免疫检查点抑制剂心脏毒性的临床热点与争议

免疫检查点抑制剂(ICIs)使多种晚期恶性肿瘤的治疗模式开启了新变革。尽管免疫检查点抑制剂相关心脏毒性较为罕见,但致死性极高。以往研究中免疫检查点抑制剂心脏毒性的发生率被低估。本综述聚焦于目前免疫检查点抑制剂心脏毒性方面的研究进展,包括流行病学、评估、诊断、治疗和预后等。接受ICIs治疗者的最佳肿瘤心脏病管理模式仍面临诸多挑战。     

晚期肺癌患者接受免疫检查点抑制剂治疗后发生免疫相关不良反应的危险因素

目的 分析晚期肺癌患者接受免疫检查点抑制剂（ICIs）治疗后发生免疫相关不良反应（irAE）的危险因素。方法 163例晚期肺癌患者根据接受ICIs治疗后是否发生irAE分为irAE组（63例）和非irAE组（120例），采用单因素及多因素Logistic回归分析法分析晚期肺癌患者接受ICIs治疗后发生irAE的影响因素和危险因素。结果单因素分析显示，免疫疾病史、抗生素暴露史及血清CRP、IL-4、IL-6、IL-10、TNF-α水平是晚期肺癌患者接受ICIs治疗后发生irAE的影响因素（P均<0.05）；多因素分析显示，高IL-4水平和既往自身免疫疾病史是晚期肺癌患者接受ICIs治疗后发生irAE的独立危险因素（P均<0.05）。结论 晚期肺癌患者接受ICIs治疗后发生irAE的危险因素是高IL-4水平和既往自身免疫疾病史。     

免疫检查点抑制剂相关肝毒性的评价与管理

正免疫检查点抑制剂(ICIs)是靶向免疫检查点分子的单克隆抗体,是治疗众多晚期恶性肿瘤的新型免疫疗法。目前有Nivolumab等7种用于临床,主要治疗转移性黑色素瘤、肝细胞癌(HCC)等。ICIs促进免疫介导的肿瘤细胞消亡,主要靶向细胞毒性T淋巴细胞相关分子4(CTLA-4)、程序性细胞凋亡受体1(PD-1)和程序性细胞凋亡配体1(PD-L1)。其不良反应可影响多个器官,肝毒性是重要的不良反应之一,     

免疫检查点抑制剂所致肝脏不良反应的研究进展

免疫检查点抑制剂通过阻断T淋巴细胞负性调控信号以达到增强T淋巴细胞抗肿瘤效应的同时,也可能造成免疫耐受失衡或正常免疫亢进从而导致免疫性肝炎。本文主要通过对免疫检查点抑制剂的治疗机制,导致肝损伤的不良反应机制、危险因素以及发生率等方面进行回顾分析,并且对免疫检查点抑制剂导致肝损伤的治疗方法进行初步归纳。认为免疫检查点抑制剂在促进抗肿瘤免疫的同时,由于作用机制的非肿瘤组织靶点特异性,可能造成非同质化的免疫相关的肝损伤,治疗上以恢复免疫稳态为主。因此,免疫检查点抑制剂应用患者的管理往往需要在治疗窗、毒性和特定损伤治疗之间取得平衡,并开展多学科协作。     

免疫检查点抑制剂相关心脏毒性的研究进展

免疫检查点抑制剂(ICI)通过阻断肿瘤细胞的免疫逃逸,调动自身免疫反应达到治疗肿瘤的目的.ICI可导致多种免疫相关不良反应,其中心脏毒性是少见但致命的不良反应.随着ICI在临床中使用的增加,其导致的心脏毒性逐渐引起更多关注.本文就ICI相关心脏毒性临床表现、机制、诊治及预后进行综述.     

以免疫检查点抑制剂为基础的抗肿瘤免疫治疗相关肝损伤

<正>免疫检查点起着分子开关的作用,可以抑制或促进免疫系统对肿瘤细胞等威胁的反应。自第一个免疫检查点抑制剂(ICIs)伊匹单抗ipilimumab在2011年获批以来,FDA又增加了6种针对免疫检查点的抗体制剂,已成为癌症治疗标准的一部分。随着临床研究中ICIs的数量增加,且越来越多地与其他治疗方式和药物合作,其出现毒性的风险增加。免疫介导型肝炎是一种重要的免疫不良事件(imAEs),需要临床医师的高度警惕,及时诊断和治疗。一、发病机制与病理学BRAF抑制剂和/或抗CTLA4抗体治疗的联合方案可在     

肿瘤免疫检查点抑制剂相关的肝毒性

肿瘤免疫检查点抑制剂治疗为肿瘤患者带来生存获益的同时,也面临了许多挑战,例如免疫介导的肝毒性的发生。深入了解免疫检查点抑制剂治疗肿瘤过程中导致肝损伤的发生情况、可能机制、危险因素等,有助于更好地临床管理。     

