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High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells

Synat Kang, Yanyan Li, Yifeng Bao, Yi Li

《医学前沿（英文）》 2019年 第13卷 第1期   页码 69-82 doi: 10.1007/s11684-018-0677-1

摘要：

Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptor-engineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1157–165 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing. Furthermore, the high-affinity TCR-CATs delivered significantly better activation and cytotoxicity than the equivalent TCR-engineered T cells (TCR-Ts) in terms of interferon-g and granzyme B production and in vitro cancer cell killing ability. TCR-CAT may be a very good alternative to the expensive TCR-T, which is considered an effective personalized cyto-immunotherapy.

关键词： cytokine-activated T cells     high-affinity T cell receptor     cancer immunotherapy     TCR-CAT    

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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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γδ T cells in liver diseases

null

《医学前沿（英文）》 2018年 第12卷 第3期   页码 262-268 doi: 10.1007/s11684-017-0584-x

摘要：

γδ T cells display unique developmental, distributional, and functional patterns and can rapidly respond to various insults and contribute to diverse diseases. Different subtypes of γδ T cells are produced in the thymus prior to their migration to peripheral tissues. γδ T cells are enriched in the liver and exhibit liver-specific features. Accumulating evidence reveals that γδ T cells play important roles in liver infection, non-alcoholic fatty liver disease, autoimmune hepatitis, liver fibrosis and cirrhosis, and liver cancer and regeneration. In this study, we review the properties of hepatic γδ T cells and summarize the roles of γδ T cells in liver diseases. We believe that determining the properties and functions of γδ T cells in liver diseases enhances our understanding of the pathogenesis of liver diseases and is useful for the design of novel γδ T cell-based therapeutic regimens for liver diseases.

关键词： γδT cells     liver infection     non-alcoholic fatty liver disease     autoimmune hepatitis     liver fibrosis and cirrhosis     liver cancer     liver regeneration    

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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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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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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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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： 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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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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Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes

null

《医学前沿（英文）》 2015年 第9卷 第2期   页码 139-145 doi: 10.1007/s11684-015-0377-z

摘要：

In obesity, chronic inflammation is believed to induce insulin resistance and impairs adipose tissue function. Although this view is supported by a large body of literature, it has been challenged by growing evidence that pro-inflammatory cytokines may favor insulin sensitivity through induction of energy expenditure. In this review article, interleukin 15 (IL-15) is used as a new example to explain the beneficial effects of the pro-inflammatory cytokines. IL-15 is secreted by multiple types of cells including macrophages, neutrophils and skeletal muscle cells. IL-15 expression is induced in immune cells by endotoxin and in muscle cells by physical exercise. Its transcription is induced by transcription factor NF-κB. IL-15 binds to its receptor that contains three different subunits (α, β and γ) to activate JAK/STAT, PI3K/Akt, IKK/NF-κB and JNK/AP1 pathways in cells. In the regulation of metabolism, IL-15 reduces weight gain without inhibiting food intake in rodents. IL-15 suppresses lipogenesis, stimulates brown fat function, improves insulin sensitivity through weight loss and energy expenditure. In human, circulating IL-15 is negatively associated with body weight. In the immune system, IL-15 stimulates proliferation and differentiation of T cells, NK cells, monocytes and neutrophils. In the anti-obesity effects of IL-15, T cells and NK cells are not required, but leptin receptor is required. In summary, evidence from human and rodents supports that the pro-inflammatory cytokine IL-15 may enhance energy expenditure to protect the body from obesity and type 2 diabetes. The mechanism of IL-15 action remains to be fully uncovered in the regulation of energy expenditure.

关键词： inflammation     obesity     cytokine     energy expenditure     insulin resistance    

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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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Study of recombinant human IFN-α-2b bacilli Calmette–Guerin activated killer cells and against bladder

FAN Xiaodong, HAN Ruifa

《医学前沿（英文）》 2007年 第1卷 第4期   页码 377-380 doi: 10.1007/s11684-007-0073-8

摘要： Presently, one of the most potent immunotherapies is the application of bacillus Calmette Guerin (BCG) to prevent recurrences of the superficial bladder cancer. Despite its successful use, nonresponders and certain side effects remain a major obstacle. Therefore, current studies aim at developing recombinant BCG (rBCG) strains secreting Th1-like cytokines to improve the effectiveness of the therapy. In this study, a new type of rBCG strain constructed by Tianjin institute of Urology was tested for its immunostimulatory capacity . Peripheral blood monocytes (PBMC) were stimulated by recombinant BCG and transformed into bacilli Calmette–Guerin activated killer (BAK) cells, and the effect of anticancer BAK cells was studied. Recombinant IFN--2b-BCG, wild-type BCG (wBCG), wild-type BCG and IFN--2b were coincubated with PBMCs respectively , and the proliferation of PBMC was detected with MTT in different time. BAK cells have the ability to kill bladder tumor cells, and the antitumor activity of effecter cells was determined by LDH release assay. The result of MTT showed that the proliferation of PBMC in the recombinant BCG group was more powerful than in the other two groups (<0.05). The result of LDH release assay showed that the antitumor activity of BAK cells stimulated by Recombinant BCG was the highest in all groups. We conclude that the recombinant BCG can activate more PBMCs to anti-bladder cancer than wild-type BCG does.

