免疫检查点抑制剂治疗肝细胞癌相关不良反应及管理

免疫检查点抑制剂的应用显著提高了多种实体瘤的免疫治疗效果。随着Nivolumab和Pembrolizumab被美国食品药品监督管理局批准用于肝癌的二线治疗,免疫检查点抑制剂,特别是与其他治疗方法的联合应用在肝细胞癌中的应用也越来越广泛。这些药物在接触肿瘤的免疫抑制作用发挥治疗作用的同时,也激发了自身免疫引起的相关副作用...     

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。     

免疫检查点抑制剂治疗相关胃肠道不良反应的临床诊疗管理

免疫检查点抑制剂(ICI)是一种新型的抗肿瘤药物,可有效提高肿瘤患者生存率,在肿瘤治疗中发挥着越来越重要的作用。然而,在ICI的使用过程中,不少患者出现了严重程度不一、累及器官不同的不良反应,其中胃肠道不良反应作为次常见的多发免疫相关不良反应备受关注。本文介绍了ICI治疗相关胃肠道不良反应的发生率、诊断、治疗和前沿进展...     

免疫检查点及其抑制剂的发展

<正>免疫检查点的发现与发展人体的免疫系统是受双重信号系统调控的精细化内稳态管理系统。其中一个信号系统是共刺激信号,主要负责效应淋巴细胞的活化;另外一个系统是共抑制信号,负责效应淋巴细胞的抑制。只有2种信号处于平衡状态,才可以保持机体组织细胞既不被自身免疫系统攻击破坏,又可以有效地清除外来微生物的入侵或癌变的细胞。上述两套系统统称为共信号系统或免疫检查点^[1]。     

非小细胞肺癌免疫检查点抑制剂治疗进展

<正>肺癌是当前全球男性、发达国家女性死亡率最高的恶性肿瘤疾病,是我国恶性肿瘤第一位死因。在所有的肺癌亚型中,非小细胞肺癌(non-small-cell lung cancer,NSCLC)占肺癌总数的85%[1]。尽管肺癌的治疗方法在不断进展,但肺癌的预后仍不乐观,据报道NSCLC患者的5年生存率不足20%[2]。癌症免疫治疗是一种通过动员自身免疫系统识别和破坏癌细胞的治疗方式,尽管T细胞受体(T cell receptors,TCRs)具有识别和根除肿瘤细胞的能力,但癌细胞能够表达     

免疫检查点抑制剂相关毒性的机制及其治疗的研究进展

免疫检查点抑制剂在肿瘤治疗中的地位日益突出,显著延长肿瘤患者的生存时间。其关键机制是特异性结合PD-1/PD-L1或CTLA-4靶点,破坏肿瘤免疫耐受,激活淋巴细胞和免疫细胞从而杀灭肿瘤细胞。然而,免疫检查点抑制剂相关毒性的机制还尚未完全明了,故了解其机制并早诊断和早治疗仍是降低毒副反应发生的重要措施。本文对免疫检查点抑制剂相关毒性的机制和治疗的研究进展进行综述。     

免疫检查点抑制剂引起的内分泌系统免疫相关不良反应专家共识(2020)

免疫检查点抑制剂(immune checkpoint inhibitors,ICPis)通过阻断免疫抑制分子,重新激活效应T细胞特异性杀伤肿瘤细胞的功能,发挥抗肿瘤作用。ICPis通过调控免疫应答杀伤肿瘤的同时,过度活化的免疫细胞也可能导致机体产生自身免疫损伤,即免疫相关不良反应(immune-related adverse events,irAEs)。内分泌不良反应是最为常见的不良反应之一,主要涉及垂体、甲状腺、胰腺、肾上腺等内分泌腺体,引起相应的内分泌功能紊乱。ICPis致内分泌腺体损伤是临床医学技术发展带来的新问题,很多临床医生对其诊治存在诸多疑惑。国内外虽已陆续推出多个指南/共识,但目前国内尚无针对ICPis引起的内分泌系统免疫相关不良反应的诊治流程和共识。为规范和提高临床诊治水平,中华医学会内分泌学分会免疫内分泌学组组织专家根据国内外专家共识和相关临床研究,综合肿瘤学、免疫学专家意见后撰写制订本共识,以供在临床实践和临床研究中参考。     

