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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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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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Engineers as business leaders: A need to investigate formative collegiate experiences of highly successful

《工程管理前沿（英文）》 2022年第9卷第1期页码 159-162 doi: 10.1007/s42524-021-0183-z

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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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强震成功预报的曙光

李玶,杨美娥

《中国工程科学》 2009年第11卷第6期页码 19-27

摘要： 20世纪50年代以来，我国30多次成功预报了中、强地震的发生；近20年来国外有些地震学家对几次强震预测失败感到失望，逐渐将地震研究的主攻方向转变为对建筑物抗震能力的鉴定、加强建筑物抗震措施和建立现代数字台网，以便迅速准确确定强震的发生地点，可以即刻到现场救援;国内地震界部分地震学家受他们的悲观情绪的影响，也放弃了对强震预报的努力。所幸的是部分专业和业余地震学家仍在强震预报领域做出了不懈的努力，取得了可喜的成绩。

关键词：汶川地震强震预报强震发生断层

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网络安全研究——成功的数字化未来的关键

Jackie Craig

《工程（英文）》 2018年第4卷第1期页码 9-10 doi: 10.1016/j.eng.2018.02.006

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Functional tolerance theory in incremental growth design

YANG Bo, ZE Xiangbo, YANG Tao

《机械工程前沿（英文）》 2007年第2卷第3期页码 336-343 doi: 10.1007/s11465-007-0059-x

摘要： The evolutionary tolerance design strategy and its characteristics are studied on the basis of automation technology in the product structure design. To guarantee a successful transformation from the functional requirement to geometry constraints between parts, and finally to dimension constraints, a functional tolerance design theory in the process of product growth design is put forward. A mathematical model with a correlated sensitivity function between cost and the tolerance is created, in which the design cost, the manufacturing cost, the usage cost, and the depreciation cost of the product are regarded as control constraints of the tolerance allocation. Considering these costs, a multifactor-cost function to express quality loss of the product is applied into the model. In the mathematical model, the minimum cost is used as the objective function; a reasonable process capability index, the assembly function, and assembly quality are taken as the constraints; and depreciation cost in the objective function is expressed as the discount rate terminology in economics. Thus, allocation of the dimension tolerance as the function and cost over the whole lifetime of the product is realized. Finally, a design example is used to demonstrate the successful application of the proposed functional tolerance theory in the incremental growth design of the product.

关键词： successful transformation mathematical automation technology tolerance allocation minimum

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Identifying the driving factors of successful megaproject construction management: Findings from three

Qinghua HE, Junyan XU, Ting WANG, Albert P. C. CHAN

《工程管理前沿（英文）》 2021年第8卷第1期页码 5-16 doi: 10.1007/s42524-019-0058-8

摘要： The construction of megaprojects has always resulted in extensive and long-term impacts on the society. However, the performance of megaproject management is poor, and improving it remains an urgent and necessary issue. Although many studies on megaproject success have been conducted, existing studies on the driving factors of successful megaproject construction are rather limited. Therefore, this study aims to systematically explore the key factors that can lead to successful megaproject construction management based on three cases: The Beijing–Shanghai High-Speed Railway, the Three Gorges Dam, and the Hong Kong–Zhuhai–Macao Bridge. Mixed research methods, such as literature review, case studies, and expert interviews, were used in this study. Consequently, 11 driving factors, namely, government support, public support, accumulation and application of technology and experience, development and innovation of technology, innovation and application of management system, organizational mode and structure, top management support, project culture, megaproject citizenship behavior, corporate reputation, and fulfillment of social responsibilities, were identified and grouped into five categories, namely, project environment, construction capabilities, organization, positive culture and behavior, and requirements for sustainable development. The contributions of this study lie in two aspects. First, the driving factors of successful megaproject construction are identified to deepen the understanding of industrial practitioners, assist them in focusing on key factors, and aid them in effectively managing megaprojects. Second, researchers could use the identified driving factors in conducting further empirical studies and apply them in future projects to enhance their chances of success.

关键词： megaproject management driving factors project success case study China

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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