PD-1/PD-L1抑制剂治疗非小细胞肺癌脑转移的临床研究进展

脑转移是非小细胞肺癌（NSCLC）常见的并发症之一,预后较差。近年来,程序性死亡因子-1（PD-1）/ 程序性死亡因子配体-1（PD-L1）免疫检查点抑制剂（ICI）已逐渐发展为NSCLC的一线治疗,但在脑转移中 的疗效尚未明确。本综述即对PD-1/PD-L1抑制剂在NSCLC脑转移治疗中的研究进展进行总结。     

非小细胞肺癌PD-L1蛋白表达、EGFR基因突变状态及二者相关性研究

目的探讨非小细胞肺癌(NSCLC)中程序性死亡因子配体1(PD-L1)蛋白的表达、表皮生长因子受体(EGFR)基因突变状态及二者的相关性。方法采用免疫组织化学EnVision两步法检测93例NSCLC石蜡组织标本中PD-L1蛋白的表达情况,同时运用突变扩增系统(ARMS)-qPCR法检测EGFR基因突变状态;结合患者临床资料,对PD-L1蛋白表达、EGFR基因突变的临床病理特征及两者的相关性进行研究。结果 93例肺癌组织中PD-L1蛋白表达阳性率为55.9%(52/93)。PD-L1蛋白表达与TNM分期相关,TNMⅡ、Ⅲ期的阳性率显著高于Ⅰ期(P0.05),而与性别、年龄、吸烟史、病变部位、肿瘤大小、淋巴结转移、组织学类型及分化类型无关(P0.05)。EGFR基因突变状态与性别、吸烟史、肿瘤大小和组织学类型相关(P0.05),更易发生于女性、无吸烟史、肿瘤大小≤3cm、腺癌患者,而与患者的年龄、病变部位、淋巴结转移、分化类型和临床分期无关(P0.05)。Logistic回归分析发现,性别可显著影响EGFR基因突变状态(P0.05)。Spearman等级相关分析发现,PD-L1蛋白表达与EGFR基因突变状态无相关性(P0.05)。结论检测PD-L1蛋白表达、EGFR基因突变状态,有助于高效筛选免疫治疗和靶向治疗的检测对象,为临床用药提供理论依据。     

非小细胞肺癌中卵巢肿瘤泛素异肽酶1与程序性死亡受体-1配体的表达相关性

目的 探讨非小细胞肺癌(NSCLC)中卵巢肿瘤泛素异肽酶1(OTUB1)与程序性死亡受体-1配体(PD-L1)的相关性.方法 分析肿瘤基因组数据库(TCGA)中NSCLC与癌旁正常组织OTUB1 mRNA的差异性.基于基因表达谱数据动态分析(GEPIA)探讨NSCLC中OTUB1与PD-L1 mRNA表达相关性.免疫组化法检测46例NSCLC及41例癌旁正常组织蜡块OTUB1及PD-L1蛋白表达,收集临床病例数据及随访资料.分析OTUB1在癌组织与癌旁组织中的表达差异,OTUB1与PD-L1相关性、临床病理特征的关系以及无复发生存期(RFS)预测意义.结果 NSCLC与癌旁正常组织的OTUB1 mRNA及蛋白表达差异均有统计学意义(P＜0.05).NSCLC的OTUB1与PD-L1 mRNA无相关性(P＞0.05),但两者蛋白表达有相关性(P =0.029).OTUB1与TNM分期有相关性(P =0.039),与年龄、吸烟史、分化程度、转移淋巴结数及病理类型无相关性(P＞0.05).Kaplan-Meier分析显示,TNM分期(P ＜0.001)、转移淋巴结数(P =0.001)及分化程度(P =0.042)是RFS的影响因素;OTUB1阴性及阳性中位RFS分别是18、19个月,差异无统计学意义(P＞0.05).COX多因素分析结果提示,分化程度(P=0.005)及TNM分期(P=0.006)是影响RFS的独立危险因素.结论 NSCLC中OTUB1 mRNA及蛋白表达均高于癌旁正常组织.在蛋白水平方面,OTUB1与PD-L1呈正相关.OTUB1表达与TNM分期相关.     

