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...     

肿瘤免疫检查点抑制剂相关肺炎的管理

以免疫检查点程序性死亡因子-1（programmed death 1，PD-1）抑制剂、程序性死亡因子配体-1（programmed death ligand 1，PD-L1）抑制剂及细胞毒性T淋巴细胞相关蛋白4（cytotoxic T lymphocyte antigen 4，CTLA-4）抑制剂为代表的肿瘤免疫治疗，近年来在肿瘤治疗中广泛开展，有效延长了肿瘤患者的生存期，但也可能导致免疫治疗相关不良事件（immune-related adverse events，irAEs）。免疫检查点抑制剂（immune checkpoint inhibitor，ICIs）相关肺炎是常见的irAEs之一，可导致部分肿瘤患者治疗暂停、治疗失败、甚至威胁生命。正确了解ICIs相关肺炎的临床特点，早期诊断并恰当治疗，对影响肿瘤患者的预后、延长生命有重要意义。     

PD-1/PD-L1抑制剂相关性皮肤免疫不良反应护理对策的研究进展

程序性细胞死亡蛋白1(PD-1)抑制剂/程序性细胞死亡蛋白配体1(PD-L1)抑制剂是目前临床应用最多的免疫检查点抑制剂,成为治疗肿瘤的新手段,在肿瘤治疗的无进展期和生存期有显著的疗效。然而,其独特的作用机制导致了不同于化疗放疗的皮肤不良反应,需要采用不同的护理路径。本文根据现有的研究报告和临床指南将PD-1/PD-L1抑制剂相关性皮肤免疫不良反应的护理对策归纳为共同性护理对策、专科性护理对策以及必要性护理对策共3类,为护理人员早期识别并采取相应的护理措施提供参考。     

免疫检查点抑制剂致甲状腺损伤的诊治进展

正免疫检查点抑制剂(immune checkpoint inhibitor, ICI)是一类用于癌症免疫治疗的新型药物,近年来其在晚期癌症患者中的应用越来越广泛,其适应证已从黑色素瘤扩展到其他晚期癌症~([1])。目前临床应用的ICI主要包括细胞毒性T淋巴细胞相关蛋白4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)抑制剂、程序性死亡蛋白1(programmed death-1,PD-1)抑制剂和PD-1配体(programmed death-ligand 1,PD-L1)抑制剂三类。     

PD-1/PD-L1免疫检查点抑制剂对右心室功能的影响

目的:采用二维斑点追踪技术评估PD-1/PD-L1免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)对肿瘤患者右心室功能的影响.方法:选择2018年6月至2020年11月在天津医科大学第二医院泌尿外科和肿瘤科住院的肿瘤患者46例,患者均未使用过ICIs,且进一步需要ICIs治疗.患者...     

外周血淋巴细胞亚型预测晚期肺癌患者免疫相关不良反应的价值

目的 观察晚期肺癌患者免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)治疗前、后外周血淋巴细胞亚型变化,探讨其与免疫相关不良反应(immune-related adverse events, irAEs)的关系。方法 34例晚期肺癌患者均接受ICIs治疗,包括程序性死亡受体1(programmed death-1, PD-1)抑制剂单药,化疗联合PD-1抑制剂或小分子抗血管生成药物联合PD-1抑制剂治疗。ICIs治疗前、第3个周期治疗前应用流式细胞仪检测外周血淋巴细胞亚型,包括Treg细胞、B细胞、NK细胞、CD45⁺T细胞、CD8⁺T细胞、CD4⁺T细胞、CD3⁺T细胞绝对值及PD-1⁺/CD45⁺T细胞、PD-1⁺/CD8⁺T细胞、PD-1⁺/CD4⁺T细胞、PD-1⁺/CD3⁺T细...     

免疫检查点抑制剂的抗肿瘤临床实践与展望

基于靶向免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的肿瘤免疫治疗在近10年取得了重要进展,程序性死亡因子-1(PD-1)/程序性死亡因子配体-1(PD-L1)抗体治疗则成为肿瘤治疗领域最具潜力的新型疗法.中国肿瘤学者与发达国家学者基本同步开展的肿瘤免疫疗法的临床实践,进一步验...     

