatment of patients with ICI-induced CVAEs. Studies with dose escalation or fewer than 11 patients in each group and all case reports, retrospective analyses, letters, reviews, and editorials were excluded from study 1. Studies not published in English were excluded from study 2.Data Extraction and SynthesisThe PRISMA guidelines and Cochrane Handbook for Systematic Reviews were followed. Data were extracted independently by 2 researchers. A meta-analysis of the incidence of CVAEs in clinical trials and a systematic review of the evidence for the management of myocarditis were performed. Data were pooled using a random-effects model.Main Outcomes and MeasuresIn study 1, the primary outcome was incidence CVAEs in clinical trials with ICIs and ICI combination therapies. Study 2 examined evidence supporting specific management strategies that may decrease the mortality rate of myocarditis. The primary outcomes were planned before data collection began.ResultsIn study 1, a total of 83 315 unique participants in 589 unique trials were included in the meta-analysis. Incidence of CVAEs induced by anti–programmed cell death 1 and/or programmed cell death ligand 1 was 0.80% (95% CI, 0%-1.66%) in clinical trials, with no differences between the compounds, except for cemiplimab, which was associated with a higher risk of CVAEs. Incidence of CVAEs following ipilimumab treatment was 1.07% (95% CI, 0%-2.58%). The incidence of myocarditis was significantly higher following treatment with dual ICIs. However, CVAE incidence was not higher with dual ICIs, ICI combination with chemotherapy, or tyrosine kinase inhibitors. Evidence from randomized clinical trials on recommended monitoring and treatment strategies for ICI-induced myocarditis was lacking. Study 2 showed that myocarditis-associated mortality occurred in 83 of 220 patients (37.7%). Prospective data from 40 patients with myocarditis indicated that systematic screening for respiratory muscle involvement, coupled with active ventilation, prompt use of abatacept, and the addition of ruxolitinib, may decrease the mortality rate.Conclusions and RelevanceImmune checkpoint inhibitor–induced CVAEs and/or myocarditis were recorded in 1.07% of patients in clinical trials. The CVAE mortality risk remains high, justifying the need for monitoring and management strategies for which evidence from randomized clinical trials is absent. Early recognition, ICI therapy cessation, prompt initiation of corticosteroid therapy, and escalation of therapy are all crucial elements for achieving optimal outcomes. Prospective clinical trials or at least prospective registration of treatments and outcomes are highly warranted.

ABSTRACT The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

AbstractTargeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, a long‐established inhibitor of mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent of MPC expression. However, the mechanisms by which UK5099 inhibit inflammatory responses remain unclear. Here, it is shown that UK5099 is a potent inhibitor of the NLRP3 inflammasome in both mouse and human primary macrophages. UK5099 selectively suppresses the activation of the NLRP3 but not the NLRC4 or AIM2 inflammasomes. Of note, UK5099 retains activities on NLRP3 in macrophages devoid of MPC expression, indicating this inhibitory effect is MPC‐independent. Mechanistically, UK5099 abrogates mitochondria‐NLRP3 interaction and in turn inhibits the assembly of the NLRP3 inflammasome. Further, a single dose of UK5099 persistently reduces IL‐1β production in an endotoxemia mouse model. Importantly, structure modification reveals that the inhibitory activities of UK5099 on NLRP3 are unrelated to the existence of the activated double bond within the UK5099 molecule. Thus, this study uncovers a previously unknown molecular target for UK5099, which not only offers a new candidate for the treatment of NLRP3‐driven diseases but also confounds its use as an MPC inhibitor in immunometabolism studies.

The long-term survivorship of patients diagnosed with cancer has improved due to accelerated detection and rapidly evolving cancer treatment strategies. As such, the evaluation and management of cancer therapy related complications has become increasingly important, including cardiovascular complications. These have been captured under the umbrella term “cardiotoxicity” and include left ventricular dysfunction and heart failure, acute coronary syndromes, valvular abnormalities, pericardial disease, arrhythmia, myocarditis, and vascular complications. These complications add to the burden of cardiovascular disease (CVD) or are risk factors patients with cancer treatment are presenting with. Of note, both pre- and newly developing CVD is of prognostic significance, not only from a cardiovascular perspective but also overall, potentially impacting the level of cancer therapy that is possible. Currently, there are varying recommendations and practices regarding CVD risk assessment and mitigating strategies throughout the cancer continuum. This article provides an overview on this topic, in particular, the role of cardiac imaging in the care of the patient with cancer. Furthermore, it summarizes the current evidence on the spectrum, prevention, and management of chemotherapy-related adverse cardiac effects.