非小细胞肺癌免疫治疗临床新进展

肺癌作为我国病死率、发病率均较高的恶性肿瘤疾病,临床中最为多见的组织学类型是非小细胞肺癌(non-small cell lung cancer,NSCLC),约占总数80％以上.目前主要通过放化疗、手术治疗NSCLC,但是由于多数患者就诊时病情已发展至晚期,延误手术时机,只能接受放化疗治疗,不过从临床治疗效果来看,放化...     

CD155表达水平对非小细胞肺癌PD1免疫疗法反应性的影响

目的 探讨CD155表达水平对非小细胞肺癌PD1免疫疗法反应性的影响。方法 纳入该院2014年至2018年收治的非小细胞肺癌患者111例,其中男69例、女42例。使用免疫组织化学(IHC)对接受PD1免疫疗法的非小细胞肺癌患者治疗前样本中的CD155蛋白水平进行了表征。对患者的疗效展开评估,分为完全缓解(CR)、部分缓解(PR)、疾病稳定(SD)与疾病进展(PD)。分析CD155表达水平对疗效的影响。无进展生存期(PFS)Kaplan-Meier曲线和Cox比例风险模型评估CD155与治疗反应之间的关联。比较不同CD155与PDL1表达情况的非小细胞肺癌患者PD1免疫治疗结果。检测非小细胞肺癌组织中免疫浸润的PD1⁺CD8⁺T细胞与CD155表达水平的关系。结果 根据IHC染色水平,17.12%(19/111)的非小细胞肺癌标本为CD155阴性(评分0+),27.03%(30/111)分类为评分1+,25.23%(28/111)评分为2+,30.63%(34/111)评分为3+。与CD155低表达的肿瘤患者相比(评分为0+、1+),治疗前为C...     

非小细胞肺癌免疫治疗新进展

随着肿瘤免疫机制的研究发展,非小细胞肺癌（NSCLC）的免疫治疗逐渐成为研究热点。目前,一些针对NSCLC的抗体或者疫苗,如抗程序性死亡受体1抗体、表皮生长因子疫苗、黑色素瘤相关抗原-A3、BLP25脂质体疫苗,已进行了系列临床研究,并取得了重要的突破。现就此作一综述。     

1例Nivolumab治疗非小细胞肺癌病人出现免疫相关性肺炎的护理

正肺癌位居我国恶性肿瘤发病率和死亡率第一位,每年新发病例达78.1万例[1],年死亡率过去20年每年上升7.7%,且未来5年仍呈上升趋势[2],其中最为常见的肺癌类型为非小细胞肺癌,约占总数的 80%～85%,由于早期症状的隐匿性大多数病人就诊时已是晚期[3]。晚期非小细胞药物治疗主要是化学治疗和靶向治疗。2018年6月15日我国首个程序性死亡受体1(programmed death 1,PD-1)免疫检查点抑制剂(PD-1单抗)正式获批     

