抗血管生成药物联合化疗治疗进展期非小细胞肺癌研究现状

大部分非小细胞肺癌患者需要进行系统化疗。研究表明以铂类药物为基础的标准一线系统化疗联合贝伐单抗能一定程度改善晚期非小细胞肺癌患者的预后。另有一些研究对多靶点抗血管生成的酪氨酸激酶抑制剂(如:索拉非尼,舒尼替尼,西地尼布,凡德他尼等)联合标准化疗的疗效进行了评估,为非小细胞肺癌患者提供了更多的治疗策略。本文主要对抗血管生成药物联合细胞毒性化疗药物治疗非小细胞肺癌的临床研究进行系统回顾。     

贝伐珠单抗联合化疗二线及以上治疗晚期非鳞型非小细胞肺癌的临床观察

目的：考察贝伐珠单抗联合化疗二线及以上治疗晚期非鳞型非小细胞肺癌的疗效和安全性。方法：28 例经病理组织学或细胞学证实的晚期非鳞型非小细胞肺癌患者接受贝伐珠单抗联合化疗的二线及以上治疗,其间,贝伐珠单抗所用剂量为7.5 mg ? kg -1,在化疗第1 d 静滴给予;化疗方案包括培美曲塞加或不加铂类、白蛋白结合型紫杉醇加或不加铂类及替吉奥以及吉西他滨/ 紫杉醇/ 多西紫杉醇加或不加铂类。各治疗方案每3 周为1 个周期,持续4 个周期,然后维持治疗,直至受试者不能耐受或疾病进展。按RECIST 1.1 版评价疗效,按NCI-CTC 4.0版评价不良反应。结果：28 例受试者中,无完全缓解病例,部分缓解11 例(39.3％ ),稳定16 例（57.1％ ),进展1 例(3.6％ );客观缓解率为39.3％ (11/28),疾病控制率为96.4％ (27/28);中位无进展生存期为5 个月,中位总生存期为10 个月。亚组数据分析可见,贝伐珠单抗联合化疗各方案亚组中,培美曲塞方案受试者的中位无进展生存期为6 个月,疗效最好,较其他各方案亚组有统计学差异（P=0.028）。安全性数据分析显示,与贝伐珠单抗相关的主要不良反应有Ⅰ ~ Ⅲ度高血压以及Ⅰ / Ⅱ度蛋白尿/ 出血/ 发热。结论：贝伐珠单抗联合化疗用于二线及以上治疗晚期非鳞型非小细胞肺癌的疗效较单纯化疗有一定改善,且毒副反应可耐受,对经济上可以接受的患者值得推荐使用。     

小剂量环磷酰胺联合参一胶囊治疗进展期非小细胞肺癌

目的：应用小剂量环磷酰胺（CTX）联合参一胶囊治疗Ⅲ、Ⅳ期非小细胞肺癌,观察其临床疗效及毒副作用。方法：Ⅲ、Ⅳ期非小细胞肺癌患者经标准化、放疗后随机分为两组,治疗组（38例）：CFX 50mg每日一次、参一胶囊20mg日两次口服,三至六个月;对照组（34例）：化疗后不用任何药物治疗。结果：联合治疗组患者外周血血管内皮生长因子（VEGF）表达下降。T淋巴细胞亚群CD4＋及CD4＋／CD8＋升高,病人生存质量及生存期提高。结论：Ⅲ、Ⅳ期NSCLC患者化疗后联合应用小剂量CTX联合参一胶囊治疗是一种安全有效的治疗方法,可以提高患者的生存质量及生存期。     

用于非小细胞肺癌治疗的第三代 EGFR-TKIs 研究进展

肺癌是全球致死率最高的恶性肿瘤,其中非小细胞肺癌(NSCLC)占全部肺癌病例的 80% 左右。相较于传统化疗,表皮生长因 子受体酪氨酸激酶抑制剂(EGFR-TKIs)用于 EGFR 突变型 NSCLC 患者,可获得更为卓越的疗效。但是,EGFR-TKIs 长期使用会产生 获得性耐药,主要机制为 EGFR T790M 突变。临床研究表明,以奥希替尼、rociletinib 和 HM61713 为代表的第三代 EGFR-TKIs 对 EGFR T790M 突变阳性 NSCLC 具有较好的疗效,为 EGFR T790M 突变阳性患者的有效治疗带来了新的希望。综述第三代 EGFR-TKIs 的最新临床研究及耐药机制研究进展。     

