鼻咽癌抗独特型抗体疫苗的研究进展

抗独特型抗体因叮模拟肿瘤抗原，打破免疫耐受，已应用于卵巢癌、乳腺癌、黑色素瘤、结肠癌、淋巴瘤、胰腺癌等多种肿瘤的综合治疗中，并已取得一定疗效。文章就抗独特型抗体在鼻咽癌免疫治疗中的应用及发展趋势作一综述。     

用抗独特型疫苗主动免疫治疗鼻咽癌病人的临床研究

目的：探讨抗独特型疫苗主动免疫治疗鼻咽癌病人的抗肿瘤效应。;用两标具有鼻咽癌相关抗原内像的抗独特型单克隆抗体２Ｈ４,５Ｄ３,经氢氧化铝凝胶沉淀示制备成抗独特型疫苗Ａｌｕｍ－２Ｈ４,Ａｌｕｍ－５Ｄ３,对１９例晚期鼻咽癌放疗病人作主动免疫治疗,９例放疗加生理盐水注射为对照组。用ＥＬＩＳＡ检测治疗前后病人血清抗体和细胞因子水平。     

鼻咽癌抗独特型抗体的基础和初期临床研究

基于抗独特型抗体在免疫网络中的特殊地位，尤其是抗独特型抗体在肿瘤免疫治疗及预防中的潜力引起了广泛兴趣，国外已对多种实体瘤制备了相应抗独特型抗体．并已(或准备)试用于临床。但未见有鼻咽癌抗独特型抗体的研究报导。鼻咽癌为我国有区域性分布的高发肿瘤，对其常规治疗之外的免疫治疗研究不够充分     

抗独特型抗体在肿瘤主动免疫治疗研究中的进展

抗独特型抗体具有模拟抗原及免疫调节双重作用，能代替肿瘤抗原，诱发特异性免疫反应，临床初步应用显示出一定疗效。本文对抗独特型抗体及其在肿瘤主动免疫治疗研究中的进展作一综述。     

鼻咽癌人源抗独特型单链抗体的制备及筛选

背景与目的:抗独特型抗体作为肿瘤抗原替代物可用于肿瘤治疗,这已在临床试验中得到证实。但由于目前所使用的抗独特型抗体多为鼠源性,用于人体可产生人抗鼠抗体反应,从而影响疗效。本实验拟构建噬菌体人源抗独特型抗体库,并从中筛选出能模拟鼻咽癌相关抗原的β型抗独特型单链抗体scFv(Ab2βscFv),以解决鼠源性抗独特型抗体用于临床所产生的人抗鼠抗体反应。方法:体外致敏并用EB病毒(Epstein-Barrvirus,EBV)转化鼻咽癌患者的外周血单个核细胞(peripheralbloodmononuclearcell,PBMC),用RT-PCR分别扩增VH和VL基因并连接成scFv基因,将scFv基因与载体fUSE5连接后,转化大肠杆菌MC1061,构建噬菌体呈现型scFv库。在用单抗FC2对文库进行4轮筛选后,用SandwichELISA和结合抑制法从中筛选出β型Ab2scFv。结果:用单抗FC2体外致敏并经EBV转化的10例鼻咽癌患者的PBMC中,8例有鼻咽癌抗独特型抗体产生。经PCR分别扩增出5种VH(γ、μ)和7种VL(κ、λ)基因,经连接组成14种scFv基因。在与载体连接后,导入大肠杆菌MC1061,得到库容为1.5×108的初级噬菌体抗独特型抗体库。经富集筛选后,从中随机挑取270个克隆进行ELISA筛选,得到91个Ab2scFv单克隆,阳性率为33.7%。再用结合抑制法从中初步筛选出5个可能为β型的Ab2scFv。结论:联     