非小细胞肺癌PD-1PD-L1表达与EGFR基因突变临床特征及预后的相关性

目的探讨非小细胞肺癌患者肺组织中程序性死亡受体-1、程序性死亡配体-1蛋白表达与表皮生长因子受体基因突变、临床特征及预后的相关性,为临床治疗提供参考.方法将117例非小细胞肺癌患者设为研究组,60例良性病例设为对照组,采用免疫组化法检测两组肺组织中程序性死亡受体-1、程序性死亡配体-1蛋白表达,采用荧光聚合酶链式反应法检测研究组表皮生长因子受体基因突变情况,对研究组不同临床特征患者的表皮生长因子受体基因突变及程序性死亡受体-1、程序性死亡配体-1蛋白表达进行分析.结果研究组肺组织中程序性死亡受体-1、程序性死亡配体-1蛋白阳性表达率(35.0%、54.7%)显著高于对照组(19.0%、15.5%)(P<0.05或0.01);研究组女性、高分化患者表皮生长因子受体基因突变率高,肿瘤分期Ⅲ期、Ⅳ期患者程序性死亡配体-1蛋白表达阳性率高,程序性死亡配体-1蛋白表达与表皮生长因子受体基因突变呈显著正相关,程序性死亡配体-1蛋白表达阳性较阴性患者的无进展生存期显著缩短(P<0.05或0.01).结论非小细胞肺癌患者肺组织中程序性死亡受体-1、程序性死亡配体-1蛋白表达阳性率高,程序性死亡配体-1蛋白表达与表皮生长因子受体基因突变显著相关;对表皮生长因子受体基因突变型非小细胞肺癌患者使用表皮生长因子受体的酪氨酸激酶抑制剂治疗,程序性死亡配体-1蛋白表达阳性患者可能预后较差.     

非小细胞肺癌免疫检查点抑制剂治疗进展

肺癌是全球范围内发病率及死亡率极高的恶性肿瘤,其中以非小细胞肺癌(non-small cell lung cancer,NSCLC)最为常见。NSCLC的传统治疗主要依靠化学药物,近年来免疫治疗成为NSCLC治疗的热点,并取得了令人瞩目的进展。大量新型生物免疫制剂被开发并应用于临床,其中免疫检查点抑制剂的应用最广、疗效最为肯定。本文将对近年NSCLC免疫治疗生物标志物研究现状及进展进行阐述,以期提高免疫治疗精准度,更好地指导NSCLC患者的个体化治疗。     

非小细胞肺癌患者中免疫检查点抑制剂相关甲状腺炎的调查

目的 分析非小细胞肺癌(NSCLC)患者中PD-1/PD-L1免疫检查点抑制剂相关甲状腺炎(irT)的发生情况。方法 回顾性分析2019年1月至2021年12月在南京医科大学第一附属医院接受PD1/PD-L1免疫检查点抑制剂(ICI)治疗的51例NSCLC患者的临床数据,调查irT的发生情况。比较irT与非irT患者性别、年龄、病理类型、免疫检查点抑制剂类型及治疗前甲状腺功能指标(FT3、FT4和TSH)间的差异。甲状腺功能指标采用电化学发光法检测。结果 接受ICI治疗的NSCLC患者中irT的发生率为37.3%(19/51)。其中,甲减5例(9.8%),甲亢3例(5.9%),亚临床甲减8例(15.7%),亚临床甲亢3例(5.9%)。治疗前TSH水平在irT组为2.09(1.82,3.06) mIU/L,在非irT组为1.73(1.27,2.69) mIU/L,2组间差异具有统计学意义(U=201,P=0.04)。结论 接受PD1/PD-L1抑制剂治疗的NSCLC患者中irT的发生率较高。治疗前TSH水平是irT发生的影响因素。     

Immune checkpoint blockade as a potential therapeutic target in non-small cell lung cancer

ABSTRACT

Introduction: The recent emergence of immune checkpoint blockade therapy and the progression of immunobiology in cancer have spurred an increasing interest in the immunotherapy for advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs), designed to directly target immune inhibitory molecules, have demonstrated efficacy in the treatment of patients with advanced NSCLC.

Areas covered: In the present article, the authors summarize the mechanism, efficacy and safety of major ICIs for the treatment of advanced or metastatic NSCLC. Combinations of different ICIs or conventional therapy and/or targeted agents for NSCLC treatment in clinical trials are also updated. In addition, immune-related adverse events and the roles of inhibitory immune checkpoint molecules as potential biomarkers in the immune checkpoint blockade therapy for NSCLC are emphatically elucidated.

