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供体来源的CD19靶向T细胞输注可以消除异基因造血干细胞移植后对供者淋巴细胞无反应的急性B淋巴细胞白血病微小残留病 Article

程翼飞, 陈育红, 闫晨华, 王昱, 赵翔宇, 陈瑶, 韩伟, 许兰平, 张晓辉, 刘开彦, 王莎莎, 张隆基, 肖磊, 黄晓军

《工程（英文）》 2019年 第5卷 第1期   页码 150-155 doi: 10.1016/j.eng.2018.12.006

摘要： HSCT 后治疗伴有MRD 的B-ALL 的主要方法是供者淋巴细胞输注（donor lymphoblastic infusion，DLI）。虽然供体来源的CD19 导向嵌合抗原受体（chimeric antigen receptor-modified，CAR）修饰T 细胞（CART19）可能治愈白血病，但输注此类细胞的效率与安全性尚未在经过在2014 年9 月至2018 年2 月期间，6 名患者均一次或多次输注了HSCT 供者提供的CD19 导向CAR 修饰T 细胞。其中有5 名患者（83.33%）的MRD 阴性得到缓解，而另1 名患者对CAR T 细胞并无反应。6 名患者中有3 名至今存活，白血病也并未复发。对于在allo-HSCT 后出现MRD 的B-ALL 患者且对DLI 并无反应的患者而言，供体来源的CAR T 细胞输注似乎是一种有效而安全的干预手段。

关键词： 供体来源的CD19靶向T细胞输注     造血干细胞移植     急性B淋巴细胞白血病     微小残留病    

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Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function ofCD19-specific CAR T-cells via TGF-β signaling

《医学前沿（英文）》 doi: 10.1007/s11684-023-1010-1

摘要： Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-β signaling

关键词： exosomes induce activation     impair function CD19     exosomal CD19 antigen    

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Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific

《医学前沿（英文）》 2022年 第16卷 第1期   页码 139-149 doi: 10.1007/s11684-021-0835-8

摘要： The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. However, several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight, and thus its clinical use is limited. Furthermore, multiple trials have shown that approximately 30% of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells. Here, we design and characterize two novel antibodies, A-319 and A-2019. Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures, and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function. Our in vitro, ex vivo, and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells, enhancing T-cell function, mediating B-cell depletion, and eventually inhibiting tumor growth in Raji xenograft models. The two molecules are complementary in terms of efficacy and specificity profile. The activity of A-319 demonstrated superior to that of A-2019, whereas A-2019 has an additional capability to target CD20 in cells missing CD19, suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

关键词： B-cell acute lymphoblastic leukemia     bispecific antibody     trispecific antibody     CD19     CD20    

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tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19chimeric antigen receptor T therapy

《医学前沿（英文）》 2023年 第17卷 第4期   页码 699-713 doi: 10.1007/s11684-022-0972-8

摘要： Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%–50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

关键词： anti-CD19 chimeric antigen receptor T     immunotherapy     diffuse large B cell lymphoma     tumor microenvironment     tumor-associated macrophage     metabolism    

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从药物开发的角度看工程化T细胞疗法 Review

Fang Chen, Joseph A. Fraietta, Carl H. June, 许中伟, J. Joseph Melenhorst, Simon F. Lacey

《工程（英文）》 2019年 第5卷 第1期   页码 140-149 doi: 10.1016/j.eng.2018.11.010

摘要：

癌症是全世界人口死亡的主要原因之一。细胞治疗的最新进展表明，其有可能为某些癌症患者带来第二次生命的机会。与化合物和蛋白质不同，细胞是活的、可自我复制的药物，具有精准的特异性。例如，经基因修饰后，T 细胞可表达嵌合抗原受体（chimeric antigen receptor，CAR），使其能够识别并杀死肿瘤细胞，并形成一个记忆库，准备回击持续存在的恶性细胞。抗CD19 嵌合抗原受体T 细胞（CAR T cells，CART19）对某些恶性肿瘤具有显著的临床疗效。这样，我们可以将现有的知识融会贯通，找出推进类似策略最有效的方法。本文综述了基于生物标志物的分析方法在优化CAR结构、临床前研究和临床疗效评价、不良反应（AE）和CART19 细胞动力学方面的应用。我们相信，就像胂凡纳明的发现开创了合成药物时代一样，CART19 的成功能够带来其他工程化T 细胞疗法的发展。

