肿瘤免疫治疗研究现状及发展趋势

肿瘤免疫治疗是继传统的手术、化疗、放疗之后的一种新兴的肿瘤治疗手段,因其具有特异性高、疗效显著等优点而备受学者们的关注。随着对肿瘤微环境和肿瘤逃逸机制的深入了解,调动机体免疫系统去抵御肿瘤逐渐成为一种新的研究方向。肿瘤免疫治疗主要包括特异性疗法和非特异性疗法,目前以肿瘤疫苗和单克隆抗体为代表的特异性免疫疗法在临床上得到广泛应用,并显示出良好的发展前景。但肿瘤免疫治疗仍存在认识不足、临床适应证有限等问题,与此同时,我国肿瘤免疫治疗的发展较国外仍相对不足且面临一些特殊的问题。本文将对目前已有的肿瘤免疫治疗方法及评价体系进行综述,并对一些新的技术手段和治疗思路展开讨论,此外还将结合国内外最新研究进展深入探讨这一新兴疗法的缺陷及未来的发展趋势。     

溶瘤病毒在神经胶质瘤治疗中的研究进展

神经胶质瘤是增殖能力强、复发率高的原发性脑肿瘤,手术、放化疗等传统疗法效果较差,因此需要寻找更加有效的治疗方法。溶瘤病毒作为新型免疫疗法已被证明具有靶向性强、溶瘤效果显著及副作用少等优势。近年来溶瘤病毒在神经胶质瘤的临床治疗上取得一些突破性进展,其安全性和有效性得到了验证。现对近几年来溶瘤病毒单药治疗及与放化疗、免疫疗法等其他手段联合治疗神经胶质瘤的临床前研究和临床试验进展作详细介绍,对现阶段存在的问题进行讨论,并对未来研究进行展望。     

鼻咽癌的免疫与靶向治疗

鼻咽癌的发生与EB病毒(Epstein-Barr virus,EBV)密切相关,当前临床主要运用单纯放疗或同步放化疗对鼻咽癌开展治疗。虽然该方法对放化疗敏感的患者有效,但是局部晚期或远处转移的鼻咽癌患者预后仍然不佳。随着近年来免疫治疗和分子靶向治疗的发展,过继性细胞疗法、免疫检查点以及多分子靶向治疗逐渐成为鼻咽癌临床治疗的研究热点。本文就鼻咽癌的免疫治疗和靶向治疗两方面展开综述,以期为鼻咽癌治疗手段和药物的发展提供一定依据。     

双特异性抗体构建在肿瘤临床治疗中的应用

双特异性抗体(Bispecific antibody,BsAb)是具有两个不同抗原结合位点的抗体,可分为含Fc段和不含Fc段的BsAb,不同结构的BsAb具有不同的特点和应用领域。相比于传统的单克隆抗体,BsAb的灵敏度和特异性更高。更重要的是,BsAb具有募集免疫细胞、双重阻断信号通路等功能,在免疫诊断和治疗中扮演重要角色。随着全球环境的恶化以及人们生活习惯的不规律,肿瘤的发病率越来越高,成为仅次于心脑血管疾病的全球第二大致死疾病,全球每年有1200万新发癌症病例。肿瘤的治疗手段包括手术切除、放化疗和靶向治疗等。肿瘤免疫疗法是近几年新兴的治疗方法,其通过激发自身免疫系统的能力来清除肿瘤细胞。传统的单抗药物虽在肿瘤靶向治疗和免疫治疗中取得了一定的疗效,但肿瘤具有高度的异质性和可塑性,常常引发肿瘤耐药性的出现。双特异性抗体能够同时靶向多个靶点,目前已用于肿瘤的临床治疗,并取得了一定的治疗效果。文中就双特异性抗体在肿瘤临床治疗中的研究进展和应用作一综述。     

CAR-T 对肿瘤的特异性治疗研究进展

嵌合抗原受体T细胞免疫疗法(CAR-T疗法)是一种治疗肿瘤的新免疫疗法,通过向患者自身T细胞中导入已被修饰的CAR基因,使T细胞表达结合肿瘤表面抗原的特异性受体来实现对肿瘤的精准治疗.目前已发展到第四代.该免疫疗法在血液瘤和实体瘤治疗中都有一定疗效,同时也存在一些待解决难题.本文就近年来CAR-T在血液瘤和实体瘤中的研究治疗进展及存在的问题进行综述.     