Expert opinion: Immunotherapies targeting the immune checkpoint pathways have shown potential to generate durable responses and improve survival for NSCLC patients. Although the toxicity profile of this immunotherapy is manageable, immune-related adverse events and drug resistance may cause therapeutic failure. Therefore, a better understanding of the mechanisms underpinning its function and the potential side effects of ICIs, as well as the identification of predictive biomarkers for patient selection are essential.     

Ipilimumab in non-small cell lung cancer and small-cell lung cancer: new knowledge on a new therapeutic strategy

The challenge of finding a lasting cure for autoimmune disease(s) has not been met. Although the use of systemic anti-inflammatory agents still dominates the treatment of these diseases, there is a push towards developing novel and more specific strategies. In addressing autoimmunity, there is the intrinsic need to understand the mechanisms that lead to the development and maintenance of immunological tolerance to self-antigens. Experimental evidence has shown that directed antigen expression in the thymus can induce immunological tolerance to that antigen. This forms the cornerstone of one strategy directed towards the cure of autoimmunity. In this strategy, individuals with autoimmune disease are transplanted with bone marrow stem cells that have been genetically modified and in this way allow expression of the self-antigen in the thymus.     

Sipuleucel-T and immunotherapy in the treatment of prostate cancer

Pandemic influenza A viruses of avian origin are of particular concern and have crossed the species barrier several times in recent years, giving rise to illness and occasionally death in humans. This situation could become dramatically worse if the infectivity of avian viruses for humans were increased by reassortment between the genes of human and avian viruses. Co-infection of humans or an intermediate host with an avian strain and an existing human strain could produce new viruses of unknown pathogenicity to which the entire population would be susceptible. Inactivated vaccines against influenza have been prepared for many years using viruses grown in embryonated chicken eggs. However, the use of eggs presents difficulties when vaccine supplies need to be expanded at short notice. It seems likely that future vaccines will be prepared in high-yielding cell cultures from continuous lines that are preferably anchorage-independent. At present, only certain preparations of the Vero and Madin–Darby canine kidney cell lines, grown and maintained in serum-free medium, are acceptable to all regulatory authorities. However, this situation is likely to change with increasing need for non-pandemic and pandemic vaccines.     

1例晚期非小细胞肺癌患者的全程管理

山西省肿瘤医院呼吸一病区收治1例IV期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者。患者,男,50岁,于2012年10月初无明显诱因出现刺激性咳嗽、咳痰。正电子发射计算机断层显像(positron emission tomography-computed tomography,PET-CT)提示:右肺上叶癌,右锁区、纵隔及右肺门肿大淋巴结转移。全身多发骨质破坏。病理(右肺穿刺物)检查示腺癌。变性高效液相色谱(denaturing high performance liquid chromatography,DHPLC)示EGFR19外显子突变。一线治疗给予培美曲塞二钠联合顺铂全身化疗6周期,无进展生存期(progression-free survival,PFS)为8个月;二线治疗予吉非替尼,PFS为42个月;三线治疗继续口服吉非替尼,PFS为4个月;四线治疗予口服AZD9291,PFS为11个月;五线治疗予吉非替尼联合阿帕替尼,PFS为2个月;六线治疗行右上肺楔形切除术,术后病理示:BRAF V600E突变,出现头颅转移,给予培美曲塞二钠+顺铂全身化疗2周期,并予同步左侧额叶、左侧顶叶转移灶大分割调强放疗,PFS为3个月;液滴式数字聚合酶链式反应(droplet digital polymerase chain reaction,ddPCR):T790M(+),七线治疗口服奥希替尼联合培美曲塞单药化疗2周期,疗效评估为部分缓解(partial response,PR),目前仍在随访中。     