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肠炎的诊疗进展

免疫检查点抑制剂具有恢复免疫系统识别和杀伤肿瘤细胞的能力, 近年来被应用于多种癌症的治疗。因其具有增强免疫系统活性, 破坏免疫稳态的作用, 可引起免疫相关不良反应。免疫相关不良反应可发生在各组织器官, 其中免疫检查点抑制剂相关性肠炎的发病率较高。本文结合国内外研究, 对免疫检查点抑制剂相关性肠炎的发病机制、临床表现、内镜特征及治疗进行综述, 并特别关注难治性肠炎的最新诊疗进展。     

Immune-related adverse events in various organs caused by immune checkpoint inhibitors

Current cancer immunotherapies target immune checkpoint molecules such as the inhibitory receptor programmed cell death-1 (PD-1), one of its ligands, programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), a competitive ligand for CD28 binding to stimulatory receptors CD80 and CD86. Multiple biological drugs use monoclonal antibodies targeting PD-1, PD-L1 and CTLA-4 as cancer immunotherapies. These are termed immune checkpoint inhibitors (ICIs). However, activation of the immune system by ICIs can induce the development of immune-related adverse events (irAEs), which can affect multiple organ systems. The most frequent irAEs are cutaneous and mimic various types of spontaneous skin disorders. Most irAEs are classified as autoimmune conditions mediated by ICI-activated CD8⁺ cytotoxic T cells, some of which are also related to activated B cells and production of pathogenic antibodies. Interestingly, blockade of CTLA-4 mainly induces activation of T cells and inhibition of T_reg cells. On the other hand, the mechanisms underlying anti-PD-1/PD-L1 ICI-induced irAEs are more complicated. PD-1 is a receptor expressed on T and B cells, which binds not only PD-L1, but also PD-L2. The role of PD-L1 is dominant in Th1 and Th17 immunity, while PD-L2 works mainly in Th2 immunity. Better understanding of the mechanisms underlying irAEs will allow for better management of irAEs and improve outcomes and quality of life in cancer patients.     

Immune-related adverse events with immune checkpoint inhibitors: Special reference to the effects on the lungs

Immune checkpoint inhibitors (ICIs) have emerged as evolutionary treatments for malignant diseases. Although ICIs can cause immune-related adverse events (irAEs) in various organs, precise timing after ICI initiation has been scarcely reported. Elucidating the effects of irAEs, such as time to onset, involvement of major organs, influence on progression-free survival (PFS), and overall survival (OS), are critical issues for physicians. Furthermore, lung-irAE as a whole is not well known.We conducted a retrospective study of 156 patients who were treated with ICIs and compared 82 irAE patients with 74 non-irAE patients.This study clearly demonstrated that the preferred period after induction of ICIs was significantly longer in lung-irAE than in other major organs (skin, digestive tract, and endocrine). The effect of irAEs on PFS and OS was evident PFS in the irAE group (n = 82) (median 128 days, interquartile range [IQR] 62–269 days, P = .002) was significantly longer than that in the non-irAE group (n = 74) (median 53 days, IQR 33–151 days). Similarly, OS was significantly longer in the irAE group (median 578 days, IQR 274–1027 days, P = .007) than in the non-irAE group (median 464 days, IQR: 209–842 days). However, this positive effect of irAEs in the lungs was not proportional to the extent of severity.Lung-irAEs can occur at a later phase than non-lung-irAEs and seemed not to prolong OS and PFS. However, further studies are needed to support these findings.     

Treatment of rheumatic adverse events of cancer immunotherapy

Immune checkpoint inhibitors (ICIs), used to treat many advanced cancers, activate the immune system to elicit an antitumor response. ICIs can also cause immune-related adverse events (irAEs) when nontumor tissues are affected by excess inflammation and autoimmunity. Rheumatic irAEs include inflammatory arthritis, myositis, sicca syndrome, polymyalgia rheumatica, and several other rare phenotypes. Treating rheumatic irAEs requires balancing the desire to decrease off-target inflammation while not negatively impacting the antitumor immune response. In this review, treatment recommendations for rheumatic irAEs have been discussed. Pathogenesis of rheumatic irAEs has been briefly reviewed. Knowledge about the effects of corticosteroids and steroid-sparing agents on tumor responses has been detailed to give context for treatment decisions. Recommendations ultimately depend not only on the clinical presentation and severity of the irAE but also on the goals of cancer treatment. Finally, how to safely use ICI therapy in patients with preexisting autoimmune diseases is considered.     

