抗CD19嵌合抗原受体T细胞治疗弥漫性大B细胞淋巴瘤不良反应的研究进展

美国食品与药品监督管理局（FDA）已批准抗CD19嵌合抗原受体（chimeric antigen receptor，CAR）T细胞axicabtagene cilo-leucel、tisagenlecleucel用于复发/难治性弥漫性大B细胞淋巴瘤（recurrent/refractory diffuse large B-cell lymphoma，r/r DLBCL）的治疗，但该疗法易发生一系列不良反应，包括急性毒性细胞因子释放综合征、免疫效应细胞相关神经毒性综合征和噬血细胞综合征，长期毒性如血细胞减少症和B细胞发育不全，以及少见不良反应。本文主要介绍细胞因子释放综合征及免疫效应细胞相关神经毒性综合征的发病机理、临床表现、分级与处理、危险因素与预防措施，同时对血细胞减少症、B细胞耗竭在内的延迟毒性及少见不良反应做出综述。      

细胞因子表达异常与肿瘤

细胞团于促进细胞生长的特性早已为人们所熟知。静止期细胞需要具有生长刺激活性的细胞因子作为配基与细胞膜表面的相应受体结合，然后通过受体后信号传递途径使细胞出现分裂增殖。体外实验观察到，多种恶性肿瘤细胞与相应正常细胞的区别在于少需或无需外加细胞因子即可自主地分裂和增殖。据此，198O年提出了肿瘤细胞“自分泌”的概念，认为恶性肿瘤细胞能产生、释放具有生长刺激作用的内源性细胞因子，并具有相应细胞因子的膜受体，随即对自身产生的细胞因子发生受体反应，以调节、维持自身的恶性状态。为研究细胞因子异常表达与癌变的关…     

CAR-T细胞治疗消化系统肿瘤的研究进展

嵌合抗原受体基因修饰T细胞（chimeric antigen receptor gene modified T lymphocyte, CAR-T cell）治疗血液肿瘤显示了良好的效果，也为治疗食管癌、胃癌、肝细胞癌、胆管癌、胰腺癌和结直肠癌等消化系统肿瘤提供了新选择。消化系统不同部位肿瘤的细胞特征和肿瘤微环境存在差异，故靶向抗原的选择和CAR-T细胞的设计也相应地有所不同。CAR-T细胞治疗与其他免疫治疗联合使用也取得了一定的进展，但主要体现在细胞实验和小鼠体内实验。目前存在的脱靶效应、细胞因子释放综合征等副作用严重阻碍了CAR-T细胞的研究进展，限制了其在实体瘤中的应用。本文就近年来CAR-T细胞治疗消化系统肿瘤的研究进展作一阐述。     

CAR-T细胞免疫治疗肿瘤的毒副反应及临床对策

嵌合抗原受体T细胞(chimeric antigen receptorT cell,CAR-T)是肿瘤免疫治疗的重要手段,具有较强的抗肿瘤活性,但临床毒副反应明显.CAR-T细胞可通过识别共表达靶抗原及交叉抗原的组织等机制,引起肿瘤溶解综合征(tumor lysis syndrome,TLS)和细胞因子释放综合征(cytokine release syndrome,CRS)等全身性损伤.有效监测和及时处理是防治毒副反应的关键,本文结合多个CAR-T细胞治疗肿瘤临床研究的结果与经验,对CAR-T细胞治疗肿瘤的相关毒副反应及临床对策作一阐述.     