7516 Background: Immune effector cell hemophagocytic lymphohistiocytosis IEC-HS is a complication of CAR T cell therapy (CART). This study aims to look at the outcomes of CART patients who develop IEC-HS. Methods: Patients who developed IEC-HS after receiving CART and patients who developed IEC-HS without (nonCART) between December 2020 and March 2022 were included. Results: The 20 CART patients were older than the 25 nonCART patients. Peak ferritin, fibrinogen, CRP, serum creatinine and transaminases were similar between the 2 group. CART patients had lower white blood cell count and platelets and bilirubin than the nonCART patients. CART patients were more like to have markedly elevated IL-6 levels (> 315 mg/ml), higher IL-18, higher MCP-1, and suppressed IL-1β and GMCSF than nonCART patients (Table). Treatment of IEC-HS included tocilizumab (n = 19), anakinra (n = 18) siltuximab (n = 4) and basiliximab (n = 4), dexamethasone (n = 18) methylprednisolone (n = 6), etoposide (n = 1) and ruxolitinib (n = 1). A significant response defined by a 90% reduction or normalization of the cytokine was observed with IL-10 and IFN-ϒ in 92.3% and 84.6% of the CART patients respectively. An intermediate response was noted with TNF, IL-6, MCP-1 and MIP-1 in 38.4%, 30.8% and 61.6% and 38.5% of the patients respectively. No patient had a significant response in IL-2Rα or IL-1β and only 7.7% had a significant response in IL-18. Of the 5 patients who had a MIP-1 response, 4 were on basiliximab +/- high flow continuous venovenous hemofiltration and the only patient that had an IL-18 response was on both modalities. The 100-day mortality after IEC-HS in the CART patients was 40% and was associated with higher peak and lower best ferritin but not the percentage reduction (Table). Higher TNF (90.3 pg/ml vs 37.2 pg/ml, p = 0.05), markedly elevated levels of IL-6 (92% vs 50%, p = 0.03) and IL-10 (33% vs 0%) and an IL-6 response (44.4% vs 0%) were associated with survival at day 100. IL-6 responders had lower peak ferritin vs IL-6 nonresponders (14066 mcg/L vs 45051 mcg/L, p = 0.08). Enterococcus faecium bacteremia developed in 75% of the nonsurvivors vs 16.6% of the 100-day survivors (p = 0.009). Survivors cleared the enterococcus bacteremia within days while nonsurvivors had protracted bacteremia. Conclusions: IEC-HS is devastating complication of CART. Anti-cytokine therapy can reduce some cytokines and ferritin but overimmunosuppression may lead infectious complication, in particular with E. faecium. Better biomarkers are needed to finetune immunosuppressive therapy in order to avoid over-immunosuppression. [Table: see text]

Abstract Aims Doxorubicin (DXR) is a chemotherapeutic agent that causes dose-dependent cardiotoxicity. Recently, it has been proposed that the NADase CD38 may play a role in doxorubicin-induced cardiotoxicity (DIC). CD38 is the main NAD+-catabolizing enzyme in mammalian tissues. Interestingly, in the heart, CD38 is mostly expressed as an ecto-enzyme that can be targeted by specific inhibitory antibodies. The goal of the present study is to characterize the role of CD38 ecto-enzymatic activity in cardiac metabolism and the development of DIC. Methods and results Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody, we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38-CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in wild-type but not in CD38-CI mice treated with DXR. Second, blocking CD38-NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. A reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects. Conclusion NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model.

Introduction: Cardiotoxicity is a serious side effect of anthracycline treatment, most commonly manifesting as a reduction in left ventricular ejection fraction (LVEF) on cardiac imaging. Cost-effective alternatives to cardiac imaging are currently not available. Artificial intelligence (AI) models have been developed to detect a reduced LVEF from 12-lead electrocardiograms (ECGs) in the general population. Hypothesis: AI-ECG model can detect a reduced LVEF after anthracycline therapy (i.e. cardiotoxicity). Methods: We included an unbiased oncological population of 989 female breast cancer patients receiving (neo)adjuvant anthracycline chemotherapy. Average follow-up time was 9.83±4.2 years. Patients with incomplete transthoracic echocardiography (TTE) data, HER-2-directed therapy, significant comorbidities, upfront metastatic disease, second primary malignancy or pre-existing cardiovascular disease were excluded from the analyses. Patients with LVEF decline for reasons other than anthracycline-induced cardiotoxicity were also excluded. Primary readout was the diagnostic performance of AI-ECG by area under the curve (AUC) for various levels of LVEF <50%. Results: Using 1,877 ECGs from 703 unique patients, the AI-ECG model detected an LVEF <50% and ≤35% after anthracycline therapy with an AUC of 0.93 and 0.94, respectively. Conclusions: These data support the use of AI-ECG for cardiomyopathy (cardiotoxicity) screening after anthracycline-based chemotherapy. This technology could serve as a gatekeeper to more costly testing and could enable patients to monitor themselves over long periods of time.

Introduction: Assessing baseline cardiovascular (CV) risk factors is crucial for identifying cancer patients at higher risk of cardiotoxicity (CT). While both CT specific scores, including Heart Failure Association-International Cardio Oncology Society (HFA-ICOS) and our institutional score, as well as general CV scores like Atherosclerotic cardiovascular disease (ASCVD), have been used to assess CT risk; in lymphoma patients undergoing anthracycline therapy, their utility remains unknown. Aim: Evaluate the performance of each risk score to predict CT in a cohort of newly diagnosed lymphoma patients undergoing anthracycline treatment, followed for a median of 5.4 years. Methods: 326 Hodgkin and non-Hodgkin lymphoma patients treated and followed from 2013 to 2021 were prospectively assessed. Baseline measurements of the three risk scores were obtained. ASCVD score was not assessed in patients >80 or <40 years old or without baseline cholesterol. CT was defined during or after one year of chemotherapy as severe, moderate, or mild according to 2022 ESC guidelines. Logistic regression and AUC were used to assess the association of each score and compare the models. Results: Among 326 patients, 78 developed CT (8 severe, 21 moderate, 49 mild). A high-risk score from HFA-ICOS was significantly associated with severe and moderate CT(OR: 6.1, p=0.001), sensitivity 37%, and specificity 88%. A very high-risk classification of the institutional score was associated with severe and moderate CT (OR: 8.4, p=0.006), sensitivity 44%, and specificity 81%. No association was found between the ASCVD score stratification and CT. When mild CT was included in the analysis, the AUC values were lower (see Table 1). Conclusions: Cardio-oncology risk scores were associated with severe and moderate CT, outperforming ASCVD, but their predictive capacity was weak. Incorporating other serum or imaging biomarkers into the models may improve the predictive accuracy of CT risk assessment.