关键词： 工程化T细胞疗法     嵌合抗原受体     药物开发过程     生物标志物     CAR19     CART19    

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Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse large

《医学前沿（英文）》 2022年 第16卷 第2期   页码 285-294 doi: 10.1007/s11684-021-0843-8

摘要： Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive efficacy in treating B-cell malignancies. A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of T cells transduced with CBM.CD19 CAR, a second-generation anti-CD19 CAR bearing 4-1BB costimulatory molecule, for the treatment of patients with refractory diffuse large B-cell lymphoma (DLBCL). Ten heavily treated patients with refractory DLBCL were given CBM.CD19 CAR-T cell (C-CAR011) treatment. The overall response rate was 20% and 50% at 4 and 12 weeks after the infusion of C-CAR011, respectively, and the disease control rate was 60% at 12 weeks after infusion. Treatment-emergent adverse events occurred in all patients. The incidence of cytokine release syndrome in all grades and grade≥3 was 90% and 0, respectively, which is consistent with the safety profile of axicabtagene ciloleucel and tisagenlecleucel. Neurotoxicity or other dose-limiting toxicities was not observed in any dose cohort of C-CAR011 therapy. Antitumor efficacy was apparent across dose cohorts. Therefore, C-CAR011 is a safe and effective therapeutic option for Chinese patients with refractory DLBCL, and further large-scale clinical trials are warranted.

关键词： CAR-T cell therapy     refractory diffuse large B-cell lymphoma     cytokine release syndrome     dose-limiting toxicity    

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外泌体CD44与整合素α6β4结合激活宿主细胞重塑肿瘤微环境促进胰腺癌恶性转移 Article

牟为, 许亚婕, 顾鹏飞, 王文斌, 李井泉, 葛阳, 王慧

《工程（英文）》 2021年 第7卷 第10期   页码 1415-1425 doi: 10.1016/j.eng.2020.08.013

摘要： 其中，胰腺癌肝转移是胰腺癌患者死亡率高的原因之一。来自胰腺癌细胞的外泌体通常富含跨膜蛋白，用于支持肿瘤微环境的重编程和远处转移性病变的进展。我们的研究发现，由外泌体传递的跨膜糖蛋白CD44通过重编程肿瘤微环境，参与了胰腺癌的转移过程。CD44与整合素α6β4相互作用形成复合物，激活细胞内骨架蛋白及其信号通路，进而调控Src和Ras信号级联反应，促进肿瘤细胞的运动。值得注意的是，我们还证明了CD44-α6β4复合物可以通过外泌体的旁分泌作用传递到靶区。肝细胞选择性摄取具有高表达CD44的肿瘤外泌体，并通过刺激细胞因子、促炎因子和生长因子产生转移前生态位，最终支持肿瘤转移。我们的研究结果表明，外泌体CD44有可能作为胰腺癌临床诊断和治疗的生物标志物。

关键词： 胰腺癌     靶向器官转移     外泌体     细胞间交流     CD44    

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Clinical significance of CD34+CD117dim/CD34+CD117bri myeloblast-associatedgene expression in t(8;21) acute myeloid leukemia

Xueping Li, Yuting Dai, Bing Chen, Jinyan Huang, Saijuan Chen, Lu Jiang

《医学前沿（英文）》 2021年 第15卷 第4期   页码 608-620 doi: 10.1007/s11684-021-0836-7

摘要： t(8;21)(q22;q22) acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy with a high relapse rate in China. Two leukemic myeloblast populations (CD34 CD117 and CD34 CD117 ) were previously identified in t(8;21) AML, and CD34 CD117 cell proportion was determined as an independent factor for this disease outcome. Here, we examined the impact of CD34 CD117 /CD34 CD117 myeloblast-associated gene expression on t(8;21) AML clinical prognosis. In this study, 85 patients with t(8;21) AML were enrolled. The mRNA expression levels of CD34 CD117 -associated genes ( , , and ) and CD34 CD117 -associated genes ( , , and ) were measured using quantitative reverse transcription PCR. Associations between gene expression and clinical outcomes were determined using Cox regression models. Results showed that patients with high , , or expression had significantly inferior overall survival (OS), whereas those with high or expression showed relatively favorable prognosis. Univariate analysis revealed that CD19, CD34 CD117 proportion, mutation, minimal residual disease (MRD), and expression levels of , , , and were associated with OS. Multivariate analysis indicated that mutation, MRD and and expression levels were independent prognostic variables for OS. Identifying the clinical relevance of CD34 CD117 /CD34 CD117 myeloblast-associated gene expression may provide new clinically prognostic markers for t(8;21) AML.

