嵌合抗原受体修饰T细胞治疗急性髓细胞白血病的研究进展

急性髓细胞白血病(AML)是一种常见的血液系统恶性肿瘤,临床治疗以传统化疗方案为主,该病复发率高,且预后差.近年,应用嵌合抗原受体修饰T细胞(CAR-T)治疗血液系统恶性肿瘤的研究,尤其是采用CD19 CAR-T治疗B细胞恶性肿瘤,取得了快速发展.多项研究结果表明,CAR-T在AML治疗中,也展现出良好的发展前景.笔者拟就嵌合抗原受体(CAR)的结构、CAR-T治疗AML的研究进展,以及CAR-T免疫疗法的局限性进行综述.     

嵌合抗原受体-T细胞免疫治疗在黑素瘤中的应用进展

嵌合抗原受体(chimeric antigen receptor,CAR)-T细胞疗法是一种过继性细胞免疫疗法,近年来在肿瘤免疫治疗中极具研究前景。目前,CAR-T细胞疗法已运用于血液系统恶性肿瘤(如急性B淋巴细胞白血病等)的研究和临床治疗中,并取得了不俗成果。但对于将CAR-T细胞运用于实体肿瘤的治疗仍存在相当多的困难。本文就CAR-T细胞疗法的原理、在黑素瘤治疗中的应用及面临的挑战、CAR-T细胞治疗的副作用和相应对策等方面进行综述。     

嵌合抗原受体T细胞应用进展

随着越来越多的有关嵌合抗原受体(chimeric antigen receptor,CAR)T细胞的临床试验成功开展,应用嵌合抗原受体制备的肿瘤特异性T淋巴细胞开始逐渐进入人们的视野。嵌合抗原受体T细胞免疫治疗是近年来迅速发展的肿瘤过继免疫治疗方法。该技术近年来无论在血液系统恶性肿瘤还是在实体瘤领域都取得了巨大的突破,但CAR-T技术在不断前进的道路上仍然面临着诸多困难。本文针对CAR-T细胞的临床应用情况、目前面临的挑战及发展趋势等作一综述。     

嵌合抗原受体T细胞治疗T淋巴细胞肿瘤靶点及制备工艺的探索

T淋巴细胞肿瘤是一组高度异质性的血液系统恶性肿瘤,复发和耐药通常是导致治疗失败的主要原因。既往治疗主要采用放化疗,尽管获得较高的治愈率,但仍有相当比例的患者最终治疗失败。随着单克隆抗体、免疫治疗和细胞治疗进入临床实践,恶性血液病的治愈率得到了显著提高。尤其是嵌合抗原受体T细胞(CAR-T)进入临床,其针对B细胞淋巴瘤和急性B淋巴细胞白血病的疗效已经超越既往任何治疗策略。但是,该治疗方法对T淋巴细胞肿瘤的治疗仍是难题,相关的研究和临床试验均显著落后于B淋巴细胞肿瘤。本文就CAR-T细胞在治疗T淋巴细胞肿瘤中的发展进程,及正在进行的临床试验和已经证实的主要潜在不良反应作一综述。     

嵌合抗原受体基因修饰T细胞免疫疗法在肺癌治疗中的研究进展

肺癌是全世界所有癌症中发病率和病死率最高的恶性肿瘤之一，目前仍缺乏较好的治疗手段。嵌合抗原受体基因修饰T(CAR-T)细胞免疫疗法作为一种新的治疗方法在血液系统恶性肿瘤中疗效显著，也为肺癌等实体肿瘤的免疫治疗开辟了新途径。然而，由于实体瘤的异质性、肿瘤微环境免疫抑制、肿瘤靶抗原逃逸及脱靶毒性等问题，造成CAR-T细胞免疫疗法在肺癌治疗中的应用存在挑战和障碍。本文总结了CAR-T细胞免疫疗在肺癌治疗中的最新研究进展，包括CAR-T细胞生物学特征、靶点选择、早期临床研究和治疗不良反应，并提出肺癌CAR-T细胞免疫疗法的优化策略，旨在为肺癌的临床免疫治疗提供新思路。     

靶向抑制PD-1/PD-L1信号通路在嵌合抗原受体T细胞免疫治疗血液肿瘤中的研究现状

嵌合抗原受体T细胞(CAR-T)免疫疗法已在治疗血液肿瘤方面已取得巨大成功, 然而大部分患者在接受CAR-T免疫治疗后复发, 复发的主要原因之一是CAR-T耗竭。研究发现, CAR-T耗竭和程序性死亡受体(PD)-1的持续表达, 以及与PD配体(PD-L)1的相互作用有关。靶向抑制PD-1/PD-L1信号通路可以部分逆转CAR-T耗竭的状态, 提高CAR-T抗肿瘤活性。笔者拟就PD-1/PD-L1信号通路参与肿瘤免疫逃逸, 抑制CAR-T抗肿瘤活性, 以及靶向抑制PD-1/PD-L1信号通路联合CAR-T免疫疗法治疗血液肿瘤的基础研究和临床试验等方面的研究现状进行总结。     

嵌合抗原受体T细胞在恶性血液肿瘤的临床应用中的研究进展

随着肿瘤免疫学理论和技术的发展,恶性血液肿瘤的治疗迎来新的纪元,过继性细胞免疫治疗(ACI)已成为研究热点.其中,利用嵌合抗原受体(CAR)修饰的T细胞治疗恶性血液肿瘤,在各项试验中均获得显著疗效.笔者拟就CAR-T细胞的构建及靶点选择,近年来与CAR-T细胞治疗相关的体内、外试验和临床研究,以及CAR-T细胞治疗目前尚待解决的问题进行综述.     