鼻咽癌抗独特型单克隆抗体的主动免疫初探

用湖南鼻咽癌细胞株HNI2为免疫原,制备了数株抗鼻咽癌单抗(Abl).再用两株Abl(FC_2、HNI-5)为免疫原,制备了两株抗独特型单抗Ab2(2H4和5D3).体外和体内实验证实,2H4、5D3能替代鼻咽癌抗原,诱导体液和细胞免疫应答.因而认为它们可以作为新型抗鼻咽癌疫苗的候选物.选择19例晚期鼻咽癌病人用氢氧化铝凝胶沉淀的Ab2(Alum-2H4、Alum5D3),配合放疗进行主动免疫治疗;9例单纯接受放疗的晚期鼻咽癌病人作为对照组.经血清学检测发现,治疗组病人的抗抗独特型抗体(Ab3)、抗肿瘤抗体(Ab1’)水平均有不同程度增高,但也产生了人抗鼠抗体(HAMA).血清细胞因子TNF-α、IFN-γ、IL-2水平在大多数治疗组病人中升高,而对照组Ab1 TNF-α、IFN-γIFM及IL-2血清水平均未升高.初步临床研究显示,鼠源性抗独特型单抗用于临床治疗是安全的,且Ab2能模拟肿瘤相关抗原,激发机体产生主动免疫应答.     

用抗独特型疫苗主动免疫增强鼻咽癌病人的IL-2mRNA表达

用两株具有鼻咽癌相关抗原内影像的抗独特型单克隆抗体2H4,5D3,经氢氧化铝凝胶沉淀法制备成抗独特型疫苗Alum-2H4,Alum-5D3,对19例晚期鼻咽癌放疗病人作主动免疫治疗,9例放疗加生理盐水注射为对照组.用ELISA检测治疗前后病人血清抗体和细胞因子水平.用原位Northem杂交检测外周血单个核细胞(PBMC)IL-2mRNA的表达.发现接受Alum-2H4或Alum-5D3治疗的病人无1例有过敏或其他毒副反应,血清中均检测到抗抗独特型抗体(Ab3)、抗肿瘤抗体(Ab1’)水平均有不同程度的增高,但也产生了人抗鼠抗体(HAMA).血清细胞因子TNF-α,IFN-γ和IL-2水平在大多     

抗独特型疫苗在肿瘤治疗中的应用进展（下）——临床研究

肿瘤患者常处于自身肿瘤的免疫抑制状态，具有内影像作用的抗独特型抗体（ａｎｔｉ－Ｉｄ，Ａｂ２）可模拟肿瘤抗原。用ａｎｔｉ－Ｉｄ主动免疫可消除患者的免疫耐受状态，刺激机朱特异性的体液和细胞免疫反应，部分临床研究已显示ａｎｔｉ－Ｉｄ可延长肿瘤患者的生存期。     

小细胞肺癌抗独特型疫苗功能的试验研究

目的探讨小细胞肺癌(SCLC)抗独特型抗体3F6和其单链抗体(3F6ScFv)诱导体液和细胞免疫应答的能力,以证明其作为抗SCLC疫苗的可行性。方法3F6和3F6ScFv(Ab2)免疫BALB/c小鼠获得抗血清,以ELISA和Westernblot方法分别检测抗血清中Ab3结合SCLC细胞膜表面特异抗原(NCI H128抗原)的能力,用竞争Westernblot检测Ab3与2F7竞争结合NCI H128抗原的能力。以迟发型超敏反应(DTH反应)和小鼠脾脏淋巴细胞增殖实验检测3F6及3F6ScFv诱发细胞免疫应答的潜能。结果ELISA和Westernblot方法均证明,3F6和3F6ScFv免疫同系小鼠所产生的Ab3能特异的与NCI H128抗原相结合,与对照血清相比,差异有统计学意义(P<0.001),且有很强的与2F7(Ab1)竞争结合靶抗原的能力。在DTH反应中,3F6和3F6ScFv所致小鼠足垫肿胀的程度均明显高于对照组(P<0.001)。小鼠脾脏淋巴细胞增殖反应试验证明,用3F6和3F6ScFv免疫的小鼠脾脏淋巴细胞对靶细胞的再次刺激有明显的增殖反应,与阴性肿瘤细胞对照组和阴性抗体对照组相比,差异有统计学意义(P<0.05)。结论抗独特型抗体3F6和3F6ScFv均有模拟SCLC细胞膜表面特异抗原的能力,成功诱导了相应的体液和细胞免疫应答,可作为抗SCLC疫苗进行深入研究。     

抗独特型抗体在B淋巴瘤治疗上的应用

恶性肿瘤是原先已停止分化的细胞元规律、无节制增殖的结果。因此,在每个肿瘤患者,其所有的肿瘤细胞均可表现出同样的表面形态。基于这种认识,如能检出只表达于肿瘤细胞上的抗原,就能以它为靶子对肿瘤进行特异性治疗。     