关键词： t(8     21)(q22     q22) AML     CD34+CD117dim/ CD34+CD117bri cell population     gene expression     prognosis    

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光纤微针装置中增强对流药物输注的热强化表征 Article

Lyle Hood,Rudy T. Andriani,Tobias E. Ecker,John L. Robertson,Christopher G. Rylander

《工程（英文）》 2015年 第1卷 第3期   页码 344-350 doi: 10.15302/J-ENG-2015077

摘要：

增强对流输注 (CED) 是一项颇具前景的技术，其借助压力驱动流来增强输注药物进入细胞间隙的穿透力。为进一步提升CED的药物分布容积，笔者发明了一种可产生局部亚致死热量的光纤微针装置。在15 °C、20 °C、25 °C和30 °C的恒温条件下，染料的输注在质量分数为0.6%的琼脂糖组织模型中进行分析。输注指标通过自定义阴影成像技术和图像处理算法进行定量。利用所获数据构建一个分布容积的经验预测时序模型作为组织模型温度的函数。接下来通过一组概念验证实验来评估液体输注时新型光纤装置产生局部光加热的能力。恒温输注显示温度和分布容积呈正相关，在100 min时，在30 °C恒温条件下体积扩散是在15 °C恒温条件下的7倍。在光加热 (1064 nm，500 mW) 过程中，输注呈现相似的效果：与对照组 (0 mW) 相比，输注体积在4 h时增大了3.5倍。本文的分析和结果为体积扩散的热介导增强提供了特征描述及新思路。

关键词： 近红外激光     热化学疗法     琼脂糖     光加热     微导管     恶性胶质瘤    

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调节性T细胞及其在抗肿瘤免疫疗法中的临床应用 Review

解丰, 梁瑞, 李丹, 李斌

《工程（英文）》 2019年 第5卷 第1期   页码 132-139 doi: 10.1016/j.eng.2018.12.002

摘要：

癌症是可能危及生命的疾病，特点在于肿瘤细胞在宿主身上无限增殖。最近，因其具有预防肿瘤进展和转移的巨大潜力，免疫疗法受到越来越多研究者的关注。调节性T 细胞（Treg）是对维持宿主免疫稳态起重要作用的抑制性CD4+ T 细胞的一个亚群。调节性T 细胞缺陷可引起严重的自身免疫、过敏和自身炎症等疾病。调节性T 细胞通常富集在肿瘤微环境中，而大量免疫抑制调节性T细胞往往表明预后较差。因此，人们对调节性T 细胞的功能及其在抗肿瘤免疫疗法中的临床应用再次产生了兴趣。越来越多的策略关注调节性T 细胞的消耗，这在抗肿瘤免疫方面似乎有效。预计调节性T 细胞靶向策略与其他疗法（如嵌合抗原受体T 细胞疗法或免疫检查点阻断）联用将为提高抗肿瘤疗效带来重大机遇。

关键词： 调节性T细胞     癌症     免疫疗法    

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Changes of phenotype and function of human CD4 CD25 T cells induced by transfection of Foxp3

WU Kui, BI Yutian, WANG Yaoli, WANG Changzheng

《医学前沿（英文）》 2008年 第2卷 第4期   页码 366-369 doi: 10.1007/s11684-008-0070-6

摘要： The aim of this paper is to explore the effects of transfection of Foxp3 gene on the phenotype and function of naive CD4 T cells. The pMSCV-Foxp3 retroviral vector encoding Foxp3 gene was transduced into the PT67 packaging cell line. Virus-containing supernatant was applied to differentiate CD4CD25 T cells. The resulting cells were sorted with flow cytometry. The expressions of CD25, CD127, CTLA-4 and the proliferation of transfected T cells were examined. The effect of transfected CD4 T cells on the proliferation and cytokine production of CD4CD25 T cells was examined. Foxp3-gene transfected CD4 T cells could express Foxp3 and transfection of Foxp3 gene up-regulated the expressions of CD25 and CTLA-4, but down-regulated CD127 expression. After transfection, the proliferation of CD4 T cells was eliminated. Transfected T cells inhibited the proliferation of CD4CD25 T cells. CD4CD25 T cells acquired a regulatory phenotype and function after it was transduced with the Foxp3 gene. This suggested a key role of Foxp3 in the generation of CD4CD25 regulatory T cells.
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Innate and adaptive T cells in influenza disease

