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Prospects of immunotherapy for cancer

Zhinan Chen

《医学前沿（英文）》 2019年第13卷第1期页码 1-2 doi: 10.1007/s11684-019-0691-y

摘要：

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Immunometabolism: a new dimension in immunotherapy resistance

《医学前沿（英文）》 2023年第17卷第4期页码 585-616 doi: 10.1007/s11684-023-1012-z

摘要： Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.

关键词： immune cell immunometabolism metabolic reprogramming immunotherapy resistance tumor microenvironment immune checkpoint inhibitor

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Dendritic cell vaccines in cancer immunotherapy: from biology to translational medicine

Hongmei Xu, Xuetao Cao

《医学前沿（英文）》 2011年第5卷第4期页码 323-332 doi: 10.1007/s11684-011-0172-4

摘要：

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Challenges of NK cell-based immunotherapy in the new era

null

《医学前沿（英文）》 2018年第12卷第4期页码 440-450 doi: tzg@ustc.edu.cn

摘要：

Natural killer cells (NKs) have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells (PBMCs), stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.

关键词： natural killer cells immunotherapy adoptive transfer genetic modification immune checkpoint inhibitor

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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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Developing effective tumor vaccines: basis, challenges and perspectives

XU Qingwen, CHEN Weifeng

《医学前沿（英文）》 2007年第1卷第1期页码 11-19 doi: 10.1007/s11684-007-0003-9

摘要： A remarkable advance in tumor immunology during the last decade is the elucidation of the antigenic basis of tumor recognition and destruction. A variety of tumor antigens have been identified using several strategies including conventional experiments and newly developed bioinformatics. Among these antigens, cancer/testis antigen (CT antigen) is considered to be the most promising target for immunotherapy by vaccination. Successful immunotherapy of tumors requires understanding of the natural relationship between the immune system and tumor in the status of differentiation, invasion and maturation. Continued progress in development of effective cancer vaccines depends on the identification of appropriate target antigens, the establishment of optimal immunization strategies without harmful autoimmune responses and the ability of manipulating tumor microenvironment to circumvent immune suppression and to augment the anti-tumor immune response.

关键词： development conventional identification elucidation Successful immunotherapy

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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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Radial porous SiO

Chuangnian Zhang, Ying Dong, Jing Gao, Xiaoli Wang, Yanjun Jiang

《化学科学与工程前沿（英文）》 2021年第15卷第5期页码 1296-1311 doi: 10.1007/s11705-020-2034-6

摘要： Here, we reported a cancer nanovaccine based on SiO nanoflowers with a special radial pore structure, which greatly enhanced cross-presentation and induced the production of cytotoxic T lymphocyte cells secreting granzymes B and interferon- . The antigen ovalbumin was covalently conjugated onto the as-synthesized hierarchical SiO nanoflowers, and the adjuvant cytosine-phosphate-guanine was electrostatically adsorbed into their radial pore by simple mixing before use. The nanovaccine exhibited excellent storage stability without antigen release after 27 days of incubation, negligible cytotoxicity to dendritic cells, and a high antigen loading capacity of 430±66 mg·g support. Besides, the nanovaccine could be internalized by dendritic cells via multiple pathways. And the enhancement of antigen/adjuvant uptake and lysosome escape of antigen were observed. Noteworthy, culture of bone marrow-derived dendritic cells in the presence of nanovaccine proved the activation of dendritic cells and antigen cross-presentation as well as secretion of proinflammatory cytokines. Besides, study verified the targeting of nanovaccine to draining lymph nodes, the complete suppression of tumor in six out of ten mice, and the triggering of notable tumor growth delay. Overall, the present results indicated that the nanovaccine can be served as a potential therapeutic vaccine to treat cancer.

关键词： silica nanoflower antigen delivery cancer immunotherapy nanovaccine

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and novel CD3/CD19/CD20 trispecific antibodies against B-cell acute lymphoblastic leukemia: targeted immunotherapy

《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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Activation of phagocytosis by immune checkpoint blockade

null

《医学前沿（英文）》 2018年第12卷第4期页码 473-480 doi: 10.1007/s11684-018-0657-5

摘要：

Inhibition of macrophage-mediated phagocytosis has emerged as an essential mechanism for tumor immune evasion. One mechanism inhibiting the innate response is the presence of the macrophage inhibitory molecule, signal regulatory protein-α (SIRPα), on tumor-associated macrophages (TAMs) and its cognate ligand cluster of differentiation 47 (CD47) on tumor cells in the tumor microenvironment. On the basis of a recently discovered programmed death protein 1 (PD-1) in TAMs, we discuss the potential inhibitory receptors that possess new functions beyond T cell exhaustion in this review. As more and more immune receptors are found to be expressed on TAMs, the corresponding therapies may also stimulate macrophages for phagocytosis and thereby provide extra anti-tumor benefits in cancer therapy. Therefore, identification of biomarkers and combinatorial therapeutic strategies, have the potential to improve the efficacy and safety profiles of current immunotherapies.