鼻咽癌的免疫治疗研究进展

鼻咽癌是中国南方地区发病率较高的恶性肿瘤,鼻咽癌的治疗目前以同步放化疗为主要治疗方式,早期鼻咽癌的预后较好,而晚期鼻咽癌的预后较差。免疫治疗作为一种治疗恶性肿瘤的新方法,在临床上应用越来越广泛,并在一些恶性肿瘤的治疗上取得较好效果,成为目前临床研究热点。本文对免疫治疗应用在鼻咽癌方面的研究进行综述,以发现存在的问题和新的研究方向。     

鼻咽癌精准治疗转化研究及临床应用现状

随着基础研究及物理技术的不断发展,精准治疗在肿瘤治疗中的应用越来越广泛。放疗技术的革命、多模态影像技术的开发、生物靶区剂量雕刻及自适应放疗的应用、大数据背景下的放疗计划系统、化疗方案的选择都使鼻咽癌治疗越来越精准。实验室和临床工作的联系越来越紧密,转化医学起着至关重要的作用,使生物免疫治疗的开展和预后因素指标的筛选不断发展。鼻咽癌诊断和治疗进入到了一个全新时期。本文通过对61篇文献的阅读和理解对鼻咽癌精准治疗研究及临床应用现状做一综述。     

Pregnancy and nasopharyngeal carcinoma: a prognostic evaluation of 27 patients

In order to study the influence of pregnancy on the prognosis of nasopharyngeal carcinoma (NPC), we have retrospectively studied 27 patients who either were discovered to be pregnant during radiotherapy (9 patients, herein abbreviated as concurrent group) or became pregnant after treatment (18 patients, herein abbreviated as subsequent group). This material was collected from the 811 NPC patients treated in our hospital from March 1958 to 1972. The results obtained are presented as follows: Concurrent pregnancy had a disastrous effect on the prognosis of NPC patients giving a five year survival of only 11% (1/9). Of the eight patients who died, six did so within one year of the treatment, five of whom died of distant metastases. This fatal outcome was not altered by any measure we instituted. This adverse influence was not observed in the subsequent group, yet the time of gestation seemed to be relevant to the prognosis. Two of the three patients who became pregnant within one year of the treatment died of disease, those who became pregnant beyond the second year after irradiation had the best prognosis. All seven patients who became pregnant after the second year of treatment survived. The frequency of pregnancy did not influence the prognosis of patients if the conception occurred beyond the second year in the subsequent group. All the five patients who gave birth to two, three or even four children survived for more than five years without any evidence of tumor. A total of 21 children were born to the patients of these two groups. They have been followed regularly for 10 to 20 years. No deformity, or retardation in growth or mentality was discovered, nor was there any evidence of radiation tumor or leukemia observed.     

Epstein-Barr virus-targeted immunotherapy for nasopharyngeal carcinoma

Epstein-Barr virus (EBV) is constantly present in undifferentiated and poorly-differentiated nasopharyngeal cancer. Thus, tumour-associated viral antigens are potential targets for immunotherapy. Recently, both preclinical and early clinical studies have shown that various strategies can enhance EBV-specific immunity. Moreover, significant anti-tumour effect has been observed, and was generally correlated with biological response. The present review discusses the rational for EBV-targeted immunotherapy and summarises the latest developments in this area.     

Ifosfamide and doxorubicin combination chemotherapy for recurrent nasopharyngeal carcinoma patients