Prognostic significance of adverse events associated with preoperative radiotherapy for rectal cancer

Purpose

Adverse events may occur in patients receiving preoperative radiotherapy (PRT) for rectal cancers. The aim of this study is to clarify the clinical and pathological features of the patients with PRT-related adverse events, and the significance of the adverse events on the clinical outcome.

Methods

Seventy-five patients with T3 or T4 low rectal cancers curatively resected following PRT were studied. Thirty-one patients received radiotherapy, and 44 patients received chemoradiotherapy with tegafur-uracil and leucovorin. The total radiation dose was 50?C50.4?Gy given in 25?C28 fractions and the operation was performed 4?C8?weeks after PRT. PRT-related adverse events were graded in accordance with the Common Terminology Criteria for Adverse Events v3.0.

Results

The most frequent adverse events were leukocytopenia and diarrhea, observed in 12% and 24% of patients, respectively. The majority of the leukocytopenia and diarrhea was grade 1?C2 toxicity. Women experienced leukocytopenia more frequently than men (28% vs. 7%, p?=?0.0317); however, no other predisposing factor for adverse events was recognized. Patients with leukocytopenia or diarrhea showed a better 5-year relapse-free survival rate than those without (94?±?5% vs. 49?±?9%, p?=?0.00054), and the presence of these adverse events was an independent prognostic factor in a multivariate analysis.

Conclusions

The presence of leukocytopenia or diarrhea was an independent predictor of a fair prognosis after curative operation following PRT, and thus these adverse events seem not to discourage oncologists and patients from considering PRT for rectal cancers.     

Proteasome inhibitors in lung cancer

Proteasome inhibition is a novel therapeutic approach that is being investigated in non-small cell and small cell lung cancer (NSCLC and SCLC). Proteasome inhibition affects a range of intracellular signals and disrupts the levels of numerous proteins, causing apoptosis via multiple pathways. Importantly, malignant cells are more sensitive to proteasome inhibition than normal cells. A number of proteasome inhibitors have demonstrated activity in preclinical studies, both as single agents and in combination with conventional and novel antineoplastic agents. However, only bortezomib, a dipeptide boronic acid analog, has been investigated in lung cancer clinical trials, in which it has shown activity as a single agent and in combination regimens. Numerous preclinical and clinical studies are ongoing in both NSCLC and SCLC. Proteasome inhibition could potentially play a significant role in the future management of these conditions.     

Safety aspects of protease inhibitors for chronic hepatitis C: adverse events and drug-to-drug interactions

The standard of care therapy of chronic hepatitis C with the combination of pegylated interferon and ribavirin for 24 or 48 weeks was a remarkable accomplishment of the past decade. However, sustained virological responses rates of about 80% (genotypes 2–3) and 50% (genotype 1) were not satisfactory especially for patients infected with genotype 1. Important advances in the biology of HCV have made possible the development of the direct-acting antiviral agents boceprevir and telaprevir with substantial increase in the rates of sustained virological response with shorter duration of therapy for a large number of patients. However, the complexity of triple therapy is higher and several new side effects are expected suggesting greater expertise in the patient management. Anemia and disgeusia are frequent with boceprevir while cutaneous rash, ranging from mild to severe, is expected with telaprevir. Higher risk of drug–drug interactions demand further clinical consideration of the previous well-known adverse events of pegylated interferon and ribavirin. Identification and prompt management of these potential new problems with boceprevir and telaprevir are crucial in clinical practice for optimizing treatment and assuring safety outcomes to HCV-genotype 1 patients.     

免疫检查点抑制剂相关致命性不良反应及管理策略

免疫检查点抑制剂(immune checkpointinhibitors, ICIs)是针对程序性死亡受体1(programmed cell death protein 1,PD-1)/程序性死亡受体配体1(programmed cell death protein ligand1,PD-L1)和细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte associated antigen-4,CTLA-4)的单克隆抗体,主要通过阻断上述免疫检查点通路的抑制性免疫调节作用从而增强人体的抗肿瘤免疫反应。