肿瘤免疫检查点抑制剂联合治疗策略及临床应用

目的：免疫检查点抑制剂（immune checkpoint inhibitions，ICIs）的应用显著改善了多种肿瘤的预后，是当前肿瘤治疗中备受重视的手段。以程序性死亡因子-1（programmed death 1，PD-1）、程序性死亡因子配体-1（programmed death ligand 1，PD-L1）和细胞毒性T淋巴细胞相关抗原4（cytotoxic T lymphocyte antigen 4，CTLA-4）单克隆抗体为主的免疫检查点的临床研究结果显示，单一ICIs临床效果有限。不同ICIs的联合治疗、联合化疗及联合抗肿瘤血管生成药物可明显提高疗效，新发现的免疫检查点淋巴细胞激活基因-3（lymphocyte activation gene-3，LAG-3）、T细胞免疫球蛋白黏液素3（T cell immunoglobulin mucin-3，TIM-3）、T细胞免疫球蛋白和ITIM域（T cell immunoglobulin and ITIM domain，TIGIT）等抑制剂的转化和联合应用，对难治性或ICIs耐药患者的疗效值得期待。     

细胞程序性死亡受体-1/细胞程序性死亡配体-1抑制剂相关内分泌不良反应及处理现状

近年来,免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)开始用于治疗多种癌症,疗效显著.细胞程序性死亡受体-1 (programmed death 1,PD-1)抑制剂和细胞程序性死亡配体-1 (programmed cell death-ligand 1,PD-L1)抑制剂都是临...     

免疫检查点抑制剂相关心肌炎分子机制研究进展

免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）已成为目前应用最广的恶性肿瘤免疫疗法，主要包括CTLA-4（cytotoxic T lymphocyte associated antigen-4）抑制剂、PD-1/PD-L1（programmed death protein-1/ligand-1）抑制剂和LAG-3（lymphocyte activation gene-3）抑制剂。ICIs导致的最致命的免疫相关不良反应（immune-related adverse events, irAE）之一为免疫检查点抑制剂相关的心肌炎（immune checkpoint inhibitor-associated myocarditis, ICIAM）。ICIs联合治疗时ICIAM的发病率多高于单药治疗。其分子机制主要包括免疫检查点作为新抗原、肿瘤同源抗原的异位识别、免疫检查点心脏保护的阻断、自身抗体和炎症因子的产生以及微生物的调节作用等。目前已有多种治疗ICIAM药物及非药物性方案。对于ICIAM分子机制的探索和治疗管理方案的进步仍需多学科共同努力。     

PD-1抑制剂免疫相关不良反应的研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICI)的应用是肿瘤治疗领域的重大突破,是恶性肿瘤患者新的选择和希望。国家食品与药品管理监督局(Chinese Food and Drug Administration,CFDA)批准程序性细胞死亡蛋白-1(programmed cell death protein 1,PD-1)免疫抑制剂用于多种肿瘤的治疗。但是PD-1抑制剂可引起自身免疫毒性,虽然大多数免疫相关不良反应(immune-related adverse events,irAEs)以1~2级为主,但仍有部分患者发生危及生命的3~4级免疫毒性反应。     

免疫检查点抑制剂血液系统不良事件

<正>免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)包括程序性死亡受体-1 (programmed death-1,PD-1)单抗、程序性死亡受体-配体1 (programmed death-ligand 1,PD-L1)单抗和细胞毒性T淋巴细胞相关抗原-4(cytotoxic T-lymphocyte-associated protein-4,CTLA-4)单抗等,是通过抑制或阻断CTLA-4或PD-1等信号通路重新激活T淋巴细胞来识别癌细胞,从而达到抗肿瘤作用。随着ICIs的广泛应用,免疫治疗所致免疫耐受失衡导致免疫相关不良事件(immune-related adverse events,irAEs)得到关注及重视,内分泌器官、免疫系统器官、皮肤、肺、胃肠道相关不良事件较为常见,而血液系统不良事件的报告相对较少。对9324例使用ICIs的患者进行meta分析显示,贫血、中性粒细胞减少和血小板减少的发生率分别为9.8%、0.94%和2.8%^[1]。     