程序性死亡因子-1抑制剂在血液系统恶性肿瘤治疗中的研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的应用是一种新型免疫治疗手段。阻断程序性死亡因子-1(programmed death 1,PD-1)与其配体(PD-L1)结合,可避免免疫逃逸,恢复机体免疫应答,发挥其抗肿瘤效应,是目前抗肿瘤治疗中炙手可热的方法之一。PD-1抑制剂在越来越多的实体瘤治疗中表现出较好疗效,但在血液系统恶性肿瘤中的应用仍相对有限。本文回顾PD-1抑制剂在血液系统恶性肿瘤中的临床研究,探讨其临床应用前景。     

84例肺癌患者应用程序性死亡蛋白-1的免疫不良反应及护理

目的 探讨程序性死亡蛋白-1（programmed death protein 1,PD-1）抑制剂治疗肺癌患者的免疫不良反应发生情况及护理。方法 2019年7月—2020年1月,125例肺癌住院患者接受PD-1抑制剂治疗,总结免疫不良反应的发生概率、时机、程度及其护理对策。结果 84例患者出现免疫不良反应。（1）发生率：不良反应为67%（84/125）,其中37%（31/84）为皮肤毒性反应,35%（29/84）为甲状腺功能异常;（2）发生时机：43%（36/84）发生在化疗第1周期,38%（32/84）发生在化疗第2周期。（3）程度：G1、G2级反应（轻度、中度）分别为50%、42%（42/84、35/84）。（4）不良反应转归：82%（69/84）顺利完成治疗;18%（15/84）停用PD-1抑制剂,10例免疫不良反应,5例癌症加重,其中肺毒性-肺炎和心脏毒性-心肌炎各1例患者死亡。（5）护理对策：加强评估和观察,及时给予对症护理,重视心理护理和健康教育随访。结论 肺癌患者接受PD-1抑制剂治疗后,67%出现免疫不良反应,以皮肤反应、甲状腺功能异常为主,发生在化疗第1、第2周期,以轻中度反应为主;79%为男性,77%只发生1种不良反应;警惕肺炎、心肌炎等严重/致死性不良反应的判断、观察和干预。护理上加强对症护理,心理护理和健康教育随访,促进患者顺利完成治疗。     

PD-1抑制剂治疗复发或难治性经典型霍奇金淋巴瘤的疗效和安全性分析北大核心CSCD

目的回顾性分析程序性细胞死亡蛋白-1(programmed cell death protein-1,PD-1)抑制剂单药或联合化疗治疗复发或难治性经典型霍奇金淋巴瘤(R/R cHL)的疗效和安全性。方法共纳入2016年9月至2020年12月就诊于中国医学科学院血液病医院的35例R/R cHL患者,其中17例给予PD-1抑制剂单药治疗,另18例接受PD-1抑制剂联合化疗。回顾性分析其临床资料和随访数据,采用Kaplan-Meier法和Cox比例风险模型进行生存分析。结果35例R/R cHL患者中位年龄29(11~61)岁,男性占54.3%,62.9%的患者Ann Arbor分期为进展期,48.6%伴有结外侵犯。PD-1抑制剂治疗前的中位治疗线数为2(1~3)线。28例患者获得客观缓解[其中22例为完全缓解(CR)],客观缓解率(ORR)和CR率分别为80.0%和62.9%;其中PD-1单药治疗组的ORR和CR率分别为64.7%和58.8%,PD-1联合化疗组的ORR和CR率分别为94.4%和66.7%。18例[13例CR和5例部分缓解(PR)]患者序贯自体造血干细胞移植(auto-HSCT)治疗,其中8例患者auto-HSCT后给予PD-1抑制剂单药巩固治疗;移植后患者均获得并维持CR状态,与未序贯auto-HSCT的患者相比无进展生存(PFS)率显著升高(4年PFS率分别为100%和53.5%,P=0.041)。免疫相关的不良事件发生率为29%,仅1例患者出现≥3级不良反应,整体安全性良好。结论PD-1抑制剂治疗R/R cHL安全、有效,PD-1抑制剂联合化疗显著提高缓解率。对于挽救治疗敏感的患者,auto-HSCT巩固治疗进一步改善长期生存。     

