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调节性T细胞 3

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CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells

null

《医学前沿（英文）》 2017年第11卷第4期页码 554-562 doi: 10.1007/s11684-017-0543-6

摘要：

T cells engineered with chimeric antigen receptor (CAR) have been successfully applied to treat advanced refractory B cell malignancy. However, many challenges remain in extending its application toward the treatment of solid tumors. The immunosuppressive nature of tumor microenvironment is considered one of the key factors limiting CAR-T efficacy. One negative regulator of T cell activity is lymphocyte activation gene-3 (LAG-3). We successfully generated LAG-3 knockout T and CAR-T cells with high efficiency using CRISPR-Cas9 mediated gene editing and found that the viability and immune phenotype were not dramatically changed during in vitro culture. LAG-3 knockout CAR-T cells displayed robust antigen-specific antitumor activity in cell culture and in murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates an efficient approach to silence immune checkpoint in CAR-T cells via gene editing.

关键词： CAR-T CRISPR-Cas9 LAG-3

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CAR-T细胞产品的质量控制和非临床研究——一般原则和关键问题 Review

李永红, 霍艳, 于雷, 王军志

《工程（英文）》 2019年第5卷第1期页码 122-131 doi: 10.1016/j.eng.2018.12.003

摘要：

采用嵌合抗原受体T 细胞（chimeric antigen receptor T cells, CAR-T cells）的过继性细胞治疗是一种很有前途的肿瘤免疫治疗策略，近年来发展迅速。CAR-T 细胞是通过基因修饰能够特异性识别肿瘤细胞表面特定抗原的T 细胞，对肿瘤细胞具有强大的杀灭作用。目前CAR-T 细胞在恶性血液病患者中的临床应用已经取得振奋人心的结果，国内外对于CAR-T 细胞针对多种靶点以及用于治疗实体瘤的研究开发形成了很大的热点，越来越多的产品将会进入临床试验和上市使用。本文在相关细胞治疗和基因治疗产品指导原则的基础上，结合CAR-T 细胞产品的具体特点，探讨其质量控制和非临床前研究的一般原则，以及其中的一些关键问题。

关键词：嵌合抗原受体T细胞质量控制非临床研究安全性有效性临床试验癌症免疫治疗

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Management of cytokine release syndrome related to CAR-T cell therapy

Hongli Chen, Fangxia Wang, Pengyu Zhang, Yilin Zhang, Yinxia Chen, Xiaohu Fan, Xingmei Cao, Jie Liu, Yun Yang, Baiyan Wang, Bo Lei, Liufang Gu, Ju Bai, Lili Wei, Ruili Zhang, Qiuchuan Zhuang, Wanggang Zhang, Wanhong Zhao, Aili He

《医学前沿（英文）》 2019年第13卷第5期页码 610-617 doi: 10.1007/s11684-019-0714-8

摘要： Chimeric antigen receptor T (CAR-T) cell therapy is a novel cellular immunotherapy that is widely used to treat hematological malignancies, including acute leukemia, lymphoma, and multiple myeloma. Despite its remarkable clinical effects, this therapy has side effects that cannot be underestimated. Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-threatening toxicities. This syndrome is a systemic immune storm that involves the mass cytokines releasing by activated immune cells. This phenomenon causes multisystem damages and sometimes even death. In this study, we reported the management of a patient with recurrent and refractory multiple myeloma and three patients with acute lymphocytic leukemia who suffered CRS during CAR-T treatment. The early application of tocilizumab, an anti-IL-6 receptor antibody, according to toxicity grading and clinical manifestation is recommended especially for patients who suffer continuous hyperpyrexia, hypotensive shock, acute respiratory failure, and whose CRS toxicities deteriorated rapidly. Moreover, low doses of dexamethasone (5–10 mg/day) were used for refractory CRS not responding to tocilizumab. The effective management of the toxicities associated with CRS will bring additional survival opportunities and improve the quality of life for patients with cancer.