非小细胞肺癌中血管生成拟态和VEGF的表达及意义

目的探讨血管生成拟态(vasculogenic mimicry,VM)与血管内皮生长因子(vascular epithelial growth factor,VEGF)在非小细胞肺癌(non-small cell lung cancer,NSCLC)中的表达及意义。方法收集NSCLC术后标本160例和20例正常肺组织,应用免疫组化法和组织化学法检测NSCLC和正常肺组织中VM和VEGF的表达情况。结果在NSCLC组织和正常肺组织中,VM和VEGF的阳性率分别为36.9%、51.3%和0%、0%,差异有统计学意义;含有VM的NSCLC的VEGF表达高于无VM者(P<0.05),且VM与NSCLC的组织学分级、淋巴结转移及临床分期等有关(P<0.05);多因素分析:PTNM分期、VM、VEGF的表达是影响NSCLC根治术后患者预后的独立因素(P<0.05);VM阳性组与阴性组的5年生存率分别为1.7%和41.6%,差异有统计学意义;VEGF阳性组与阴性组的5年生存率分别为2.4%和52.6%,差异有统计学意义。结论具有VM的NSCLC组织分化低,患者临床预后差;VEGF的表达水平和VM与NSCLC的发展及预后有一定的关系。     

转移性结直肠癌抗血管生成靶向治疗的研究进展

近年来,由于各种新的化疗药物及分子靶向药物的使用,转移性结直肠癌(metastatic colorectal cancer,m CRC)的个体化治疗逐步取得了重要的成果。研究表明,抗血管生成靶向药物与化疗药物的联合使用作为转移性结直肠癌的一线治疗方案,可明显改善治疗效果,延长患者的生存时间。血管内皮生长因子(vascularendothelial growth factor,VEGF)是肿瘤血管生成过程中最主要的因子。贝伐单抗是通过基因工程技术得到的针对血管内皮生长因子-A(VEGF-A)的单克隆抗体,作为抗血管生成靶向药物用于转移性结直肠癌的临床治疗。本文对近年来转移性结直肠癌的抗血管生成靶向治疗,尤其是贝伐单抗治疗的相关研究进展进行综述并展望未来抗血管生成靶向治疗的发展前景。     

非小细胞肺癌EGFR-TKIs治疗及PET分子成像的研究进展

表皮生长因子受体(epithelial growth factor receptor,EGFR)信号转导通路在非小细胞肺癌(Non-Small Cell Lung Cancer,NSCLC)中发挥重要作用,尤其胞内酪氨酸激酶结构域的突变状态决定了目前NSCLC的靶向治疗。针对EGFR突变的分子靶向药物表皮生长因子受体酪氨酸激酶抑制剂(epithelial growth factor receptor tyrosine kinase inhibitors,EGFR-TKIs)已开发并应用于NSCLC的治疗。在治疗过程中,EGFR的突变状态随时间发生动态变化,因此精准掌握EGFR的突变状态是靶向治疗方案制定、优化的关键。PET分子成像可在细胞和分子水平,对在体生物活动的发生、发展过程进行实时成像,使实时、在体揭示EGFR的突变状态成为可能。因此,多种以TKIs为前体标记放射性核素作为靶向肿瘤突变EGFR胞内段分子成像探针的研究逐渐增多。本文就EGFR-TKIs在NSCLC治疗及相关PET分子成像方面的研究进展进行综述。     