Efficacy and Safety of Programmed Cell Death 1 Inhibitor Monotherapy Versus Chemotherapy as Second-Line Treatment for Advanced Esophageal Cancer: A Meta-analysis and Systematic Review

PurposeWith programmed cell death 1 (PD-1) inhibitors approved for second-line treatment of advanced esophageal cancer, immunotherapy and chemotherapy have gradually become the main treatments for second-line treatment of patients with advanced esophageal cancer (AEC). This meta-analysis and systematic review were conducted to evaluate the efficacy and safety of PD-1 inhibitors monotherapy versus chemotherapy in second-line treatment of AEC.MethodsEligible randomized controlled trials were searched in PubMed, Embase, and the Cochrane Library and abstracts presented at the American Society of Clinical Oncology or European Society of Medical Oncology were reviewed to assess the efficacy and tolerability of PD-1/programmed cell death ligand 1 (PD-L1) inhibitors relative to chemotherapy for AEC from January 2016 to October 2020. Patients diagnosed with AEC and progressing after first-line therapy were included in this study. Hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS), risk ratios (RRs) of objective response rate (ORR), and the odds ratios (ORs) of adverse effects (AEs) were calculated.FindingsThe study included 4 randomized controlled trials with 1683 patients. The results indicated that PD-1 inhibitors prolonged the OS (HR = 0.79; 95% CI, 0.71–0.88; P < 0.01) and improved the ORR (RR = 3.00; 95% CI, 2.36–3.82; P = 0.01) but did not improve the PFS (HR = 0.96; 95% CI, 0.76–1.20; P = 0.692) compared with chemotherapy in the second-line treatment of AEC. PD-1 inhibitors alone were associated with a lower incidence of all treatment-related AEs (OR = 0.29; 95% CI, 0.09–0.89; P = 0.03) and grade 3 to 5 treatment-related AEs (OR = 0.26; 95% CI, 0.16–0.44; P < 0.01) versus chemotherapy. PD-1 inhibitors prolonged OS mainly in the following patient groups: male, age <65 years, Eastern Cooperative Oncology Group performance status of 1, or PD-L1 tumor proportion score ≥10%. Asian patients had a longer OS than non-Asian patients (P = 0.01).ImplicationsThe available evidence indicates that the efficacy and tolerability of PD-1 inhibitors were better than chemotherapy in the second-line treatment of AEC, and the benefiting population of these patients was limited to males, those <65 years of age, those with a Eastern Cooperative Oncology Group performance status of 1, or those with a PD-L1 tumor proportion score ≥10%. Notably, Asian patients receiving immune monotherapy had longer OS than non-Asian patients.     

晚期非小细胞肺癌免疫治疗进展

肺癌是我国最常见的恶性肿瘤之一,其中非小细胞肺癌(NSCLC)约占85%,且大部分NSCLC患者在确诊时疾病已进展至晚期,病死率较高。近年来,临床对于晚期NSCLC的治疗已从传统的手术治疗、化学治疗、放射治疗、靶向治疗走向了免疫治疗。免疫检查点抑制剂(ICIs)治疗晚期NSCLC体现出了良好的抗肿瘤活性,尤其体现在细胞毒性T淋巴细胞相关抗原-4(CTLA-4)、程序性死亡受体-1(PD-1)、程序性死亡配体-1(PD-L1)抑制剂。基于此,本文将重点综述CTLA-4、PD-1、PD-L1抑制剂在晚期NSCLC中的治疗进展,以期提高患者的临床获益率,为临床选择合理治疗方案提供参考。     