关键词： chimeric antigen receptor T cell cytokine release syndrome tocilizumab

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A giant step forward: chimeric antigen receptor T-cell therapy for lymphoma

Houli Zhao, Yiyun Wang, Elaine Tan Su Yin, Kui Zhao, Yongxian Hu, He Huang

《医学前沿（英文）》 2020年第14卷第6期页码 711-725 doi: 10.1007/s11684-020-0808-3

摘要： The combination of the immunotherapy (i.e., the use of monoclonal antibodies) and the conventional chemotherapy increases the long-term survival of patients with lymphoma. However, for patients with relapsed or treatment-resistant lymphoma, a novel treatment approach is urgently needed. Chimeric antigen receptor T (CAR-T) cells were introduced as a treatment for these patients. Based on recent clinical data, approximately 50% of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy. Moreover, clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy. Other than the CD19-targeted CAR-T, the novel target antigens, such as CD20, CD22, CD30, and CD37, which were greatly expressed on lymphoma cells, were studied under preclinical and clinical evaluations for use in the treatment of lymphoma. Nonetheless, the CAR-T therapy was usually associated with potentially lethal adverse effects, such as the cytokine release syndrome and the neurotoxicity. Therefore, optimizing the structure of CAR, creating new drugs, and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.

关键词： chimeric antigen receptor T (CAR-T) cell lymphoma cytokine release syndrome (CRS) immune effector cell-associated neurotoxicity syndrome (ICANS)

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CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies

《医学前沿（英文）》 2021年第15卷第6期页码 783-804 doi: 10.1007/s11684-021-0904-z

摘要： The current standard of care in hematological malignancies has brought considerable clinical benefits to patients. However, important bottlenecks still limit optimal achievements following a current medical practice. The genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological disorders. Consequently, new treatment strategies are necessary to improve clinical outcomes. Chimeric antigen receptor T-cell (CAR T) immunotherapy opens a new path for targeted therapy of hematological malignancies. In this review, through a representative case study, we summarize the current experience of CAR T-cell therapy, the management of common side effects, the causative mechanisms of therapy resistance, and new strategies to improve the efficacy of CAR T-cell therapy.

关键词： CAR T cells hematological malignancies review

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Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system

Xiaohui Wang, Zhiqiang Wu, Wei Qiu, Ping Chen, Xiang Xu, Weidong Han

《医学前沿（英文）》 2020年第14卷第6期页码 726-745 doi: 10.1007/s11684-020-0746-0

摘要： Chimeric antigen receptor (CAR) T cells have been indicated effective in treating B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma and have shown encouraging results in preclinical and clinical studies. However, CAR T cells have achieved minimal success against solid malignancies because of the additional obstacles of their insufficient migration into tumors and poor amplification and persistence, in addition to antigen-negative relapse and an immunosuppressive microenvironment. Various preclinical studies are exploring strategies to overcome the above challenges. Mobilization of endogenous immune cells is also necessary for CAR T cells to obtain their optimal therapeutic effect given the importance of the innate immune responses in the elimination of malignant tumors. In this review, we focus on the recent advances in the engineering of CAR T cell therapies to restore the immune response in solid malignancies, especially with CAR T cells acting as cellular carriers to deliver immunomodulators to tumors to mobilize the endogenous immune response. We also explored the sensitizing effects of conventional treatment approaches, such as chemotherapy and radiotherapy, on CAR T cell therapy. Finally, we discuss the combination of CAR T cells with biomaterials or oncolytic viruses to enhance the anti-tumor outcomes of CAR T cell therapies in solid tumors.

关键词： CAR T cells immunoregulatory molecules endogenous immune response solid malignancies

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Chimeric antigen receptor T cell therapies for acute myeloid leukemia

Bin Gu, Jianhong Chu, Depei Wu

《医学前沿（英文）》 2020年第14卷第6期页码 701-710 doi: 10.1007/s11684-020-0763-z

摘要： Abstract Chimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.

关键词： acute myeloid leukemia CAR T immunotherapy

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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。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。然而，目前对CAR-Treg 工程的研究非常有限，并且关于治疗用途的最佳设计存在不确定性。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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CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a

《医学前沿（英文）》 2022年第16卷第3期页码 322-338 doi: 10.1007/s11684-021-0901-2

摘要： Immune-based therapies have experienced a pronounced breakthrough in the past decades as they acquired multiple US Food and Drug Administration (FDA) approvals for various indications. To date, six chimeric antigen receptor T cell (CAR-T) therapies have been permitted for the treatment of certain patients with relapsed/refractory hematologic malignancies. However, several clinical trials of solid tumor CAR-T therapies were prematurely terminated, or they reported life-threatening treatment-related damages to healthy tissues. The simultaneous expression of target antigens by healthy organs and tumor cells is partly responsible for such toxicities. Alongside targeting tumor-specific antigens, targeting the aberrantly glycosylated glycoforms of tumor-associated antigens can also minimize the off-tumor effects of CAR-T therapies. Tn, T, and sialyl-Tn antigens have been reported to be involved in tumor progression and metastasis, and their expression results from the dysregulation of a series of glycosyltransferases and the endoplasmic reticulum protein chaperone, Cosmc. Moreover, these glycoforms have been associated with various types of cancers, including prostate, breast, colon, gastric, and lung cancers. Here, we discuss how underglycosylated antigens emerge and then detail the latest advances in the development of CAR-T-based immunotherapies that target some of such antigens.