免疫检查点抑制剂不良反应的研究进展

正癌症的诊断及治疗策略。免疫检查点抑制剂通过阻断免疫内在的负性因子如细胞毒性T淋巴细胞相关抗原4 (cytotoxic T lymphocyte-associated antigen 4,CTLA-4),程序性死亡受体-1(programmed death receptor-1,PD-1)/程序性死亡配体-1(programmed death-ligand 1,PD-L1)来增强抗肿瘤免疫[1]。PD-1抑制剂如nivolumab和pembrolizumab,以及PD-L1抑制剂如avelumab、durvalumab和atezolizumab已被开发,并已获得美国FDA和欧洲药物管理局(European Drug Administration,EMA)的批准[2]。CTLA-4主要参与淋巴结内T细     

免疫检查点抑制剂的内分泌毒性及临床应对策略

以细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)和免疫检查点程序性死亡蛋白1(programmed cell death protein 1,PD-1)/程序性死亡分子配体1(programmed death-ligand 1,PD-...     

肿瘤免疫检查点抑制剂PD-1治疗过程中不良反应的临床观察

目的:观察免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)程序性细胞死亡蛋白-1(programmed cell death 1,PD-1)在临床应用中免疫相关不良事件(immune-related adverse events,irAEs)发生的情况。方法:回顾性研究2020年1月至2021年12月在马鞍山市中医院接受PD-1治疗的65例恶性肿瘤患者治疗期间发生的irAEs,对其临床特征及其相关血液检查数据进行分析。结果:65例癌症患者中,28例(43.07%)共计发生35次irAEs,其中2次(5.71%)为3级和4级irAEs。最常见的irAEs是皮肤疾病(34.29%),其中皮疹伴瘙痒发生最多。irAEs发生情况与患者的性别、年龄、血常规(血红蛋白、白细胞计数、血小板计数等)和肝功能差异无关(P>0.05),但与肿瘤类别相关(P<0.05)。结论:PD-1在肿瘤治疗中安全性较高,极少发生3级以上irAEs,临床运用中应密切监测,做到早发现和早干预、治疗,把irAEs控制在较低级别,保证PD-1临床应用的安全性,提高肿瘤患者的生存...     

免疫检查点抑制剂相关内分泌不良事件

免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）是一类新型抗肿瘤药物，通过增强抗肿瘤免疫应答产生抗肿瘤作用，已经在多种恶性肿瘤治疗中表现出显著疗效。由于免疫检查点抑制剂特定的作用靶点和机制，可引起自身免疫和炎症效应，称为免疫相关不良事件（immune-related adverse events，irAEs）。随着免疫检查点抑制剂的广泛应用，其导致的irAEs也越来越受到重视，其中内分泌相关不良事件（如甲状腺功能障碍、垂体炎、肾上腺功能不全等）起病时表现隐匿，不易被发现，导致治疗延误，往往带来严重不良后果甚至危及患者生命。本文将总结既往文献，对免疫检查点抑制剂相关内分泌不良事件的发生率、可能的发病机制、临床表现、诊断等进行述评。     

免疫检查点抑制剂相关心肌炎

<正>免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)引起的免疫相关不良事件(immunerelated adverse events,irAEs)可以累及身体任何器官,其导致的心肌炎是一种罕见且致命的并发症^[1]。据报道,ICIs相关心肌炎的发病率为0.04%～1.14%,是一种不常见的不良事件^[2],但其死亡率可高达25%～50%。RUBIOINFANTE^[3]的一项meta分析显示在4751例患者中,1.3%出现心脏irAEs,其中以心肌炎最常见(50.8%);一项回顾性分析中显示964例使用ICIs的患者中心肌炎发病率为1.14%^[4];SALEM等^[5]在世界卫生组织的全球个体病例安全报告数据库VigiBase中描述了2008—2018年报道的122例病例,该研究显示单独使用程序性死亡受体-1(programmed death-1,PD-1)/程序性死亡受体-配体1(programmed death-ligand 1,...     

Immune-related adverse events induced by programmed death protein-1 inhibitors from the perspective of lymphoma immunotherapy

Lymphoma, which is highly malignant, stems from lymph nodes and lymphoid tissue. Lymphoma cells express programmed death-ligand 1/2(PD-L1/PD-L2), which binds with programmed cell death 1 protein(PD-1) to establish inhibitory signaling that impedes the normal function of T cells and allows tumor cells to escape immune system surveillance. Recently, immune checkpoint inhibitor immunotherapies such as PD-1 inhibitors(nivolumab and pembrolizumab) have been introduced into the lymphoma treatment algo...     