贝伐珠单抗联合化疗治疗晚期非鳞非小细胞肺癌的临床观察

目的:观察贝伐珠单抗联合化疗对晚期非小细胞肺癌患者的疗效、安全性及影像学改变。方法:对2007年至2014年于我院治疗的晚期NSNSCLC(非鳞非小细胞肺癌non-squamous non-small cell lung cancer)患者,给予贝伐珠单抗(15 mg/kg或7.5mg/kg)联合化疗(紫杉醇175 mg/m~2,d1,卡铂AUC=5或6,d1,q3 w)6周期及贝伐珠单抗维持治疗(15 mg/kg或7.5 mg/kg,d1,q3w)。观察疗效、不良反应、肺部病灶空洞改变的情况、恶性胸腔积液的治疗效果及部分患者EGFR、KRAS基因突变状况。结果:共观察26例患者,均接受贝伐珠单抗联合化疗,17例行贝伐珠单抗维持治疗。部分缓解(partial response,PR)、疾病稳定(stable disease,SD)、疾病进展(disease progression,PD)率分别为53.8%、42.3%、3.8%。中位无进展生存期(progression free survival,PFS)为11.0个月,中位总生存期(overall survival,OS)达25.8个月。26例患者中15.4%治疗后病变发生空洞改变,空洞组的2年、3年生存率略高于无空洞组,但无统计学差异(P值分别为0.586、0.509)。13例患者伴有恶性胸腔积液,胸腔积液的疾病控制率为100%。11例患者标本可进行EGFR基因检测,敏感突变占36.4%,未突变占63.6%。对10例患者标本行KRAS基因检测,均为突变阴性。不良反应包括骨髓抑制、消化道反应、鼻衄、咯血、高血压、蛋白尿等。大多数不良反应程度较轻,可控制。结论:贝伐珠单抗联合化疗治疗晚期NSNSCLC患者疗效确切,副反应可耐受,控制恶性胸腔积液效果较好。肺部病灶空洞改变的临床意义有待进一步研究。     

化疗联合放疗治疗非小细胞肺癌疗效观察

目的:研究化疗联合放疗治疗非小细胞肺癌的临床疗效及毒副作用.方法:58例非小细胞肺癌患者随机分为观察组与对照组两组各29例,观察组患者采用化疗联合放疗治疗,对照组患者只采用化疗治疗.观察比较两组患者的临床疗效、1,2,3年生存率及毒副作用.结果:观察组患者的有效率(79.3％)明显高于对照组(41.4％),两组相比差异有统计学意义(P＜0.05).观察组患者1,2,3年生存率均高于对照组,两组相比差异有统计学意义(P＜0.05,P＜0.01).两组患者的Ⅱ-Ⅳ级白细胞减少率,Ⅲ-Ⅳ级血红蛋白减少率,Ⅲ-Ⅳ级消化系统反应无显著差别,两组相比差异均无统计学意义(P＞0.05).结论:相对于单纯化疗,化疗联合放疗治疗非小细胞肺癌临床效果更好,毒副作用并未加重,可以显著提高患者生存率,值得临床推广应用.     

贝伐珠单抗联合紫杉醇/卡铂方案治疗晚期非小细胞肺癌的临床疗效分析

目的:探讨贝伐珠单抗联合紫杉醇/卡铂方案治疗晚期非小细胞肺癌的临床疗效和安全性.方法:选择本研究中心入组SAiL (MO19390)研究的13例患者为研究对象,给予贝伐珠单抗15 mg/kg,化疗d1静点,以后每3周重复;联合化疗方案为175mg/m2紫杉醇,d1,卡铂AUC=6,d1,每3周重复.化疗4-6周期,贝伐珠单抗每3周应用一次直至病情进展.评价患者的不良反应、客观有效率(objective response rate,ORR)、中位无进展生存期(progression free survival,PFS)和总生存期(overall survival,OS).同时,对可取得肿瘤组织标本的患者进行回顾性EGFR和KRAS突变检测.结果:13例患者中,发生5级肺动脉栓塞1例,4级脑梗塞1例,4级蛋白尿2例,3级鼻出血1例,最常见的不良反应为鼻出血(69.2％)、蛋白尿(46.2％)、高血压(38.5％)、咯血(30.8％)、流涕(30.8％)、头晕(23.1％),大多程度较轻可以耐受.部分缓解(partial response,PR)7例(53.8％),疾病稳定(stable disease,SD)6例(46.2),总有效率53.8％,疾病控制率100％,中位PFS 7.7个月,中位OS 16.1个月.6例可进行EGFR和KRAS突变检测的患者中,1例存在EGFR 19外显子缺失突变,1例存在21外显子L858R点突变,4例未检测到EGFR敏感突变,6例患者KRAS突变均为阴性.结论:贝伐珠单抗联合紫杉醇/卡铂方案治疗中国晚期非小细胞肺癌可延长PFS和OS,患者的耐受性良好.     

