Losurdo Agnese, Panico Cristina, Catalano Chiara, Serio Simone, Giordano Laura, Monti Lorenzo, Catapano Federica, Figliozzi Stefano, D'Andrea Carla, Dipasquale Angelo, Persico Pasquale, Di Muzio Antonio, Cremonesi Marco, Marchese Alessandro, Tronconi Maria Chiara, Perrino Matteo, Finocchiaro Giovanna, Lugli Enrico, Francone Marco, Santoro Armando, Condorelli Gianluigi, Simonelli Matteo, Kallikourdis Marinos
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy.
Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy.
J Immunother Cancer. 2025 Mar 18;13(3):e010568. doi: 10.1136/jitc-2024-010568.
Immune checkpoint inhibitors (ICIs) revolutionized cancer therapy, yet require management of immune-related adverse events (irAEs). Fulminant myocarditis is a rare irAE, but lower-severity cardiac events are being reported more frequently, leading to an unmet need for irAE prevention, early diagnosis, and treatment, especially for long-life-expectancy patients. We recruited 57 patients, stratified according to therapy regime (monotherapy (30%) or combination (33%) cohort) or history of cardiac disease or presence of at least two cardiovascular risk factors other than prior or active smoking (cardiovascular cohort (37%)). We performed a complete cardiological assessment with clinical visit, 12-lead ECG, multiparametric cardiac MRI as well as peripheral blood mononuclear cell immunophenotyping, prior to ICI initiation and around 2 months later. ICI treatment was associated with a significant left ventricular ejection function (LVEF) reduction pre-ICI versus post-ICI treatment (60.1±8% to 58.1±8%, p=0.002, paired t-test) and more than 3% LVEF loss in a substantial proportion of patients (18; 32%). These patients also showed significantly higher T2 values (p=0.037, unpaired t-test), putative sign of cardiac edema. The loss of cardiac function did not differ among patients with different tumor types, therapy regimes or history of cardiac disease. Immunophenotyping analyses showed a reduction of programmed cell death protein 1 staining on both CD4 and CD8 T cells, and an upregulation of HLA-DR on CD8 T cells. Using a very sensitive and comprehensive approach in patients unselected for cardiac history, we found a subclinical but significant LVEF decrease. These findings may inform ongoing discussions on optimal management of cardiac irAEs in patients undergoing ICI treatment and warrant further evaluation.
免疫检查点抑制剂（ICIs）彻底改变了癌症治疗方式，但需要对免疫相关不良事件（irAEs）进行管理。暴发性心肌炎是一种罕见的irAE，但较低严重程度的心脏事件报告更为频繁，这导致对irAE预防、早期诊断和治疗存在未满足的需求，尤其是对于预期寿命较长的患者。我们招募了57名患者，根据治疗方案（单药治疗组（30%）或联合治疗组（33%））、心脏病史或除既往或当前吸烟外至少存在两种心血管危险因素进行分层（心血管疾病组（37%））。在开始ICI治疗前及大约2个月后，我们通过临床就诊、12导联心电图、多参数心脏磁共振成像以及外周血单个核细胞免疫表型分析进行了全面的心脏评估。ICI治疗与ICI治疗前相比，左心室射血功能（LVEF）显著降低（60.1±8%至58.1±8%，p = 0.002，配对t检验），并且相当一部分患者（18例；32%）的LVEF损失超过3%。这些患者还表现出显著更高的T2值（p = 0.037，非配对t检验），这是心脏水肿的假定迹象。不同肿瘤类型、治疗方案或心脏病史患者的心脏功能丧失情况无差异。免疫表型分析显示，CD4和CD8 T细胞上程序性细胞死亡蛋白1染色减少，CD8 T细胞上HLA-DR上调。在未根据心脏病史进行选择的患者中，我们采用非常敏感和全面的方法，发现了亚临床但显著的LVEF降低。这些发现可能为正在进行的关于接受ICI治疗患者心脏irAE最佳管理的讨论提供信息，并值得进一步评估。