细胞因子风暴综合征和细胞因子释放综合征的研究进展

细胞因子风暴（cytokine storm，CS）是一种累及全身的系统性炎症反应，可由多种诱因导致，由其发展的疾病包括细胞因子风暴综合征（cytokine storm syndrome，CSS）和细胞因子释放综合征（cytokine release syndrome，CRS）。其中CSS与感染和自身免疫性疾病等有关，而CRS与肿瘤免疫治疗的不良反应有关。目前医学工作中，对CSS和CRS认识不足，两者概念极易混淆。随着肿瘤免疫检查点抑制剂和免疫细胞治疗的广泛应用，CRS在临床上越来越常见。因此，迫切需要提高对CSS和CRS的正确诊断和认识，有助于对其临床和基础研究提供进一步的帮助。本文分别介绍了CSS和CRS各自的发展历史、分类及发生机制等，旨在为CSS和CRS的诊断、鉴别诊断、预防和治疗提供帮助。      

CAR-T治疗后细胞因子释放综合征的发生机制与临床治疗

[摘要] 靶向CD19 的嵌合抗原受体修饰T 细胞（CAR-T）疗法在B 细胞肿瘤治疗中取了重大进展,美国FDA 已批准了2 项CD19 CAR-T治疗产品上市。随着CAR-T、双特异性T细胞衔接器（BiTE）和双重高亲靶向蛋白（DART）以及基因修饰的T细胞受体疗法（TCR-T）等免疫治疗临床及机制研究的开展,其潜在风险及副作用得到更广泛的认识,尤其是细胞因子释放综合征（CRS）。CRS是目前CAR-T治疗后最常见的并发症,重者可能危及生命。CRS病理生理学机制复杂,涉及多种免疫细胞及非免疫细胞,并可累及全身各脏器,研究CRS发生发展机制对提高CAR-T治疗安全性有重要意义。近年来,研究者们在动物模型中对CRS机制进行了更深入的研究。本文论述CRS的发生、病理生理学机制、动物模型、临床特征以及分级治疗等研究进展,旨在为更深入地从机制层面了解CRS,更安全地开展CAR-T临床应用提供指导。     

关于嵌合抗原受体T细胞疗法毒性事件的分级与管理

摘 要：嵌合抗原受体T细胞（chimeric antigen receptor T cells,CAR-T）治疗是近年来迅速发展的肿瘤过继免疫治疗方法,可用于治疗多种恶性肿瘤,此外还有TCR-gene治疗、CAR-NK细胞治疗以及TCR-T细胞免疫治疗等方法。但是CAR-T细胞治疗有三大独特的毒性不良事件,即细胞因子释放综合征、CAR-T细胞治疗相关性脑病综合征、暴发性溶血性淋巴细胞增多症/巨噬细胞活化综合症。此三大毒性事件绝大部分可以控制,但有些也是致命的,所以对毒性事件的正确认知及处理非常重要。全文对CAR-T细胞免疫治疗引发的毒性事件的分级和管理行进一步综述。     

炎症细胞因子与癌症患者症状群关系的研究进展

炎症细胞因子在癌症患者行为症状的生理病理机制上可能起重要作用。外周炎症细胞因子通过神经、体液、细胞三种途径进入大脑,影响下丘脑-垂体-肾上腺轴(HPA)及各类神经递质的释放,导致症状群的发生。本文主要综述了炎症细胞因子与癌症患者症状群之间的关系,重点探讨了癌症患者症状群潜在的炎性机制,并提出调控炎症细胞因子水平在治疗癌症患者症状群方面的前景和方向。     

肿瘤治疗中的异位效应

异位效应在肿瘤治疗和控制转移方面具有重要作用,将其用于临床肿瘤治疗有重要意义.其生物学机制尚小完全清楚,发现其与免疫应答有关.异位效应可能通过抗原释放和提呈、T细胞和自然杀伤细胞活化、细胞因子作用以及炎症反应和凋亡等环节激活体内抗肿瘤免疫效应.     