本期导读

肝细胞癌(HCC)分子靶向药物及免疫检查点抑制剂(ICIs)治疗已成为不可切除HCC一线治疗方案及根治性治疗高复发风险患者抗复发治疗的选择之一。本期执行主编南月敏教授为本刊组织了HCC靶向及免疫治疗肝损伤应对策略的重点号专题。南月敏教授等从HCC分子靶向药物、ICIs及其联合治疗方案的适应证, 与靶向药物、ICIs单用和联合用药相关肝损伤的管理策略方面进行了评述(南月敏等, 第1121 ～ 1124页)。HCC一线治疗的ICIs均需靶免联合或双免联合治疗, 这增加了免疫相关不良事件的风险, 如ICIs肝毒性。茅益民教授等总结了ICIs相关肝毒性的流行病学、风险因素、临床特征及管理策略(支阳等, 第1125 ～ 1128页) 。分子靶向药物已成为晚期HCC患者的重要治疗手段, 肝损伤是靶向药物常见的不良反应之一。赵素贤教授等总结了HCC靶向药物导致肝损伤的发生情况、机制、危险因素、诊断和治疗策略(赵素贤等, 第1129 ～ 1132页)。大多数HCC患者发现时已为中晚期, 靶免联合治疗成为主要的治疗方案。然而, 不少患者由于存在肝脏基础病变肝功能不能满足靶免治疗的要求, 影响疗效。张缭云...     

免疫检查点抑制剂及其相关性结肠炎的研究进展

免疫疗法作为一种抑制肿瘤生长的新兴治疗方法,目前受到广泛关注。免疫检查点抑制剂(ICIs)通过抑制细胞毒性T淋巴细胞相关抗原4(CTLA-4)和程序性死亡受体/配体1(PD-1/PD-L1)的活性,增强T细胞识别和杀伤肿瘤细胞的能力。由于CTLA-4、PD-1/PD-L1在调节机体对自身抗原的耐受性中有至关重要的作用,因此,ICIs可能会导致机体正常耐受的缺失,从而导致免疫相关不良反应(irAEs),结肠炎为常见的irAEs之一。本文就ICIs相关结肠炎的发生率、临床表现、诊断、危险因素、发生机制、治疗研究进展作一综述。     

免疫检查点抑制剂相关性心肌炎的研究进展

免疫检查点抑制剂(ICIs)是一类新型的抗癌药物,被广泛应用于多种恶性肿瘤的治疗。免疫检查点是阻断T细胞免疫反应负调节因子的抗体,包括细胞毒性T淋巴细胞相关抗原-4(CTLA-4)、程序性细胞死亡蛋白-1(PD-1)和PD-1配体(PD-L1)。虽然ICIs存在能够降低多种肿瘤病死率的显著优势,但其增强的免疫反应导致了一系列与免疫相关的毒性,包括与ICIs相关的心肌炎,后者通常表现为心律失常、心源性休克或猝死。本文就ICIs相关心肌炎的流行病学、诊断、病理生理学及治疗作一综述。     

Cancer immunotherapy and its potential cardiac complications

Recent advances in immune therapy for cancer have significantly improved the clinical outcomes of patients with advanced cancers, where prognosis has historically been very poor. With these new treatments have come new toxicities and, as the use of immunotherapy increases, we will see an increasing incidence of immune-related adverse events, with patients presenting as an emergency. It is important that all cardiologists, and other physicians who see these patients, are aware of life-threatening immune-related toxicities, in addition to their recommended investigation and treatment.We describe a patient with acute cardiotoxicity secondary to immune therapy to illustrate the complexity of these adverse cardiovascular events, providing recommendations for screening, diagnosis and management.Key words: cardio-oncology, cardiotoxicity, immune checkpoint inhibitors, Immunotherapy     

Does immune checkpoint inhibitor exhibit limited efficacy against non-viral hepatocellular carcinoma?: A review of clinical trials

Immunotherapy with immune checkpoint inhibitors has been shown to be beneficial for cancers originating from various organs. In May 2020, combination therapy with anti-programmed death-ligand 1 antibody atezolizumab and anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was approved as a novel first-line systemic therapy for hepatocellular carcinoma (HCC). The number of patients with HCC not caused by hepatitis virus infection (non-viral HCC), including non-alcoholic steatohepatitis (NASH)-related HCC, has been increasing in recent years. Recently, Pfister and colleagues reported that immune checkpoint inhibitors may exhibit limited efficacy against NASH-related HCC, based on basic research and clinical data. This review will discuss the mechanism of impaired tumor immune surveillance in NASH and analyze the results of previously published clinical trials of immune checkpoint inhibitors to investigate whether patients with non-viral HCC are less likely to benefit from immunotherapy with immune checkpoint inhibitors. Furthermore, we also discuss the possibility of enhancing the therapeutic effect of immune checkpoint inhibitors for NASH-related HCC by combining anti-VEGF agents.     