PD-1/PD-L1 antagonists in gastric cancer: Current studies and perspectives

Immune checkpoints release suppressive signals for T cells, which enable the tumors to escape from immune destruction and provide a new concept that uses the capabilities of the immune system as a therapeutic target for tumors. At present, programmed death receptor 1 (PD-1)/programmed death ligand-1 (PD-L1) has become the most promising therapeutic target. PD-1/PD-L1 blockades exhibit long-lasting antitumor efficacy and safety in patients with various cancers, such as melanoma and non-small-cell lung cancer. Moreover, PD-L1 is highly expressed in the peripheral blood and tumor specimens of patients with cancer, and the expression of PD-L1 is positively correlated with various pathological features and may serve as a predictor of poor prognosis or a diagnostic tool. Clinical trials have verified that PD-1/PD-L1 blockade therapy benefits patients with advanced gastric cancer or gastroesophageal junction cancer. Furthermore, there are many molecules involved in the regulation of PD-1/PD-L1 expression, and the modification of these molecules via drugs and combinations with PD-1/PD-L1 inhibitors may further improve the efficacy of immunotherapy for gastric cancer. In this review, the efficacy, safety, and possible combination treatment options of PD-1/PD-L1 in gastric cancer are reviewed in experimental and clinical settings.     

参与调控细胞程序性死亡蛋白1及其配体1信号通路的研究进展

细胞程序性死亡蛋白1及其配体1(PD-1/PD-L1)通路已经成为研究热点,无论在抗肿瘤还是在抗炎方面均取得了一定的成果,但具体的机制目前尚不完全清楚。本文介绍了PD-1及PD-L1的分子结构、功能以及与其他通路之间的关系。PD-1蛋白是免疫抑制分子,与其配体PD-L1结合起促进细胞凋亡的作用。在肿瘤或炎症中,JAK/STAT、NF-κB、MAPK、PI3K以及TIM-3/Gal-9等其他信号通路被激活,诱导免疫细胞及肿瘤细胞高表达PD-1及PD-L1,使免疫细胞活性降低,消耗增加,募集减少,从而使机体抗肿瘤、抗炎能力下降。PD-1/PD-L1与JAK/STAT、NF-κB、MAPK、PI3K以及TIM-3/Gal-9等其他信号通路也起相互调控作用。PD-1/PD-L1抑制剂与JAK/STAT、NF-κB、MAPK、PI3K以及TIM-3/Gal-9等通路抑制剂联合应用,在抗肿瘤以及肿瘤耐药性方面取得了突破性进展。然而,相对于PD-1/PD-L1对肿瘤作用的研究而言,PD-1/PD-L1在炎症方面的研究相对较少,无相应的药物应用于临床,需要大量的基础研究支持。     

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...     

中晚期恶性肿瘤患者应用PD-1抑制剂多周期治疗对外周血淋巴细胞亚群影响的动态变化研究

目的　研究中晚期恶性肿瘤患者应用程序性死亡受体-1（programmed death recepter-1, PD-1）抑制剂治疗过程中淋巴细胞亚群数量的动态变化,探索 PD-1 抑制剂治疗对患者细胞免疫功能及近期疗效的影响。方法　选取2019 年1 月～ 2021 年1 月入住陕西省人民医院肿瘤内科的144 例接受4 个周期治疗的中晚期恶性肿瘤患者,随机分为PD-1单抗+ 化疗（联合治疗）组（n=54）、PD-1 单抗组（n=38）和化疗组（n=52）。流式细胞术检测患者治疗前及每周期治疗后外周血淋巴细胞亚群:T 细胞(CD3+, CD4+, CD8+),B 细胞（CD19+）及 NK 细胞（CD16+CD56+）数量,应用重复测量方差分析获得不同治疗方案患者淋巴细胞亚群的动态变化趋势。CT 或磁共振成像（MRI）检查评价治疗前及第4 周期治疗后瘤体大小,根据临床效果评价分为治疗有效组（CR 和 PR）和无效组（SD 和 PD）,比较三种治疗方案疗效差异。结果　联合治疗组和 PD-1 单抗治疗组患者外周血 CD3+T, CD4+T, CD4+/CD8+ 细胞数量与治疗前相比显著升高,差异均有统计学意义（F联合治疗组=44.978~315.579, FPD-1 单抗治疗组= 15.174~87.558, 均 P<0.05）,CD8+T 细胞数量显著降低,差异有统计学意义（F联合治疗组=636.362, FPD-1 单抗治疗组=189.966, 均 P<0.05）。经过4 个周期治疗,联合治疗组和 PD-1 单抗治疗组患者CD4+T ,CD4+/CD8+ 细胞与化疗组相比显著升高,CD8+T 细胞显著降低,差异均有统计学意义（F=3.365~5.362, 均 P<0.05）;联合治疗组 NK 细胞数量与其他两组治疗方案相比显著升高,差异有统计学意义（F=18.062,P<0.05）;三组治疗方案 B 细胞比较,差异无统计学意义（F=0.434, P>0.05）。联合治疗组和 PD-1 单抗治疗组患者治疗有效率高于化疗组（81.48 %, 84.21 % vs 63.46 %）,差异有统计学意义（χ2=6.710, P<0.05）。结论 　PD-1 抑制剂联合化疗或单独使用能显著提高中晚期恶性肿瘤患者的淋巴细胞亚群数量,治疗有效率显著高于化疗组,临床获益优于化疗。     