转染嵌合性T细胞受体基因小鼠T淋巴细胞的体外抗肿瘤作用

目的:研究小鼠T淋巴细胞在转染嵌合性T细胞受体基因后的体外抗肿瘤作用.方法:应用重组DNA技术,将HER2特异性嵌合性T-细胞受体构建入逆转录病毒载体;转入包装细胞后,收集病毒上清,转染小鼠T淋巴细胞,转基因后的小鼠T淋巴细胞分别与HER2阳性(SK-OV-3)或阴性(MCF-7)的肿瘤细胞系共培养,检测其细胞因子γ干扰素释放,51Cr释放法检测CTL评价其抗肿瘤效应.结果:所构建载体经酶切鉴定符合要求,乒乓法转染包装细胞系GP E86,检测病毒滴度为1.2×106,Retronectin结合离心法转染经抗CD3/CD28单抗活化的小鼠T淋巴细胞,转染效率可达50%以上;转染嵌合性T细胞受体基因的T淋巴细胞与HER2阳性或阴性的肿瘤细胞系共培养后可检测到HER2特异性的细胞因子γ干扰素释放,51Cr释放法测CTL可见转染嵌合性T细胞受体基因T淋巴细胞对HER2阳性的肿瘤细胞具显著杀伤效应.结论:转染嵌合性T细胞受体基因的小鼠T淋巴细胞在体外可通过细胞因子释放和CTL效应发挥显著的抗肿瘤作用.     

Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy in Children With Central Nervous System Leukemia

Backgroundchimeric antigen receptor–modified T cell (CAR-T) therapy is an effective and promising treatment for refractory and multiply relapsed B-cell acute lymphoblastic leukemia (B-ALL). Because of its side effects and poor responses such as neurotoxicity and cytokine release syndrome, patients with central nervous system leukemia were excluded in most previous clinical trials of CAR-T treatment.Patients and MethodsWe enrolled 3 B-ALL patients with central nervous system leukemia relapse. They were infused with CD19-specific CAR-Ts, and their clinical responses were evaluated by bone marrow smear, flow cytometry, and cytogenetic alterations detected by quantitative PCR, interleukin-6, and the expansion and persistence of circulating CAR-Ts in peripheral blood and cerebrospinal fluid.ResultsAfter CAR-T infusion, 2 of the 3 patients experienced bone marrow minimal residual disease–negative complete remission, and all patients tested negative for residual leukemia cells in cerebrospinal fluid tested by flow cytometry. These 3 patients experienced grade 2 or 3 cytokine release syndrome, which resolved completely after symptomatic treatment. None experienced neurotoxicity or needed further intensive care.ConclusionCAR-T infusion is a potentially effective treatment for relapsed/refractory B-ALL patients with central nervous system involvement.     

Chimeric Antigen Receptor-Natural Killer Cells: A New Breakthrough in the Treatment of Solid Tumours

Natural killer (NK) cells can quickly and directly eradicate tumour cells without recognising tumour-specific antigens. NK cells also participate in immune surveillance, which arouses great interest in the development of novel cancer therapies. The chimeric antigen receptor (CAR) family is composed of receptor proteins that give immune cells extra capabilities to target specific antigen proteins or enhance their killing effects. CAR-T cell therapy has achieved initial success in haematological tumours, but is prone to adverse reactions, especially with cytokine release syndrome in clinical applications. Currently, CAR-NK cell therapy has been shown to successfully kill haematological tumour cells with allogeneic NK cells in clinical trials without adverse reactions, proving its potential to become an off-the-shelf product with broad clinical application prospects. Meanwhile, clinical trials of CAR-NK cells for solid tumours are currently underway. Here we will focus on the latest advances in CAR-NK cells, including preclinical and clinical trials in solid tumours, the advantages and challenges of CAR-NK cell therapy and new strategies to improve the safety and efficacy of CAR-NK cell therapy.     