嵌合抗原受体T细胞治疗急性B淋巴细胞白血病研究进展

基因工程修饰的嵌合抗原受体T细胞(chimeric antigen receptor engineered T cell,CAR-T)疗法是一种治疗血液系统恶性肿瘤的新方法。过去10年,CAR-T疗法自实验室研究过渡至临床Ⅰ期实验,尤其是在急性B淋巴细胞白血病(B-cell acute lymphoblastic leukemia,B-ALL)治疗中取得了一定成果。本文就CAR-T基本结构、抗肿瘤机制、靶向CD19的CAR-T治疗B-ALL的效果及不良反应的研究进展作一综述。     

血液系统肿瘤病人嵌合性抗原受体T细胞治疗的全程护理

从全程护理的角度,综述了嵌合性抗原受体T细胞(CAR-T)治疗的流程及相关并发症的护理,以期为今后建立规范统一的血液系统肿瘤CAR-T治疗护理规范提供依据。     

纳米技术在嵌合抗原受体T细胞肿瘤免疫治疗中的应用进展

肿瘤免疫治疗主要通过解除免疫抑制作用与增强免疫应答反应来实现对其有效治疗.纳米技术能够提高免疫刺激分子的聚集度与作用力,在完成局部免疫调节的基础上有效治疗癌症.嵌合抗原受体T细胞(CAR-T)是肿瘤免疫治疗中的一种有力手段,能够对肿瘤患者的T细胞进行转化处理,令其成为可表达嵌合肿瘤细胞表面抗原受体的CAR-T细胞,随后将相应的CAR-T细胞回输至肿瘤患者体内,并通过特异性识别、杀伤肿瘤细胞的方式,有效杀灭肿瘤病毒.将纳米技术应用至CAR-T肿瘤免疫治疗中,有望提高肿瘤免疫治疗的疗效与安全性.本文就纳米技术在CAR-T肿瘤免疫治疗中的应用进展进行综述.     

嵌合抗原受体T细胞治疗恶性血液病的研究进展

嵌合抗原受体(CAR)-T细胞治疗是一种新的免疫疗法.该方法是将识别肿瘤细胞相关抗原的受体与T细胞胞内信号域在体外进行基因重组,再将这些质粒转染至T细胞中,而这类表达CAR的T细胞可特异性识别具有靶抗原的肿瘤细胞并发挥杀伤作用.目前,CAR-T细胞在肿瘤治疗,尤其是在恶性血液病治疗上获得良好疗效,但其疗效、安全性、不良反应、质量控制方面均需进一步验证.笔者拟就CAR-T细胞治疗中的CAR设计、细胞制备、临床试验及不良反应进行综述.     

Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Cancer: A Systematic Review and Meta-Analysis

Promising efficacy results of chimeric antigen receptor (CAR) T-cell therapy have been tempered by safety considerations. Our objective was to comprehensively summarize the efficacy and safety of CAR-T cell therapy in patients with relapsed or refractory hematologic or solid malignancies. MEDLINE, Embase, and the Cochrane Register of Controlled Trials (inception – November 21, 2017). Interventional studies investigating CAR-T cell therapy in patients with malignancies were included. Our primary outcome of interest was complete response (defined as the absence of detectable cancer). Two independent reviewers extracted relevant data, assessed risk of bias, and graded the quality of evidence using established methods. A total of 42 hematological malignancy studies and 18 solid tumor studies met were included (913 participants). Of 486 evaluable hematologic patients, 54.4% [95% CI, 42.5%-65.9%] experienced complete response in 27 CD19 CAR-T cell therapy studies. Of 65 evaluable hematologic patients, 24.4% [95% CI, 9.4%-50.3%] experienced complete response in seven non-CD19 CAR-T cell therapy studies. Cytokine release syndrome was experienced by 55.3% [95% CI, 40.3%-69.4%] of patients and neurotoxicity 37.2% [95% CI, 28.6%-46.8%] of patients with hematologic malignancies. Of 86 evaluable solid tumor patients, 4.1% [95% CI, 1.6%-10.6%] experienced complete response in eight CAR-T cell therapy studies. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. There was a strong signal for efficacy of CAR-T cell therapy in patients with CD19+ hematologic malignancies and no overall signal in solid tumor trials published to date. These results will help inform patients, physicians, and other stakeholders of the benefits and risks associated with CAR-T cell therapy.     