关键词： cancer immunotherapy chimeric antigen receptor solid tumors tumor-associated antigen glycosylation O-glycans adoptive cell therapy

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exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CART-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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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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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：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。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。同时还探讨了能够发现最佳靶标、新型CAR 结合结构域以及预测临床反应和不良反应的生物标志物的先进技术和计算工具。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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Precision medicine in acute lymphoblastic leukemia

Ching-Hon Pui

《医学前沿（英文）》 2020年第14卷第6期页码 689-700 doi: 10.1007/s11684-020-0759-8

摘要： The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno- and cellular-therapy approaches together with precise risk stratification. Children with or hyperdiploid>50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment. Patients with Philadelphia chromosome (Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib. BH3 profiling and other preclinical methods have identified several high-risk subtypes, such as hypodiplod, early T-cell precursor, immature T-cell, -rearranged, Ph-positive and -positive ALL, that may respond to BCL-2 inhibitor venetoclax. There are other fusions or mutations that may serve as putative targets, but effective targeted therapy has yet to be established. For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions, current approaches that offer hope include blinatumomab, inotuzumab and CAR-T cell therapy for B-ALL, and daratumumab and nelarabine for T-ALL. With the expanding therapeutic armamentarium, we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.

关键词： acute lymphoblastic leukemia molecular therapeutics targeted therapy tyrosine kinase inhibitors immunotherapy CAR T-cell therapy

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中国私用轿车发展的现状与问题

郭孔辉

《中国工程科学》 2000年第2卷第8期页码 25-30

摘要：

目前国内对中国应不应该发展私用轿车，中国应着重发展什么样的轿车，中国应不应该发展自己的轿车工业，中国轿车工业的出路在哪里，以及应如何发展中国的轿车工业，……等等，讨论颇多，已经成为社会上普遍关心的问题。文章试图分析目前提出的有代表性的各种观点，并对有关问题提出笔者自己的见解，以供参考。笔者认为解决"汽车灾难"问题的根本出路不在抑制私用轿车的发展，而在于发展汽车高新技术，加强城市规划与交通管理。文章在肯定引进合资对提高我国汽车制造技术和管理水平的重要作用的同时，指出它的负面影响是逐渐丧失产品开发的主动权；提出中国汽车工业的总战略应是："自强不息加国际合作"，其中包括：高新技术战略、自主双赢战略、内联自强战略、自主品牌战略和跨越赶超战略。

关键词：中国汽车工业私用轿车家用轿车现状与问题

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Thermal response of steel framing members in open car park fires

Xia YAN; Marion CHARLIER; Thomas GERNAY

《结构与土木工程前沿（英文）》 2022年第16卷第9期页码 1071-1088 doi: 10.1007/s11709-022-0879-0

摘要： For open car park structures, adopting a performance-based structural fire design is often justified and allowed because the fire does not reach flashover. However, this design approach requires an accurate assessment of temperatures in structural members exposed to car fires. This paper describes a numerical study on the thermal exposure on steel framing members in open car park fires. Steel temperatures are computed by the coupling of computational fluid dynamics and finite element modeling, and by analytical models from the Eurocodes. In addition, the influence of galvanization on the steel temperature evolution is assessed. Results show that temperatures in unprotected beams and columns are influenced by the section geometry, car fire scenario, modeling approach, and use of galvanization. Galvanization slightly delays and reduces peak temperature. Regarding the different models, CFD-FEM (CFD: computational fluid dynamics, FEM: finite-element method) coupled models predict lower temperatures than the Hasemi model, because the latter conservatively assumes that the fire flame continuously touches the ceiling. Further, the Hasemi model cannot account for the effect of reduced emissivity from galvanization on the absorbed heat flux. Detailed temperature distributions obtained in the steel members can be used to complete efficient structural fire designs based on the member sections, structure layout, and use of galvanization.

关键词： open car park localized fire steel frame numerical modeling computational fluid dynamics