Rituximab and Cytokine Release Syndrome

Rituximab is a biologic agent that is usually well tolerated. With its increasing use for a myriad of rheumatologic and immunologic conditions, post-marketing surveillance has revealed more side effects. Systemic inflammatory response syndrome associated with cytokine release syndrome (CRS) is a very rare entity associated with the use of rituximab and carries a very high morbidity and case fatality rate. Cases of CRS reported within the literature are of patients with a very high tumor burden leading to a catastrophic cascade of events. We report the case of a patient having post-transplant lymphoproliferative disorder who died of fatal lactic acidosis and CRS within 24 h of receiving rituximab. Understanding the pathophysiology of such cases and identifying patients at risk may help to possibly avert this life-threatening complication.Key words: Rituximab, Cytokine release syndrome, Systemic inflammatory response syndrome, Mortality, Fatality, Lactic acidosis, Post-transplant lymphoproliferative disorder     

Recent Advances in CAR-T Cell Therapy for Non-Hodgkin Lymphoma

Adoptive cellular immunotherapy with anti CD19 chimeric antigen receptor (CAR)-T cell has changed the treatment landscape in relapsed/refractory B cell lymphomas. They have emerged as effective therapy in patients with multiple relapsed/refractory disease, capable of sustaining durable remissions. Two CAR-T cell products (axicabtagene ciloleucel and tisagenlecleucel) are currently approved by the United States Food and Drug Administration. A third anti CD19 CAR-T cell, lisocabtagene ciloleucel is currently being evaluated in large clinical trials and may also be United States Food and Drug Administration-approved soon. CAR-T cell-related toxicities, including infections, cytokine release syndrome, and neurotoxicity are potential complications of therapy. With increasing use of CAR-T cells, the mechanism of toxicities and mitigation strategies needs to be developed. Additionally, reasons for CAR-T cell failure and progression following this therapy needs to be further studied. We describe the recent developments in this field, with emphasis on the complications of therapy and factors contributing to toxicities, efficacy, and resistance. We also describe the ongoing research in this field and the newer CAR-T cell constructs that are being developed to counter the challenges that have been identified in this field.     

CAR-T细胞免疫治疗相关的不良反应研究进展

CAR-T细胞治疗血液系统恶性肿瘤疗效显著,但是,同时观察到不良反应的发生,常见的非血液学不良反应有:细胞因子释放综合征、CAR-T治疗相关脑病综合征,血液学不良反应有:噬血细胞淋巴组织细胞增多症、弥散性血管内凝血、B细胞发育不良、造血功能恢复延迟。这些不良反应经积极治疗,多数可得到纠正,但是仍有部分不良反应加重后危及患者生命,如果能早期识别、对高危患者采取预防措施,避免严重不良反应的发生,那么该疗法就能使更多的患者获益。为此,本文就上述不良反应的临床特征、病理生理机制、处理措施及高风险患者的评估和预测作一综述。     

Different types of FCgamma-receptors are involved in anti-Lewis Y antibody induced effector functions in vitro

Stimulation of monocytes by interaction of monoclonal antibodies (mAbs) with Fc gamma receptors (FcgammaRs) results in the activation of various monocyte effector functions. In the present investigation we show that the anti-Lewis Y (LeY) anti-tumour mAb ABL 364 and its mouse/human IgG1 chimaera induce both antibody-dependent cellular cytotoxicity (ADCC) and the release of tumour necrosis factor alpha (TNF-alpha) during mixed culture of monocytes with LeY+ SKBR5 breast cancer cells in vitro. Although anti-LeY mAb-mediated TNF-alpha release paralleled ADCC activity, cytokine release required a higher concentration of sensitizing mAb than the induction of cytolysis. The determination of the FcgammaR classes involved in the induction of the distinct effector functions showed that anti-LeY mAb-induced cytolysis was triggered by interaction between anti-LeY mAbs and FcgammaRI. In contrast, mAb-induced TNF-alpha release mainly depended on the activation of monocyte FcgammaRII. Neutralization of TNF-alpha showed no influence on monocyte ADCC activity towards SKBR5 target cells. Our data indicate an independent regulation of anti-LeY mAb induced effector functions of ADCC and TNF-alpha release which seemed to be triggered by activation of different types of FcgammaR.