PD-1/PD-L1抑制剂治疗非小细胞肺癌脑转移患者疗效的Meta分析

目的 对PD-1/PD-L1抑制剂对比化疗治疗非小细胞肺癌(non-small cell lung cancer, NSCLC)脑转移患者的疗效进行Meta分析。方法 计算机检索Pubmed、Embase、Sciencedirect、Cochrane、X-mol、中国知网、万方等数据库的文献,由2名研究者筛选文献、提取资料并对纳入研究进行偏倚风险评估,采用RevMan 5.3软件对NSCLC脑转移患者的整体生存期(overall survival, OS)、无进展生存期(progress free survival, PFS)进行Meta分析。结果 共纳入7篇随机对照试验(randomized controlled trial,RCT),包括451例NSCLC脑转移患者。Meta分析结果显示:与化疗相比,PD-1/PD-L1抑制剂能够显著提高患者的OS[HR=0.71,95%CI(0.56,0.92),P=0.008]和PFS[HR=0.53,95%CI(0.41,0.69),P<0.01];单纯化疗作为对照组,PD-1/PD-L1抑制剂联合化疗组OS[HR=0.41,95%CI(0.24,0.70),P=0.001]、PFS[HR=0.44,95%CI(0.30,0.63),P<0.01]比单药组OS[HR=0.83,95%CI(0.63,1.11),P=0.21]、PFS[HR=0.64,95%CI(0.45,0.91),P=0.01]能够更显著地降低患者的死亡风险和疾病进展风险。结论 PD-1/PD-L1抑制剂单药治疗或联合化疗对于NSCLC脑转移患者对比化疗疗效更好,其中联合化疗组优于单用组,是NSCLC脑转移患者治疗的一个优选方案。     

Pembrolizumab for the treatment of non-small cell lung cancer

ABSTRACT

Introduction: Immune checkpoint inhibitors targeting programmed death protein 1 (PD-1) receptor and its ligand, PD-L1, have recently led to significant and durable improvements in the clinical outcomes of some types of cancers including lung cancer.

Areas covered: Pembrolizumab was approved by the US FDA for the treatment of advanced or metastatic NSCLC whose disease has progressed after other treatments and with tumors that express PD-L1. In the phase I KEYNOTE-001 trial, the overall response rate (ORR) was 19.4%, the median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 12.0 months for 495 unselected NSCLC patients. Strong PD-L1 expression (≥ 50%) was associated with higher ORR, longer PFS, and longer OS. The phase II/III randomized KEYNOTE-010 trial demonstrated that pembrolizumab improved OS versus docetaxel in patients with previously treated NSCLC.

Expert opinion: Pembrolizumab, demonstrated durable response and prolonged OS especially in NSCLC patients with high expression of PD-1, thereby suggests a new treatment paradigm. However, many issues remain to be explored, including the identification of other robust biomarkers that can accurately predict the immune-responsiveness of tumors. Along with the identification of predictive biomarkers, further understanding of the tumor microenvironment is necessary to improve treatment outcomes through combinations of immunotherapy or combined with other targeted therapies.