null

《医学前沿（英文）》 2018年 第12卷 第1期   页码 34-47 doi: 10.1007/s11684-017-0606-8

摘要：

Influenza is a major global health problem, causing infections of the respiratory tract, often leading to acute pneumonia, life-threatening complications and even deaths. Over the last seven decades, vaccination strategies have been utilized to protect people from complications of influenza, especially groups at high risk of severe disease. While current vaccination regimens elicit strain-specific antibody responses, they fail to generate cross-protection against seasonal, pandemic and avian viruses. Moreover, vaccines designed to generate influenza-specific T-cell responses are yet to be optimized. During natural infection, viral replication is initially controlled by innate immunity before adaptive immune responses (T cells and antibody-producing B cells) achieve viral clearance and host recovery. Adaptive T and B cells maintain immunological memory and provide protection against subsequent infections with related influenza viruses. Recent studies also shed light on the role of innate T-cells (MAIT cells, gd T cells, and NKT cells) in controlling influenza and linking innate and adaptive immune mechanisms, thus making them attractive targets for vaccination strategies. We summarize the current knowledge on influenza-specific innate MAIT and gd T cells as well as adaptive CD8+ and CD4+ T cells, and discuss how these responses can be harnessed by novel vaccine strategies to elicit cross-protective immunity against different influenza strains and subtypes.

关键词： influenza     innate T cells     CD4+ and CD8+ T cells     vaccination    

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嵌合抗原受体和调节性T细胞——移植中人类白细胞抗原特异性免疫抑制的潜力 Review

Sabrina Wright, Conor Hennessy, Joanna Hester, Fadi Issa

《工程（英文）》 2022年 第10卷 第3期   页码 30-43 doi: 10.1016/j.eng.2021.10.018

摘要：

嵌合抗原受体（CAR）是基因工程领域的一项突破，它彻底改变了过继细胞疗法（ACT）领域。表达这些受体的细胞通过在合成的CAR构建体中包含抗原特异性结合区域而被重新定向到预定的靶点。程序化特异性细胞在肿瘤学领域的优势已被临床证明，与同类未修饰的细胞相比，这种细胞具有更高的准确性、效力与更少的脱靶效应。与常规T细胞（Tconvs）不同，调节性T细胞（Treg）在抑制免疫激活和调节宿主免疫反应方面发挥着重要作用。本文综述了CAR-Treg 发展的理论基础、其对人类移植的意义、潜在的设计、安全性考虑因素，以及迄今为止CAR-Treg在移植模型中的对比。

关键词： 嵌合抗原受体（CAR）     调节性T细胞     异性免疫     CAR设计     基因编辑    

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survival of patients with relapsed or refractory non-Hodgkin lymphoma after chimeric antigen receptor T

Lili Zhou, Ping Li, Shiguang Ye, Xiaochen Tang, Junbang Wang, Jie Liu, Aibin Liang

《医学前沿（英文）》 2020年 第14卷 第6期   页码 786-791 doi: 10.1007/s11684-020-0751-3

摘要： Factors associated with complete and durable remissions after anti-CD19 chimeric antigen receptor T (CAR-T) cell immunotherapy for relapsed or refractory non-Hodgkin lymphoma (r/r NHL) have not been well characterized. In this study, we found that the different sites of extranodal involvement may affect response, overall survival (OS), and progression-free survival (PFS) in patients with r/r NHL treated with anti-CD19 CAR-T cells. In a cohort of 32 treated patients, 12 (37.5%) and 8 (25%) patients exhibited soft tissue lymphoma and bone marrow (BM) infiltrations, respectively, and 13 (41%) patients exhibited infiltration at other sites. The factors that may affect prognosis were identified through multivariable analysis. As an independent risk factor, soft tissue infiltration was the only factor significantly correlated with adverse prognosis ( <0.05), whereas other factors did not reach statistical significance. Furthermore, the site of extranodal tumor infiltration significantly and negatively affected OS and PFS in patients with r/r NHL treated with anti-CD19 CAR-T cell therapy. PFS and OS in patients with BM involvement were not significantly different from those of patients with lymph node involvement alone. Thus, anti-CD19 CAR-T cell therapy may improve the prognosis of patients with BM infiltration.