Background: We assessed the efficacy and toxicity of ifosfamide and doxorubicin combination chemotherapy(CT) regimen retrospectively in Turkish patients with recurrent or metastatic nasopharyngeal carcinoma (NPC)previously treated with platinum-based chemotherapy. Methods: A total of thirty patients who had receivedcisplatin based chemotherapy/chemoradiotherapy as a primary treatment received ifosfamide 2500 mg/m2 days1-3, mesna 2500 mg/m2 days 1-3, doxorubicin 60 mg/m2 day 1 (IMA), repeated every 21 days. Eligible patientshad ECOG PS< 2, measurable recurrent or metastatic disease, with adequate renal, hepatic and hematologicfunctions. Results: Median age was 47 (min-max; 17-60). Twenty six (86.7 %) were male. Median cycles ofchemotherapy for each patient were 2 (range:1-6). Twenty patients were evaluable for toxicity and response. Nopatient achieved complete response, with nine partial responses for a response rate of 30.0% in evaluable patients.Stable disease, and disease progression were observed in five (16.7%) and six (20.0%) patients, respectively.Clinical benefit was 46.7%. Median time to progression was 4.0 months. Six patients had neutropenic fever afterIMA regimen and there were one treatment-related death due to tumor lysis syndrome in first cycle of the CT.No cardiotoxicity was observed after CT and treatments were generally well tolerated. Conclusion: Ifosfomideand doxorubicin combination is an effective regimen for patients with recurrent and metastatic NPC. For NPCpatients demonstrating failure of cisplatin based regimens, this CT combination may be considered as salvagetherapy.     

鼻咽癌患者的营养治疗共识

鼻咽癌在欧美等西方国家的发病率较低,而在中国南方诸省却较为高发。鼻咽癌患者对放疗和化疗均有较高的敏 感性,放疗是其主要的治疗方法。与其他肿瘤相比,鼻咽癌患者更易出现营养不良,尤其是患者经过放化疗后,其食欲降低、进 食和消化能力下降,进而引起摄入不足和/或吸收不良,导致营养不良的发生。而营养不良又会使患者治疗效果降低、生活质 量下降,甚至导致死亡,因此及早预防和治疗营养不良对患者的治疗效果和生活质量有着很大帮助。鼻咽癌营养治疗途径的 选择原则与其他恶性肿瘤基本一致,但也有其特点：①由于治疗不良反应患者极易放弃经口进食,因此,鼻饲管是短期肠内营 养治疗常用的途径;②若肠内营养治疗大于4周,多考虑采用经皮内镜下胃造瘘术或空肠造瘘术,该方法创伤小、置管时间长、 不易堵塞,从而使患者有更好的生活质量;③肠内营养补充不足或不耐受时采用肠外营养,而患者病情一旦好转,应尽早改为 肠内营养;④鼻咽癌患者营养治疗应适当提高脂肪的供能比例,同时蛋白质供给量推荐为1.0～1.5 g/(kg·d)。     

Favorable prognosis of female patients with nasopharyngeal carcinoma

The female sex is traditionally considered a favorable prognostic factor for nasopharyngeal carcinoma (NPC). However, no particular study has reported this phenomenon. To explore the prognostic impact of gender on patients with NPC after definitive radiotherapy, we reviewed the clinical data of 2,063 consecutive patients treated between 1st January 2000 and 31st December 2003 in the Sun Yat-sen University Cancer Center. The median follow-up for the whole series was 81 months. The female and male patients with early stage disease comprised 49.4% and 28.1% of the patient population, respectively. Both the 5-year overall survival (OS) and disease-specific survival (DSS) rates of female patients were significantly higher than those of male patients (OS: 79% vs. 69%, P 0.001; DSS: 81% vs. 70%, P 0.001). For patients with locoregionally advanced NPC, the 5-year OS and DSS rates of female vs. male patients were 74% vs. 63% (P 0.001) and 76% vs. 64%, respectively (P 0.001). A multivariate analysis showed that gender, age, and TNM stage were independent prognostic factors for the 5-year OS and DSS of NPC patients. The favorable prognosis of female patients is not only attributed to the early diagnosis and treatment but might also be attributed to some intrinsic factors of female patients.     

鼻咽癌放疗后未复发患者的生存质量评价

目的：研究鼻咽癌未复发患者放疗后的生存质量变化情况。方法：采用UW-QOL简体中文第4版对放疗后未复发的鼻咽癌患者进行问卷调查,并增加了3个专项问题：耳部症状、视力、鼻部症状。结果：不同年龄、性别和临床分期的生存质量（QOL）总分无统计学差异（P〉0.05）。大学以上文化程度患者的QOL总分高于其他患者,差别有统计学意义（P〈0.05）。唾液、耳部症状、咀嚼及鼻部症状4项得分较低。QOL的时间趋势是呈下降后上升变化,治疗后第5～9年得分较低,以第7年为最低。结论：鼻咽癌放疗后未复发患者的QOL不受年龄、性别和临床分期的影响。QOL得分最低的项目所对应的器官均在放疗照射野的覆盖范围。