Diabetic ketoacidosis induced by a single dose of pembrolizumab

Immune checkpoint inhibitors are a new class of anticancer drugs recently approved by the US Food and Drug Administration (FDA) for the treatment of various malignancies. Pembrolizumab is an immune checkpoint inhibitor that targets the programmed cell death protein-1 (PD-1) receptor and blocks its interaction with programmed cell death ligand-1 (PD-L1) and programmed cell death ligand-2 (PD-L2). Pembrolizumab was first approved by the FDA in 2014 for the treatment of advanced melanoma and is currently approved for use in non-small cell lung cancer and several other neoplasms. Immune checkpoint inhibitors such as pembrolizumab have been reported to induce immune-mediated side effects, including type 1 diabetes mellitus in very rare cases (0.1% in clinical trials). Here, we report the case of a woman with no known history of diabetes who presented to our emergency department in a state of diabetic ketoacidosis within 3?weeks of receiving only a single dose of pembrolizumab therapy, and without any previous exposure to immunotherapy. This case of abrupt adult-onset type 1 diabetes mellitus is an example of the undesirable side effects that can emerge after only a brief exposure to an immune checkpoint inhibitor. Close monitoring of patients receiving immune checkpoint inhibitors is warranted for the early diagnosis and management of imminent and potentially life-threatening complications.     

Diagnosis and Management of Immune Checkpoint Inhibitor–related Toxicities in Ovarian Cancer: A Series of Case Vignettes

Use of immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1 have led to improved survival outcomes for advanced solid-tumor malignancies. This report helps the reader gain a better understanding of adverse events in patients with ovarian cancer on checkpoint inhibitor therapy. We describe 3 hypothetical case vignettes of patients with gynecologic cancer on checkpoint inhibitor immunotherapy and discuss common immune-related adverse events. The typical presentation and onset of immune-related events are different from those associated with conventional chemotherapy. This report highlights the importance of early recognition and management of these events.     

Dynamic changes in the radiologic manifestation of a recurrent checkpoint inhibitor related pneumonitis in a non-small cell lung cancer patient: A case report

BACKGROUNDAs immune checkpoint inhibitors (ICIs) have become widely used in lung cancer treatment, immune-related adverse events (irAEs) warrant sufficient attention. Checkpoint inhibitor-related pneumonitis (CIP) is one of the most concerning adverse events as it is uncommon but life threatening.CASE SUMMARYThe patient whose case is reported here experienced three episodes of CIP in a span of 4 mon. Interestingly, the three episodes of CIP involved different regions of the lung separately. Taking these pneumonitis areas together makes nearly a whole lung area.CONCLUSIONThis case showed that recurrent CIPs may occur repeatedly until the whole lung is involved, suggesting that the follow-up period of CIP should be long enough, and the rechallenge of ICI should be done with due caution.     

Association of immune-related adverse events induced by nivolumab with a battery of autoantibodies

BackgroundThe aim of this study was to assess the diagnostic performance of an autoantibody battery in patients receiving immune checkpoint inhibitors who experienced immune-related adverse events (irAEs).MethodsWe retrospectively analyzed several variables potentially related to irAEs, namely, demographic, clinical, and laboratory characteristics, including an autoantibody battery (antinuclear, anti-neutrophil cytoplasmic, anti-thyroid antibodies and rheumatoid factor).ResultsSixty-nine patients (48 men; 61.8 ± 10.9 years at baseline) diagnosed with stage-4 solid-organ cancer and treated with nivolumab were followed up for 12 ± 10.3 months. Thirty-two irAEs were detected in 26 patients (37.5%). Adverse events occurred more commonly in women (62% vs. 27%, p = .006), and younger patients (irAEs: 58.1 ± 9.8, no irAEs: 64.1 ± 10.9 years, p = .024). Autoantibody battery results were available for 26 patients and were more frequently positive in patients with irAEs (87% vs. 30%, p = .009). The positive predictive value, negative predictive value, and diagnostic accuracy of the battery were 82.3%, 77.8%, and 80.8%, respectively. Among the 64 patients with an evaluable response, 23 (38.5%) experienced tumour progression, this being less frequent in patients with irAEs (19% vs. 48.5%, p = .03). Overall survival was higher in patients developing irAEs (HR = 1.88, p = .05).ConclusionPositivity in a readily available autoantibody battery may be associated with the occurrence of irAEs.