Ipilimumab (MDX-010) in the treatment of non-small cell lung cancer

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and pneumonia in young children and the elderly. Despite its clinical importance, there is no licensed vaccine available at present. Vaccine development has been hampered by observations of increased pathology after RSV infection in infants vaccinated with formalin-inactivated RSV; incomplete immunity following natural infection; and the need to be effective during the neonatal period when levels of maternal antibody are high. Four categories of RSV vaccine carriers – live-attenuated RSVs, recombinant vectors expressing the protective antigens of RSV, DNA vaccines and subunit vaccines – have been evaluated in animal models and/or clinical trials. So far, studies with live-attenuated virus vaccines highlight the need to improve immunogenicity whilst maintaining a suitable level of attenuation. Studies with recombinant vectors, DNA and subunit vaccines illustrate the pivotal nature of the vaccine carrier in determining the balance between immune-mediated protection against infection and the induction of immune-mediated pulmonary pathology.     

多西他赛单药一线治疗晚期非小细胞肺癌临床研究

目的探讨多西他赛单药一线治疗晚期非小细胞肺癌临床疗效及不良反应。方法48例晚期非小细胞肺癌患者,多西他赛75m4g／lm2静脉滴注,第1天。21d为1个周期,治疗2～4个周期后评价临床疗效及不良反应。结果48例患者共化疗140个周期,中位化疗2．9个周期。RR为25．O％,DCR为56．3％,中位无进展生存期5．3个月,中位生存期8．6个月,1年生存率35．4％。不良反应以粒细胞减少、贫血、腹泻、脱发为主。结论多西他赛单药一线治疗晚期非小细胞肺癌临床疗效良好,患者耐受性较好。     

CIMAvax-EGF,a therapeutic non-small cell lung cancer vaccine

Introduction: Lung cancer represents the most common cause of cancer death worldwide. While the prognosis remains poor, immunotherapy is giving a positive impact on survival. Cancer vaccines represent a form of active immunotherapy that historically has given modest results in terms of efficacy.

The overexpression of the EGFR by tumor cells was reported in more than half of cases of lung cancer, representing a mechanism of cancerogenesis. CIMAvax-EGF, a therapeutic vaccine for non-small cell lung cancer (NSCLC) developed in Cuba, consists of a human recombinant EGF able to induce antibodies against the autologous EGF, resulting in serum EGF withdrawal and lower EGF-EGFR interaction.

Area covered: We critically reviewed the existing literature about CIMAvax-EGF, from the Pilot studies to the efficacy controlled studies. We also overviewed the ongoing trials.

Expert opinion: CIMAvax-EGF demonstrated to be safe and immunogenic. In a phase III randomized study CIMAvax-EGF, used as a switch maintenance treatment after platinum-based chemotherapy, did not significantly improve survival. Current data are not sufficient to recommend CIMAvax-EGF as a treatment option for advanced stage NSCLC. Further studies, conducted in a context of worldwide standardized clinical practice, are needed to better define if a subpopulation of patients can benefit from the vaccination.     

一线和二线免疫治疗对非小细胞肺癌患者外周血免疫抑制细胞的影响

目的:探讨一线和二线免疫治疗对非小细胞肺癌(non-small cell lung cancer,NSCLC)的临床疗效及外周血免疫抑制细胞的影响.方法:选择2018年1月至2019年10月复旦大学附属中山医院收治的NSCLC患者27例,其中接受PD-1抑制剂一线免疫治疗者7例(一线组)、二线免疫治疗20例(二线组),...     

多西紫杉醇联合顺铂治疗晚期非小细胞肺癌的临床研究

目的观察多西紫杉醇（艾素）联合顺铂治疗晚期非小细胞肺癌的疗效及不良反应。方法对经病理或细胞学证实的60例非小细胞肺癌患者给予多西紫杉醇＋顺铂联合化疗。结果全组无CR病例,部分缓解25例,稳定25例,进展10例,总有效率为83％,中位生存期10．5个月,一年生存率45％,最常见的毒副反应为骨髓抑制。结论多西紫杉醇联合顺铂一线或二线治疗非小细胞肺癌均有较好的疗效,毒性反应可以耐受。     

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.