关键词： Urology     powerful     2b-BCG     Tianjin institute     wild-type    

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Interactions between metal ions and the biopolymer in activated sludge: quantification and effects of

Yun Zhou, Siqing Xia, Binh T. Nguyen, Min Long, Jiao Zhang, Zhiqiang Zhang

《环境科学与工程前沿（英文）》 2017年 第11卷 第1期 doi: 10.1007/s11783-017-0898-6

摘要： The biopolymer showed two protein-like fluorescence peaks (peaks A and B). Interactions of Pb(II) and biopolymer were quantified at various system pH values. System pH values significantly affect the quenching constant values for both peaks. Peak B plays a more important role in the interactions than peak A. Removal mechanism of metal ions by activated sludge system was further disclosed. The quantification and effects of system pH value on the interactions between Pb(II) and the biopolymer from activated sludge were investigated. The biopolymer had two protein-like fluorescence peaks (Ex/Em= 280 nm/326–338 nm for peak A; Ex/Em= 220–230 nm/324–338 nm for peak B). The fluorescence intensities of peak B were higher than those of peak A. The fluorophores of both peaks could be largely quenched by Pb(II), and the quencher dose for peak B was about half of that for peak A. The modified Stern-Volmer equation well depicted the fluorescence quenching titration. The quenching constant (Ka) values for both peaks decreased with rising system pH value, and then sharply decreased under alkaline conditions. It could be attributed to that the alkaline conditions caused the reduction of available Pb(II) due to the occurrence of Pb(OH)2 sediments. The Ka values of peak B were bigger than those for peak A at the same system pH values. Accordingly, the aromatic protein (peak B) plays the key role in the interactions between metal ions and the biopolymer.

关键词： Metal ions     Biopolymer     Activated sludge     Three-dimensional excitation emission matrix (3D-EEM)     Fluorescence regional integration (FRI) technique     Quantification    

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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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Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

null

《医学前沿（英文）》 2018年 第12卷 第4期   页码 374-386 doi: 10.1007/s11684-018-0652-x

摘要：

A family of transcription factors known as Id proteins, or inhibitor of DNA binding and differentiation, is capable of regulating cell proliferation, survival and differentiation, and is often upregulated in multiple types of tumors. Due to their ability to promote self-renewal, Id proteins have been considered as oncogenes, and potential therapeutic targets in cancer models. On the contrary, certain Id proteins are reported to act as tumor suppressors in the development of Burkitt’s lymphoma in humans, and hepatosplenic and innate-like T cell lymphomas in mice. The contexts and mechanisms by which Id proteins can serve in such contradictory roles to determine tumor outcomes are still not well understood. In this review, we explore the roles of Id proteins in lymphocyte development and tumorigenesis, particularly with respect to inhibition of their canonical DNA binding partners known as E proteins. Transcriptional regulation by E proteins, and their antagonism by Id proteins, act as gatekeepers to ensure appropriate lymphocyte development at key checkpoints. We re-examine the derailment of these regulatory mechanisms in lymphocytes that facilitate tumor development. These mechanistic insights can allow better appreciation of the context-dependent roles of Id proteins in cancers and improve considerations for therapy.

关键词： Id proteins     lymphoma     leukemia     T cells     B cells     tumor suppressor     oncogene    

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Th17 Cells in autoimmune diseases

null

《医学前沿（英文）》 2015年 第9卷 第1期   页码 10-19 doi: 10.1007/s11684-015-0388-9

摘要：

Th17 cells are a new subset of CD4+ T cells involved in the clearance of extracellular pathogens and fungi. Accumulating evidence suggests that Th17 cells and their signature cytokines have a pivotal role in the pathogenesis of multiple autoimmune-mediated inflammatory diseases. Here, we summarize recent research progress on Th17 function in the development and pathogenesis of autoimmune diseases. We also propose to identify new small molecule compounds to manipulate Th17 function for potential therapeutic application to treat human autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sj?gren’s syndrome, inflammatory bowel disease, and multiple sclerosis.

关键词： IL-17     Th17 cells     RORγt     autoimmune diseases     posttranslational modification     inhibitors    

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标题 作者 时间 类型 操作

High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells

Synat Kang, Yanyan Li, Yifeng Bao, Yi Li

期刊论文

Innate and adaptive T cells in influenza disease

null

期刊论文

γδ T cells in liver diseases

null

期刊论文

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

期刊论文

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

期刊论文

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

期刊论文

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

期刊论文

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

期刊论文

Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes

null

期刊论文

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

期刊论文

Study of recombinant human IFN-α-2b bacilli Calmette–Guerin activated killer cells and against bladder

FAN Xiaodong, HAN Ruifa

期刊论文

Interactions between metal ions and the biopolymer in activated sludge: quantification and effects of

Yun Zhou, Siqing Xia, Binh T. Nguyen, Min Long, Jiao Zhang, Zhiqiang Zhang

期刊论文

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

WU Kui, BI Yutian, WANG Yaoli, WANG Changzheng

期刊论文

Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

null

期刊论文

Th17 Cells in autoimmune diseases

null

期刊论文