KEY MESSAGES

• Positivity in an accessible and inexpensive autoantibody battery including antinuclear, anti-neutrophil cytoplasmic, anti-thyroid antibodies and rheumatoid factor may be associated with the occurrence of immune-related adverse events.
• Patients with cancer on immune checkpoint inhibitors experiencing immune-related adverse events showed a lower risk of progression and better overall survival than patients not experiencing this type of adverse effect.

     

Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues

A combination of anti–CTLA-4 plus anti–PD-1/PD-L1 is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAEs). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrating myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFN-γ–dependent mechanism. Targeting the HIF-1α/PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated the cancer immunotherapeutic effects of anti–CTLA-4 therapy, with efficacy comparable to that of anti–CTLA-4 plus anti–PD-1 antibodies. However, while anti–PD-1 exacerbated irAEs triggered by ipilimumab, echinomycin protected mice against irAEs by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1/PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment to achieve safer and more effective immunotherapy.     

Immune Checkpoint Inhibitors in Lung Cancer and Melanoma

ObjectiveTo provide a synopsis of immune checkpoint inhibition in solid tumors with a focus on lung cancer and melanoma for the oncology nurse.Data SourcesA literature search was conducted from 2012 to the present using key search terms including: ipilimumab, pembrolizumab, nivolumab, durvalumab, atezolizumab, immune checkpoint inhibitor, NSCLC or SCLC, melanoma, incidence, toxicity, and immune-related adverse events (irAEs).ConclusionImmune checkpoint inhibition has caused a pivotal shift in the treatment of melanoma and lung cancer. Additionally, it has supported the use of immunotherapy as a modality and pillar of cancer treatment. The interdisciplinary team plays an integral role in facilitating patients’ understanding of their treatment modality, symptom management, and guidance through their cancer journey. As more research continues in various tumor types to understand how immune-modulated agents can impact tumor burden, disease control, and quality of life, it is hoped that more patients will have access to these therapies.Implications for Nursing PracticePatient safety is paramount and nurses are aligned to educate, assess, and guide patients during immune checkpoint inhibitor therapy. Developing a rapport and relationship that is based on trust and open communication are vital for helping patients adhere to therapy and safely navigate symptom reporting at the onset of symptoms.     

The potential combinational immunotherapiesfor treatment of hepatocellular carcinoma

The treatment choices available for hepatocellular carcinoma (HCC) are limited and unsatisfactory. Recent improvements in our understanding of the mechanism involving immune checkpoints, including programmed cell death protein 1 (PD1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and also progress in the development of medicines make immunotherapy a promising approach to the treatment of numerous cancers, especially HCC. However, around 40% of patients still suffer from a progressive disease when treated with a monotherapy. Several clinical trials applying a combination therapy including immune checkpoint inhibitors have demonstrated the durable antitumor activity of these approaches in HCC patients. These clinical trials were done with the intent of evaluating the safety of these combination therapies, as well as whether they help improve the overall survival of patients. This study reviewed the recent progress in the use of combination therapies including immunotherapy in treating patients with HCC.     

Research status on immunotherapy trials of gastric cancer

The breakthrough of immune checkpoint inhibitor (ICI) therapy has created extensive opportunities for cancer immunotherapy. Especially, the block of programmed death-1/programmed death ligand 1 (PD-L1) axis using ICIs has become a new therapeutic strategy to treat advanced gastric cancer (GC). However, in the past decade, single-arm and randomized trials for single-drug ICI therapy showed that the therapeutic effect was not satisfactory, including clinical trials for advanced GC. However, after selecting suitable predictive biomarkers and developing a combination of anti-angiogenic targeted drugs and other chemotherapeutic drugs, the objective response rate and progression-free survival of patients with gastric cancer were improved significantly. The United States Food and Drug Administration has approved treatment with pembrolizumab for patients with advanced GC with PD-L1 expression or microsatellite instability-high/mismatch repair deficiency. In this review, the updated data from the latest trial results of combination immunotherapy for GC are presented. Based on the outcome of combination therapy, we discuss its possible molecular mechanism and summarize effective predictive biomarkers. We also discuss possible problems stemming from results of other clinical trials of ICI treatment and propose other directions for ICI therapy.