The Efficacy of Combining Antiangiogenic Agents with Chemotherapy for Patients with Advanced Non-Small Cell Lung Cancer Who Failed First-Line Chemotherapy: A Systematic Review and Meta-Analysis

Background

The clinical outcomes of patients with NSCLC who progressed after first-line treatments remain poor. The purpose of this study was to assess the advantage of antiangiogenic therapy plus standard treatment versus standard treatment alone for this population of patients.

Methods

We conducted a rigorous search using electronic databases for eligible studies reporting antiangiogenic therapy combined with standard second-line chemotherapy versus standard second-line treatment for patient who progressed after front-line treatment. Pooled risk ratio and 95% confidence intervals were calculated using proper statistical method. Predefined subgroup analyses were conducted to identify the potential proper patients.

Results

Thirteen phase II/III RCTs which involved a total of 8358 participants were included. Overall, there was significant improvement in OS (HR 0.94, 95%CI: 0.89-0.99, p=0.03), PFS (HR 0.80, 95%CI: 0.76-0.84, p<0.00001), ORR (RR 1.75, 95%CI: 1.55-1.98, p<0.00001) and DCR (RR 1.23, 95%CI: 1.18-1.28, p<0.00001) in the group with antiangiogenic therapy plus standard treatment versus the group with standard treatment alone. Subgroup analysis showed that OS benefit was presented only in patients treated with docetaxel plus antiangiogenic agents (HR 0.92, 95%CI: 0.86-0.99, p=0.02) and patients with non-squamous NSCLC (HR for OS 0.92, 95%CI: 0.86-0.99, p=0.02).

Conclusions

This study revealed that the addition of antiangiogenic agents to the standard treatments could provide clinical benefit to NSCLC patients who failed their first-line therapy. Furthermore, proper selection of the combined standard cytotoxic agent, as well as the patient population by tumor histology, is warranted for future studies and clinical application of antiangiogenic therapy.     

DCs-CIK细胞免疫治疗联合化疗治疗晚期非小细胞肺癌的疗效观察

目的:探讨树突状细胞(DCs)和细胞因子诱导的杀伤(CIK)细胞免疫治疗联合化疗对晚期非小细胞肺癌患者的治疗效果。方法:将我院2012年2月到2014年2月就诊的72例晚期非小细胞肺癌患者随机分为对照组(n=36,单纯化疗组)和实验组(n=36,DCs-CIK细胞免疫联合化疗组)。比较两组患者治疗后的疗效、治疗前后免疫功能,并运用Kamofsky(KPS)评分来评估两组患者治疗后生活质量的改善情况。结果:实验组的疾病控制率(DCR)77.78%显著高于对照组的52.78%(P0.05)。治疗后实验组患者外周血CD3+、CD8+及NK细胞所占的比值较治疗前均上升显著(P0.05);治疗后对照组患者外周血CD3+、CD8+及NK细胞所占的比值较治疗前下降显著(P0.05)。治疗后实验组KPS评分提高率明显高于对照组(P0.05)。结论:DCs-CIK细胞免疫联合化疗能够提高晚期非小细胞肺癌患者的DCR,且显著改善患者的免疫功能和生活质量。     

Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy

Introduction

Increasing evidence has shown that immune surveillance is compromised in a tumor-promoting microenvironment for patients with non-small cell lung cancer (NSCLC), and can be restored by appropriate chemotherapy.

Methods

To test this hypothesis, we analyzed microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage NSCLC, and 20 age-, sex-, and co-morbidity-matched healthy controls. All the patients received a median of four courses of chemotherapy with cisplatin and gemcitabine for a 28-day cycle as first line treatment.

Results

Sixty-nine differentially expressed genes between the patients and controls, and 59 differentially expressed genes before and after chemotherapy were identified. The IL4 pathway was significantly enriched in both tumor progression and chemotherapy signatures. CXCR4 and IL2RG were down-regulated, while DOK2 and S100A15 were up-regulated in the patients, and expressions of all four genes were partially or totally reversed after chemotherapy. Real-time quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six up-regulated (TLR7, CRISP3, TOP1MT) and down-regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Further immunohistochemical analysis of the paraffin-embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC (p = 0.005), but also in patients with stable or progressive disease as compared to those with a partial response (p = 0.032). A high percentage of S100A15 nuclear stained cells (HR 1.028, p = 0.01) was the only independent factor associated with three-year overall mortality.