CAR-T Cell Therapies From the Transfusion Medicine Perspective

The use of chimeric antigen receptor (CAR)-T cell therapy for the treatment of hematologic malignancies has generated significant excitement over the last several years. From a transfusion medicine perspective, the implementation of CAR-T therapy as a potential mainstay treatment for not only hematologic but also solid-organ malignancies represents a significant opportunity for growth and expansion. In this review, we will describe the rationale for the development of genetically redirected T cells as a cancer therapeutic, the different elements that are required to engineer these cells, as well as an overview of the process by which patient cells are harvested and processed to create and subsequently validate CAR-T cells. Finally, we will briefly describe some of the toxicities and clinical efficacy of CAR-T cells in the setting of patients with advanced malignancy.     

Clinical CAR-T Cell and Oncolytic Virotherapy for Cancer Treatment

Immunotherapy has recently garnered success with the induction of clinical responses in tumors, which are traditionally associated with poor outcomes. Chimeric antigen receptor T (CAR-T) cells and oncolytic viruses (OVs) have emerged as promising cancer immunotherapy agents. Herein, we provide an overview of the current clinical status of CAR-T cell and OV therapies. While preclinical studies have demonstrated curative potential, the benefit of CAR-T cells and OVs as single-agent treatments remains limited to a subset of patients. Combinations of different targeted therapies may be required to achieve efficient, durable responses against heterogeneous tumors, as well as the microenvironment. Using a combinatorial approach to take advantage of the unique features of CAR-T cells and OVs with other treatments can produce additive therapeutic effects. This review also discusses ongoing clinical evaluations of these combination strategies for improved outcomes in treatment of resistant malignancies.

Chimeric antigen receptor modified T (CAR-T) cell and oncolytic viruses (OVs) are promising cancer immunotherapy platforms. Herein, Watanabe and colleagues review how these cancer gene therapy agents achieve clinical responses in tumors traditionally associated with poor outcomes and discusses emerging combinatorial strategies with radiotherapy/chemotherapy and other immunotherapies to improve clinical outcomes.     

CAR-T在治疗恶性胸膜间皮瘤中的研究进展

恶性胸膜间皮瘤（MPM）是一种具有高度侵袭性的多与石棉接触有关的胸膜疾病。MPM的局部高侵袭性导致其治疗方法的选择有限,虽然手术治疗及化学治疗药物方面的研究进展延长了部分MPM患者的生存期,但是MPM总体生存期仍低,目前仍无新的治疗方法可以改善MPM患者的结局。嵌合抗原受体（CAR）是通过现代分子生物技术构建的融合蛋白,嵌合抗原受体T细胞（CAR-T）疗法在治疗血液系统恶性肿瘤中已获较满意疗效,部分试验证实了CAR-T应用于实体肿瘤的安全性及有效性,该文就CAR-T在治疗MPM中的研究进展做一综述。     

How to train your T cell: genetically engineered chimeric antigen receptor T cells versus bispecific T-cell engagers to target CD19 in B acute lymphoblastic leukemia

Antigen-specific T cell–based immunotherapy is getting its day in the sun. The contemporaneous development of two potent CD19-specific immunotherapeutic modalities for the treatment of B-cell malignancies provides exciting opportunities for patients, physicians and scientists alike. Patients with relapsed, refractory or poor-risk B-cell acute lymphoblastic leukemia (ALL) previously had few therapeutic options and now have two potential new lifelines. Physicians will have the choice between two powerful modalities and indeed could potentially enroll some patients on trials exploring both modalities if needed. For scientists interested in tumor immunology, the advent of chimeric antigen receptor T-cell therapy and of bispecific T-cell engagers (BiTEs) provides unprecedented opportunities to explore the promise and limitations of antigen-specific T-cell therapy in the context of human leukemia. In this article, we compare chimeric antigen receptor T cells and BiTEs targeting CD19 in B-cell ALL in the setting of the available clinical literature.     

肿瘤过继性细胞免疫治疗中CAR-T及TCR-T疗法研究进展

近年来,新的生物技术不断被应用于临床,其中的肿瘤免疫治疗就是一种新型的抗肿瘤疗法。免疫治疗指在肿瘤微环境中,通过刺激免疫功能,增强抗肿瘤免疫,进而直接识别和杀伤肿瘤细胞。目前被应用于临床的肿瘤免疫治疗方法有免疫检查点治疗、细胞因子、肿瘤疫苗、过继性细胞免疫治疗（ACI）等。ACI是重要的肿瘤免疫治疗方法,由于ACI可以在不损害免疫系统及其功能的情况下杀死肿瘤细胞,而且能够避免肿瘤免疫逃逸,所以成为国内外研究的热点。经基因修饰改造T 淋巴细胞是ACI临床应用研究最深入的领域。经基因修饰改造的T淋巴细胞可分为嵌合抗原受体T细胞（CAR-T）及T细胞受体改造的T细胞（TCR-T）,该文就CAR-T及TCR-T疗法的研究进展进行综述。