嵌合抗原受体T细胞治疗的现状与展望

肿瘤严重威胁着人类健康,当前肿瘤传统的治疗方法有手术治疗、化疗、放疗和靶向药物治疗等。近年来,肿瘤免疫治疗,尤其是嵌合抗原受体（chimeric antigen receptor,CAR） T细胞免疫疗法在基础研究与临床应用中蓬勃发展,并在治疗血液系统恶性肿瘤方面取得了巨大成功。然而,大量研究显示,细胞免疫治疗后可出现不同程度的毒副反应,且部分患者缓解后再次复发。因此,了解细胞治疗面临的挑战与局限性,寻找解决的办法,对继续发挥细胞免疫疗法的潜能具有重要意义。本文就免疫细胞的CAR结构、病毒载体的选择、细胞治疗面临的挑战及前景进行综述。     

卵巢癌生物治疗的现状与进展

由于卵巢癌的早期临床症状较不明显,大部分患者就诊时就处于晚期阶段,这对其有效治疗造成了很大困难,使其成为妇科病死率最高的恶性肿瘤,一直广受关注。但目前传统的手术与放化疗方法的治疗效果不佳。近年来随着基础研究工作的不断发展与深入,生物治疗作为新的肿瘤治疗方法引起了人们的重视。生物治疗作为第四种卵巢癌的治疗模式,其采取的针对不同靶位点和靶途径的策略很大程度上促进了卵巢癌治疗的理论和实践研究。生物治疗主要是运用基因治疗、免疫治疗和重组病毒治疗的方法对患者进行治疗,基因治疗包括细胞毒性或自杀基因治疗、纠错性基因治疗、免疫增强性基因治疗和抗肿瘤血管生成基因治疗等。而免疫治疗又分为主动和被动免疫治疗,前者包括树突状细胞疫苗、自体肿瘤疫苗和分子疫苗治疗等,后者如细胞因子治疗、单克隆抗体拮抗治疗以及细胞过继免疫治疗等。上述目前在卵巢癌治疗研究中已取得了一些成果,本文就其卵巢癌的生物治疗现状与进展做一综述。     

基于纳米递药系统的肿瘤免疫检查点联合治疗研究进展

免疫治疗已成为继手术治疗、化疗、放疗之外的重要肿瘤治疗手段.在肿瘤免疫疗法中,免疫检查点阻断疗法临床疗效显著,受到广泛关注.但是,由于患者肿瘤组织免疫原性低、存在免疫抑制微环境和免疫细胞瘤内浸润缺乏等问题,免疫检查点阻断治疗仍存在临床响应率低等局限性.近年来,科研人员利用肿瘤区别于正常组织的生理和病理特性,联合物理、化...     

局部晚期食管癌新辅助治疗的研究进展

食管癌是世界范围内恶性程度高、预后不良的肿瘤之一。手术治疗是局部晚期食管癌治疗的首选方式,但单纯手术治疗效果不佳,总体5年生存率较低。因此,局部晚期食管癌的治疗更倾向于手术联合多种模式的治疗。在局部晚期食管癌中,新辅助治疗展示出了明显的生存获益、良好的临床疗效以及可接受的毒性反应,成为局部晚期食管癌的标准治疗模式之一。新辅助治疗主要包括新辅助化疗、新辅助放化疗、新辅助免疫治疗。本文就局部晚期食管癌新辅助治疗的研究进展进行综述。     

放化疗联合DC-CIK治疗脑胶质瘤复发40例的临床观察

目的:探讨放化疗联合DC-CIK治疗脑胶质瘤复发的临床疗效和安全性.方法:选择我院自2006年1月至2011年9月收治的40例脑胶质瘤复发患者,采用放化疗联合DC-CIK治疗.统计记录治疗效果、生存期、治疗并发症和生活质量评分.结果:40例患者完全缓解8例,部分缓解11例,稳定10例,恶化11例,总治疗有效率为47.5％,在消化道反应、血象异常、内分泌紊乱、感染发热、呼吸道炎症等项目上并发症的发生率均维持在低水平,3、9、15个月生存率分别为85.7％、65.7％、40.0％,KPS评分为78.5± 8.6,组间差异有统计学意义(P＜0.05).结论:放疗联合DC-CIK能提高脑胶质瘤复发患者的生活质量,延长生存期.     

Experimental immunotherapy for malignant glioma: lessons from two decades of research in the GL261 model

Nearly twenty years of experimental immunotherapy for malignant glioma yielded important insights in the mechanisms governing glioma immunology. Still considered promising, it is clear that immunotherapy does not on its own represent the magic bullet in glioma therapy. In this review, we summarize the major immunotherapeutic achievements in the mouse GL261 glioma model, which has emerged as the gold standard syngeneic model for experimental glioma therapy. Gene therapy, monoclonal antibody treatment, cytokine therapy, cell transfer strategies and dendritic cell therapy were hereby considered. Apart from the considerable progress made in understanding glioma immunology in this model, we also addressed its most pertinent issues and shortcomings. Despite these, the GL261 model will remain indispensable in glioma research since it is a fast, highly reproducible and easy-to-establish model system.     