关键词： anti-CD19 chimeric antigen receptor T cell     soft tissue     bone marrow     relapsed or refractory non-Hodgkin lymphoma    

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Chimeric antigen receptor T-cell therapy: a promising treatment modality for relapsed/refractory mantle

Ping Li, Ningxin Dong, Yu Zeng, Jie Liu, Xiaochen Tang, Junbang Wang, Wenjun Zhang, Shiguang Ye, Lili Zhou, Alex Hongsheng Chang, Aibin Liang

《医学前沿（英文）》 2020年 第14卷 第6期   页码 811-815 doi: 10.1007/s11684-020-0740-6

摘要： Mantle cell lymphoma (MCL) is a distinct histological type of B-cell lymphoma with a poor prognosis. Several agents, such as proteasome inhibitors, immunomodulatory drugs, and inhibitors of B cell lymphoma-2 and Bruton’s tyrosine kinase have shown efficacy for relapsed or refractory (r/r) MCL but often have short-term responses. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin’s lymphoma. However, long-term safety and tolerability associated with CAR T-cell therapy are not defined well, especially in MCL. In this report, we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy. CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient. This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL, who are generally elderly and have comorbid conditions.

关键词： anti-CD19 chimeric antigen receptor T cells     mantle cell lymphoma     relapsed or refractory     long-term follow-up    

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标题 作者 时间 类型 操作

供体来源的CD19靶向T细胞输注可以消除异基因造血干细胞移植后对供者淋巴细胞无反应的急性B淋巴细胞白血病微小残留病

程翼飞, 陈育红, 闫晨华, 王昱, 赵翔宇, 陈瑶, 韩伟, 许兰平, 张晓辉, 刘开彦, 王莎莎, 张隆基, 肖磊, 黄晓军

期刊论文

Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function ofCD19-specific CAR T-cells via TGF-β signaling

期刊论文

Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific

期刊论文

tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19chimeric antigen receptor T therapy

期刊论文

从药物开发的角度看工程化T细胞疗法

Fang Chen, Joseph A. Fraietta, Carl H. June, 许中伟, J. Joseph Melenhorst, Simon F. Lacey

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Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse large

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外泌体CD44与整合素α6β4结合激活宿主细胞重塑肿瘤微环境促进胰腺癌恶性转移

牟为, 许亚婕, 顾鹏飞, 王文斌, 李井泉, 葛阳, 王慧

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Clinical significance of CD34+CD117dim/CD34+CD117bri myeloblast-associatedgene expression in t(8;21) acute myeloid leukemia

Xueping Li, Yuting Dai, Bing Chen, Jinyan Huang, Saijuan Chen, Lu Jiang

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光纤微针装置中增强对流药物输注的热强化表征

Lyle Hood,Rudy T. Andriani,Tobias E. Ecker,John L. Robertson,Christopher G. Rylander

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调节性T细胞及其在抗肿瘤免疫疗法中的临床应用

解丰, 梁瑞, 李丹, 李斌

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Changes of phenotype and function of human CD4 CD25 T cells induced by transfection of Foxp3

WU Kui, BI Yutian, WANG Yaoli, WANG Changzheng

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Innate and adaptive T cells in influenza disease

null

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嵌合抗原受体和调节性T细胞——移植中人类白细胞抗原特异性免疫抑制的潜力

Sabrina Wright, Conor Hennessy, Joanna Hester, Fadi Issa

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survival of patients with relapsed or refractory non-Hodgkin lymphoma after chimeric antigen receptor T

Lili Zhou, Ping Li, Shiguang Ye, Xiaochen Tang, Junbang Wang, Jie Liu, Aibin Liang

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Chimeric antigen receptor T-cell therapy: a promising treatment modality for relapsed/refractory mantle

Ping Li, Ningxin Dong, Yu Zeng, Jie Liu, Xiaochen Tang, Junbang Wang, Wenjun Zhang, Shiguang Ye, Lili Zhou, Alex Hongsheng Chang, Aibin Liang

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