Conclusions

Our results suggest a potential role of the IL4 pathway in immune surveillance of advanced stage NSCLC, and immune potentiation of combination chemotherapy. S100A15 may serve as a potential biomarker for tumor staging, and a predictor of poor prognosis in NSCLC.     

老年晚期非小细胞肺癌患者对放化疗的耐受性研究现况

近年多组大规模的随机对照研究已经证实：放化疗对于老年晚期NSCLC患者好于最佳支持治疗（BSC）,放化疗组的有效率、中住生存期、一年生存率显著高于BSC组,但老年人伴随着年龄的增长器官功能衰退、药代酶活性下降等生理因素,常合并其他疾病等原因,其药效学和药动学也随之发生变化,老年NSCLC放化疗的潜在毒性危险可能增加,治疗耐受性较差,综合治疗可能带来较多的并发症,甚至高的治疗相关死亡率。中医学认为化疗副反应主要表现为气血亏损、脾胃失调及肝肾虚损等症候群,放疗副反应的症候群以热象较重,属热毒之邪耗气伤阴,进而灼津烁血以致气血、肌肤、脏腑受损的火郁、燥结、热毒症候较多。中医药在减轻放化疗的毒副作用、提高老年患者对放化疗的耐受性等方面有明显优势。     

老年晚期非小细胞肺癌患者对放化疗的耐受性研究现况

近年多组大规模的随机对照研究已经证实:放化疗对于老年晚期NSCLC患者好于最佳支持治疗(BSC),放化疗组的有效率、中位生存期、一年生存率显著高于BSC组,但老年人伴随着年龄的增长器官功能衰退、药代酶活性下降等生理因素,常合并其他疾病等原因,其药效学和药动学也随之发生变化,老年NSCLC放化疗的潜在毒性危险可能增加,治疗耐受性较差,综合治疗可能带来较多的并发症,甚至高的治疗相关死亡率。中医学认为化疗副反应主要表现为气血亏损、脾胃失调及肝肾虚损等症候群,放疗副反应的症候群以热象较重,属热毒之邪耗气伤阴,进而灼津烁血以致气血、肌肤、脏腑受损的火郁、燥结、热毒症候较多。中医药在减轻放化疗的毒副作用、提高老年患者对放化疗的耐受性等方面有明显优势。     

Multi-Targeted Antiangiogenic Tyrosine Kinase Inhibitors in Advanced Non-Small Cell Lung Cancer: Meta-Analyses of 20 Randomized Controlled Trials and Subgroup Analyses

Background

Multi-targeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have been studied in many randomized controlled trials (RCTs) for treatment of advanced non-small cell lung cancer (NSCLC). We seek to summarize the most up-to-date evidences and perform a timely meta-analysis.

Methods

Electronic databases were searched for eligible studies. We defined the experimental arm as MATKI-containing group and the control arm as MATKI-free group. The extracted data on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS) and overall survival (OS) were pooled. Subgroup and sensitivity analyses were conducted.

Results

Twenty phase II/III RCTs that involved a total of 10834 participants were included. Overall, MATKI-containing group was associated with significant superior ORR (OR 1.29, 95% CI 1.08 to 1.55, P = 0.006) and prolonged PFS (HR 0.83, 0.78 to 0.90, P = 0.005) compared to the MATKI-free group. However, no significant improvements in DCR (OR 1.08, 1.00 to 1.17, P = 0.054) or OS (HR 0.97, 0.93 to 1.01, P = 0.106) were observed. Subgroup analyses showed that the benefits were predominantly presented in pooled results of studies enrolling previously-treated patients, studies not limiting to enroll non-squamous NSCLC, and studies using MATKIs in combination with the control regimens as experimental therapies.

Conclusions

This up-to-date meta-analysis showed that MATKIs did increase ORR and prolong PFS, with no significant improvement in DCR and OS. The advantages of MATKIs were most prominent in patients who received a MATKI in combination with standard treatments and in patients who had previously experienced chemotherapy. We suggest further discussion as to the inclusion criteria of future studies on MATKIs regarding histology.     