肿瘤精准免疫诊断综合评估

近年来,肿瘤免疫治疗(cancer immunotherapies)已成为晚期恶性肿瘤治疗的重要手段之一。肿瘤免疫治疗并不直接攻击癌细胞,而是通过调节人体自身免疫系统来抗击肿瘤,有望像抗生素改变抗感染治疗一样改变肿瘤治疗范式。抗PD-1/L1和抗CTLA-4抗体药物作为肿瘤免疫治疗的代表药物,使晚期癌症患者五年生存率达成了数倍的提升,被认为是真正有希望治愈癌症的治疗方式。然而,肿瘤免疫治疗只对部分患者有效,并且存在耐药、超进展、不良反应等问题。如何准确筛选出最有可能从治疗中获益的人群成为肿瘤免疫治疗研究中的一个重大挑战。目前有多个与免疫治疗相关的生物标志物正在研究中,并且有望被用于临床筛选治疗获益人群;但这些生物标记物也存在很多缺陷。未来,围绕免疫治疗敏感性和副反应的多项指标综合评估可能成为一个趋势。     

Single-cell Analysis Technologies for Immuno-oncology Research: from Mechanistic Delineation to Biomarker Discovery

The successes with immune checkpoint blockade(ICB) and chimeric antigen receptor(CAR)-T-cell therapy in treating multiple cancer types have established immunotherapy as a powerful curative option for patients with advanced cancers. Unfortunately, many patients do not derive benefit or long-term responses, highlighting a pressing need to perform complete investigation of the underlying mechanisms and the immunotherapy-induced tumor regression or rejection.In recent years, a large number of single-cell technologies have leveraged advances in characterizing immune system, profiling tumor microenvironment, and identifying cellular heterogeneity, which establish the foundations for lifting the veil on the comprehensive crosstalk between cancer and immune system during immunotherapies. In this review, we introduce the applications of the most widely used single-cell technologies in furthering our understanding of immunotherapies in terms of underlying mechanisms and their association with therapeutic outcomes. We also discuss how single-cell analyses help to deliver new insights into biomarker discovery to predict patient response rate, monitor acquired resistance, and support prophylactic strategy development for toxicity management. Finally, we provide an overview of applying cutting-edge single-cell spatial-omics to point out the heterogeneity of tumor–immune interactions at higher level that can ultimately guide to the rational design of next-generation immunotherapies.     

Topotecan enhances immune clearance of gliomas

Despite aggressive surgery, radiation therapy, and chemotherapy, glioblastoma multiforme (GBM) is refractory to therapy, recurs quickly, and results in a median survival time of only 14 months. The modulation of the apoptotic receptor Fas with cytotoxic agents could potentiate the response to therapy. However, Fas ligand (FasL) is not expressed in the brain and therefore this Fas-inducing cell death mechanism cannot be utilized. Vaccination of patients with gliomas has shown promising responses. In animal studies, brain tumors of vaccinated mice were infiltrated with activated T cells. Since activated immune cells express FasL, we hypothesized that combination of immunotherapy with chemotherapy can activate Fas signaling, which could be responsible for a synergistic or additive effect of the combination. When we treated the human glioma cell line U-87 and GBM tumor cells isolated from patients with TPT, Fas was up regulated. Subsequent administration of soluble Fas ligand (sFasL) to treated cells significantly increased their cell death indicating that these Fas receptors were functional. Similar effect was observed when CD3⁺ T cells were used as a source of the FasL, indicating that the up regulated Fas expression on glioma cells increases their susceptibility to cytotoxic T cell killing. This additive effect was not observed when glioma cells were pre-treated with temozolomide, which was unable to increase Fas expression in tumor. Inhibition of FasL activity with the antagonistic antibody Nok-1 mitigated these effects confirming that these responses were specifically mediated by the Fas-FasL interaction. Furthermore, the CD3⁺ T cells co-cultured with topotecan treated U-87 and autologous GBM tumor cells showed a significant increase in expression in IFN-γ, a key cytokine produced by activated T cells, and accordingly enhanced tumor cytotoxicity. Based on our data we conclude that drugs, such as topotecan, which cause up regulation of Fas on glioma cells can be potentially exploited with immunotherapy to enhance immune clearance of tumors via Fas signaling. Jun Wei and Guillermo DeAngulo are Co-lead authors.     