Cardiotoxicity of Novel Targeted Chemotherapeutic Agents

Purpose of review

With the continuing development of newer targeted therapies in oncology, it is necessary to understand their potential cardiovascular side effects. In this review, we discuss the association of novel targeted agents and left ventricular systolic dysfunction.

Recent findings

Within the last 5 years, multiple new agents have been developed to target specific cancer pathways and found to have off-targeted cardiotoxicity. The most recent example is the recognition of myocarditis caused by immune checkpoint inhibitors.

Summary

The development of targeted cancer therapies has revolutionized oncology, but many of these agents are inherently toxic to the cardiovascular system. Nearly all vascular endothelial growth factor (VEGF) inhibitors cause cardiotoxicity to varying degrees. Epidermal growth factor receptor (EGFR) inhibitors developed since the discovery of trastuzumab are significantly less cardiotoxic than their predecessor, but still convene risk. BCR-ABL tyrosine kinase inhibitors (TKI), once thought to pose significant risk as a class effect, appear to only be cardiotoxic if they have anti-VEGF activity. The newer generation of proteasome inhibitors such as carfilzomib appears to have significant cardiotoxicity, with almost 5% of patients developing symptomatic heart failure (HF). Immune checkpoint inhibitors can very rarely cause rapidly fatal myocarditis. As of now, there are no sufficient guidelines to direct clinical care for patients on these new classes of agents, but this is likely to change as more data and clinical experience accumulate.

     

Lessons from Pharmacovigilance: Pulmonary Immune-Related Adverse Events After Immune Checkpoint Inhibitor Therapy

Purpose

To characterize pulmonary toxicities associated with the use of novel immune checkpoint inhibitors

Methods

Adverse event reports from immune checkpoint inhibitors targeting PD-1/L1 and CTLA-4 were captured from the W.H.O pharmacovigilance database (VigiBase) up until Dec. 31st 2019 and were analyzed to evaluate for measures of association between the use of immune checkpoint inhibitors and pulmonary toxicities. Disproportionality analysis using both frequentist and Bayesian approaches were used to detect signals between pulmonary immune-related adverse events and the use of these agents.

Results

A total of 9202 adverse pulmonary immune checkpoint inhibitor-related events were captured up until 2019. Adverse pulmonary events were compromised of 1305 airway, 18 alveolar, 5491 interstitial, 898 pleural, 560 vascular and 939 non-specific pulmonary events. We found a common association between all immune checkpoint inhibitors studied and pneumonitis, interstitial lung disease, pulmonary embolism and respiratory failure. We also noted other associations between immune checkpoint inhibitors, however not as uniformly across agents. Most of these immune-related adverse drug reactions were noted to be severe and accounted for a significant source of mortality in the reported cases.

Conclusion

Immune checkpoint inhibitors are associated with a spectrum of inflammatory pulmonary toxicities. The breadth of pulmonary complications and prevalence may be underappreciated with the use of these agents.

     

Immune checkpoint inhibitor‐related hypophysitis and endocrine dysfunction: clinical review

Immune checkpoint inhibitors are a new and effective class of cancer therapy, with ipilimumab being the most established drug in this category. The drugs’ mechanism of action includes promoting the effector T cell response to tumours and therefore increased autoimmunity is a predictable side effect. The endocrine effects of these drugs include hypophysitis and thyroid dysfunction, with rare reports of adrenalitis. The overall incidence of hypophysitis with these medications is up to 9%. Primary thyroid dysfunction occurs in up to 15% of patients, with adrenalitis reported in approximately 1%. The mean onset of endocrine side effects is 9 weeks after initiation (range 5–36 weeks). Investigation and/or screening for hypophysitis requires biochemical and radiological assessment. Hypopituitarism is treated with replacement doses of deficient hormones. Since the endocrine effects of immune checkpoint inhibitors are classed as toxic adverse events, most authors recommend both discontinuation of the immune checkpoint inhibiting medication and ‘high‐dose’ glucocorticoid treatment. However, this has been challenged by some authors, particularly if the endocrine effects can be managed (e.g. pituitary hormone deficiency), and the therapy is proving effective as an anticancer agent. This review describes the mechanism of action of immune checkpoint inhibitors and details the key clinical endocrine‐related consequences of this novel class of immunotherapies.     

Cardiotoxicity in childhood cancer survivors: strategies for prevention and management

Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.     

Cardiac Complications Associated With Checkpoint Inhibition: A Systematic Review of the Literature in an Important Emerging Area

Background

Immune checkpoint inhibitors, including programmed cell death-1, programmed cell death ligand-1 and cytotoxic lymphocyte antigen-4 inhibitors, have emerged as important therapeutic alternatives for advanced malignancies. This drug class upregulates T-cell activity, leading to an immune response against cancer cells. However, the increased activity of T cells can lead to autoimmune reactions.