Post-Progression Survival after EGFR-TKI for Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutations

Background

Non-small cell lung cancer (NSCLC) patients that harbor epidermal growth factor receptor (EGFR) mutations benefit from receiving an EGFR-tyrosine kinase inhibitor (TKI); however, post-progression survival (PPS) after EGFR-TKI treatment has not been sufficiently studied.

Methods

We retrospectively reviewed the clinical data from stage IV or recurrent NSCLC patients who harbored EGFR mutations and who received EGFR-TKI as their first-line treatment in our institute between 2009 and 2011.

Results

In total, 36 patients received EGFR-TKI treatment as their first-line therapy. Of those 36 patients, 30 experienced recurrence and were enrolled in this study. The median progression-free survival (PFS) of these patients was 8.2 months. Twelve patients received EGFR-TKI treatment beyond the diagnosis of progressive disease (PD), and 8 received second-line therapy. The PPS after EGFR-TKI treatment was 9.1 months, and survival after the termination of EGFR-TKI treatment in those patients treated with second-line chemotherapy was 13.9 months. The site of relapse was investigated and PFS in EGFR-TKI-treated patients with relapse in the brain (11.6 months) showed a trend toward a longer PFS compared with patients with relapse at other sites (8.2 months). The median PPS after EGFR-TKI treatment also showed the same trend in each group (12.9 and 9.2 months, respectively).

Conclusions

The PPS after EGFR-TKI treatment failure was 9.1 months, while the survival of patients who underwent second-line chemotherapy after the termination of EGFR-TKI treatment was 13.9 months, comparable with the overall survival of EGFR mutation-negative patients, as previously reported. The prognosis of these NSCLC patients with EGFR mutations varied according to the sites of recurrence after first-line EGFR-TKI treatment. Of particular note was the prognosis of patients with brain metastases, which tended to be better than that of patients with metastases to other sites.     

A Laboratory Prognostic Index Model for Patients with Advanced Non-Small Cell Lung Cancer

Purpose

We aimed to establish a laboratory prognostic index (LPI) in advanced non-small cell lung cancer (NSCLC) patients based on hematologic and biochemical parameters and to analyze the predictive value of LPI on NSCLC survival.

Patients and Methods

The study retrospectively reviewed 462 patients with advanced NSCLC diagnosed between 2000 and 2010 in a single institution. We developed an LPI that included serum levels of white blood cells (WBC), lactate dehydrogenase (LDH), albumin, calcium, and alkaline phosphatase (ALP), based on the results of a Cox regression analysis. The patients were classified into 3 LPI groups as follows: LPI 0: normal; LPI 1: one abnormal laboratory finding; and LPI 2: at least 2 abnormal laboratory findings.

Results

The median follow up period was 44 months; the median overall survival (OS) and median progression-free survival (PFS) were 11 and 6 months, respectively. A multivariate analysis revealed that the following could be used as independent prognostic factors: an Eastern Cooperative Oncology Group performance status score (ECOG PS) ≥2, a high LDH level, serum albumin <3 g/dL, serum calcium>10.5 g/dL, number of metastases>2, presence of liver metastases, malignant pleural effusion, or receiving chemotherapy ≥4 cycles. The 1-year OS rates according to LPI 0, LPI 1, and LPI 2 were 54%, 34%, and 17% (p<0.001), respectively and 6-month PFS rates were 44%, 27%, and 15% (p<0.001), respectively. The LPI was a significant predictor for OS (Hazard Ratio (HR): 1.41; 1.05–1.88, p<0.001) and PFS (HR: 1.48; 1.14–1.93, p<0.001).

Conclusion

An LPI is an inexpensive, easily accessible and independent prognostic index for advanced NSCLC and may be helpful in making individualized treatment plans and predicting survival rates when combined with clinical parameters.     

Combining Antiangiogenic Therapy with Adoptive Cell Immunotherapy Exerts Better Antitumor Effects in Non-Small Cell Lung Cancer Models

Introduction

Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment.

Methods

We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells.

Results

Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments.

Conclusions

Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung carcinomas and unmask the mechanisms of the synergistic antitumor efficacy, providing a new rationale for combining antiangiogenesis therapy with immunotherapy in the treatment of lung cancer.