In vivo tracking of macrophage activated killer cells to sites of metastatic ovarian carcinoma

Radio-labelling of blood cells is an established technique for evaluating in vivo migration of normal cells to sites of pathology such as infection and haemorrhage. A limitation of cellular immunotherapies to induce anti-tumour responses is in part due to the uncertain ability of cellular effectors to reach their intended target. We extended the approach of cell radiolabelling to accurately examine the in vivo distribution of cellular immunotherapy with ex-vivo macrophage activated killer (MAK) cells. We describe the use of two methods of cell labelling for tracking the destination of autologous-derived macrophage activated killer (MAK) cells linked to the bi-specific antibody MDX-H210 delivered either by intravenous (i.v.) or intraperitoneal (i.p.) injection in ten patients with peritoneal relapse of epithelial ovarian carcinoma. Our results demonstrate the feasibility of generating high numbers and purity of GMP quality MAK cells, which can be radiolabelled with (18)F-FDG or (111)In-oxime. MAK cell administration produced minimal infusional toxicity and demonstrated a reproducible pattern of in vivo distribution and active in vivo tracking to sites of known tumour following 8 of 16 i.v. infusions or 4 of 6 i.p. infusions. However, the leakage of (18)F-FDG limited the ability to confidently confirm the tracking of MAK cells to tumour in all cases and improved PET labels are required. The addition of MDX-H210 bispecific antibody did not alter the distribution of cells to tumour sites, but did accelerate the clearance of i.v. administered MAK cells from the pulmonary circulation. This data demonstrates that cellular cancer immunotherapies may be successfully delivered to the sites of active tumour following either i.v. or i.p. injection in a proportion of patients with metastatic cancer. Incorporation of tracking studies in early cycles of cellular immunotherapy may allow selection of patients who demonstrate successful targeting of the immunotherapy for ongoing treatment.     

非小细胞肺癌的免疫治疗进展

肺癌是最致命的恶性肿瘤之一,也是男性肿瘤患者致死率最高的,5年生存率低于18%。尽管非小细胞肺癌(non-small cell lung cancer,NSCLC)在手术治疗、化疗、放疗以及靶向治疗方面均取得了一定的成果,但晚期NSCLC的预后依然很差。免疫治疗为NSCLC患者提供了一个新的治疗方向。免疫治疗目前主要研究方向在免疫检查点抑制剂(Ipilimumab、Nivolumab、MK-3475)和肿瘤疫苗(MAGE-A3,L-BLP25,TG4010,Belagenpumatucel-L)等。免疫治疗具有针对性强、副作用少、效率高的特点,并在Ⅱ、Ⅲ期临床试验中取得了较好的疗效,成为在手术、化疗、放疗以及靶向治疗后一种新的重要治疗手段。本文就当前非小细胞肺癌免疫治疗原理、临床试验及待解决问题作一综述。     

Strategies for improving antitumor activity utilizing IL-2: Preclinical models and analysis of antitumor activity of lymphocytes from patients receiving IL-2

Conclusions Considerable enthusiasm remains for the successful utilization of the immune system for the immunotherapy of human cancers. Immunotherapeutic maneuvers have been able to mediate impressive antitumor responses for some patients with advanced and refractory malignancies. Unfortunately, the number of patients who benefit from current immunotherapies is low, while the toxicity for many of the patients receiving these treatments is high. It is becoming quite clear that the development of successful immunotherapeutic strategies will involve a carefully chosen combination of immunotherapeutic modalities or of immunotherapy combined with either surgery, radiation therapy, or chemotherapy. The use of an IL-2 based regimen which is clinically tolerable and can provide significant immune activation continues to remain central to many of these treatment approaches. Preclinicalin vitro and animal model systems can evaluate promising treatment strategies, including combination approaches. As an effective immunotherapeutic approach will likely require use of a combination of biologically active agents, the scheduling of these therapies may have profound importance both for optimal antitumor responses as well as clinical tolerance.     

Cell- and peptide-based immunotherapeutic approaches for glioma

Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. Although considerable progress has been made in surgical and radiation treatment for glioma patients, the impact of these advances on clinical outcome has been disappointing. Therefore, the development of novel therapeutic approaches is essential. Recent reports demonstrate that systemic immunotherapy using dendritic cells (DCs) or peptide vaccines is capable of inducing an antiglioma response. These approaches successfully induce an antitumor immune response and prolong survival in patients with glioma without major side effects. There are several types of glioma, so to achieve effective therapy, it might be necessary to evaluate the molecular genetic abnormalities in individual patient tumors and design novel immunotherapeutic strategies based on the pharmacogenomic findings. Here, we review recent advances in DC- and peptide-based immunotherapy approaches for patients with gliomas.