关键词： CD47 PD-1 PD-L1 immunotherapy TAM phagocytosis macrophage

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基于自然杀伤细胞的癌症免疫疗法的进展和前景 Review

胡渊, 田志刚, 张彩

《工程（英文）》 2019年第5卷第1期页码 106-114 doi: 10.1016/j.eng.2018.11.015

摘要：

自然杀伤（natural killer，NK）细胞是重要的先天免疫细胞，位于机体抵御病毒感染和癌症的第一道防线。尽管自然杀伤细胞可以区分“自身”和“非自身”，识别异常细胞，并实时清除恶性转化的细胞和肿瘤，但肿瘤也形成了一些逃逸自然杀伤细胞攻击的策略。这些策略包括：上调自然杀伤细胞抑制性受体的配体，产生可溶性分子或免疫抑制因子。目前，临床试验正在应用各种类型的自然杀伤细胞治疗不同类型的肿瘤，包括自体或同种异体自然杀伤细胞、脐带血（umbilical cord blood，UCB）或诱导性多能干细胞（induced pluripotent stem cell，iPSC）来源的自然杀伤细胞、记忆样自然杀伤细胞和自然杀伤细胞系NK-92 细胞。近来，嵌合抗原受体（chimeric antigen receptor，CAR）修饰的自然杀伤细胞因其再导向特异性和有效的抗肿瘤活性而展现出巨大潜力。文中总结了肿瘤逃逸自然杀伤细胞识别的机制、自然杀伤细胞免疫疗法的现状和进展、提升自然杀伤细胞体内抗肿瘤能力的途径以及该领域在临床实践中所面临的重大挑战。

关键词：自然杀伤细胞免疫疗法癌症临床试验嵌合抗原受体

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Translational medicine in hepatocellular carcinoma

null

《医学前沿（英文）》 2012年第6卷第2期页码 122-133 doi: 10.1007/s11684-012-0193-7

摘要：

Hepatocellular carcinoma (HCC) is a highly complex disease that is generally resistant to commonly used chemotherapy and radiotherapy. Consequently, there is an urgent need for the development of new treatment strategies for this devastating disease. In the past decade, tremendous progress has been achieved in the molecular stratification of HCCs for diagnosis, prognosis, and therapeutic decision-making. To date, the molecular classification of HCCs has been carried out through transcriptomic, genetic and epigenetic profiling of tumors. Such research has led to identification of several potential molecular targets in HCC, and subsequently, development of novel systemic agents for the treatment of HCC has begun in earnest. In this article, we review the current knowledge of the molecular pathogenesis of HCC and outline potential areas for application of this knowledge in a clinical setting. As a typical virus and inflammation-associated cancer, both host immune response and tumor microenvironment have crucial roles in HCC pathogenesis. In addition, we examine the potential of immunotherapy and strategies targeting various components of the tumor microenvironment, as well as novel molecular and cellular targets in HCC such as cancer stem cells.

关键词： hepatocellular carcinoma molecular classification molecular targeted therapies tumor microenvironment immunotherapy

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医学科技颠覆性技术展望

李永洁,杨俊涛,杜建

《中国工程科学》 2018年第20卷第6期页码 64-68 doi: 10.15302/J-SSCAE-2018.06.010

摘要：

随着医学与现代信息技术、材料科技等技术的深度交叉融合，极大地促进了医学科技的发展，疾病诊断和治疗模式发生革命性的变化。本文主要从医学领域的肿瘤免疫治疗、基因编辑技术、医学人工智能、合成生物学技术和干细胞与转化医学五个技术方向，分析评价其发展态势；结合文献、智库报告和专家观点，对医学科技发展方向进行初探，提出重视医学基础研究投入、优化医学科技战略顶层设计、完善政策及监管体系等政策建议。

关键词：医学科技颠覆性技术肿瘤免疫治疗基因编辑

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Emerging immunological strategies: recent advances and future directions

《医学前沿（英文）》 2021年第15卷第6期页码 805-828 doi: 10.1007/s11684-021-0886-x

摘要： Immunotherapy plays a compelling role in cancer treatment and has already made remarkable progress. However, many patients receiving immune checkpoint inhibitors fail to achieve clinical benefits, and the response rates vary among tumor types. New approaches that promote anti-tumor immunity have recently been developed, such as small molecules, bispecific antibodies, chimeric antigen receptor T cell products, and cancer vaccines. Small molecule drugs include agonists and inhibitors that can reach the intracellular or extracellular targets of immune cells participating in innate or adaptive immune pathways. Bispecific antibodies, which bind two different antigens or one antigen with two different epitopes, are of great interest. Chimeric antigen receptor T cell products and cancer vaccines have also been investigated. This review explores the recent progress and challenges of different forms of immunotherapy agents and provides an insight into future immunotherapeutic strategies.

关键词： cancer immunotherapy bispecific antibodies small molecules chimeric antigen receptor T therapy cancer vaccines

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Analysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy

《医学前沿（英文）》 2022年第16卷第3期页码 307-321 doi: 10.1007/s11684-022-0927-0

摘要： The discovery of immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4, has played an important role in the development of cancer immunotherapy. However, immune-related adverse events often occur because of the enhanced immune response enabled by these agents. Antibiotics are widely applied in clinical treatment, and they are inevitably used in combination with immune checkpoint inhibitors. Clinical practice has revealed that antibiotics can weaken the therapeutic response to immune checkpoint inhibitors. Studies have shown that the gut microbiota is essential for the interaction between immune checkpoint inhibitors and antibiotics, although the exact mechanisms remain unclear. This review focuses on the interactions between immune checkpoint inhibitors and antibiotics, with an in-depth discussion about the mechanisms and therapeutic potential of modulating gut microbiota, as well as other new combination strategies.

关键词： tumor immunotherapy immune checkpoint inhibitor antibiotics gut microbiota drug–drug interaction