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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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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

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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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Nanovaccines for remodeling the suppressive tumor microenvironment: New horizons in cancer immunotherapy

Kai Shi, Matthew Haynes, Leaf Huang

《化学科学与工程前沿（英文）》 2017年第11卷第4期页码 676-684 doi: 10.1007/s11705-017-1640-4

摘要： Despite limited successes in clinical development, therapeutic cancer vaccines have experienced resurgence in recent years due to an enhanced emphasis upon co-mitigating factors underlying immune response. Specifically, reversing the immune-suppressive effects of the tumor microenvironment, mediated by a variety of cellular and molecular signaling mechanisms, has become fundamental toward enhancing therapeutic efficacy. Therein, our lab has implemented various nano-vaccines based on the lipid-coated calcium phosphate platform for combined immunotherapy, in which antigenic, epitope-associated peptides as well as immune-suppression inhibitors can be co-delivered, often functioning through the same formulation. In probing the mechanism of action of such systems and , an improved effect synergy can be elucidated, inspiring future preclinical efforts and hope for clinical success.

关键词： vaccine nanoparticle tumor immunotherapy microenvironment

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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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PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives

Yumeng Wang, Guiling Li

《医学前沿（英文）》 2019年第13卷第4期页码 438-450 doi: 10.1007/s11684-018-0674-4

摘要： Cervical cancer (CC) is the fourth most commonly diagnosed female malignancy and a leading cause of cancer-related mortality worldwide, especially in developing countries. Despite the use of advanced screening and preventive vaccines, more than half of all CC cases are diagnosed at advanced stages, when therapeutic options are extremely limited and side effects are severe. Given these circumstances, new and effective treatments are needed. In recent years, exciting progress has been made in immunotherapies, including the rapid development of immune checkpoint inhibitors. Checkpoint blockades targeting the PD-1/PD-L1 axis have achieved effective clinical responses with acceptable toxicity by suppressing tumor progression and improving survival in several tumor types. In this review, we summarize recent advances in our understanding of the PD-1/PD-L1 signaling pathway, including the expression patterns of PD-1/PD-L1 and potential PD-1/PD-L1-related therapeutic strategies for CC.

关键词： PD-1 PD-L1 immune checkpoint blockade antibody immunotherapy cervical cancer

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Nature Conference

会议日期： 2019年06月11日

会议地点：中国/山东/青岛

主办单位：中国免疫学会；《自然-免疫学》；《中国免疫学会英文会刊（细胞与分子免疫学）》

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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Progress in systemic therapy for triple-negative breast cancer

Hongnan Mo, Binghe Xu

《医学前沿（英文）》 2021年第15卷第1期页码 1-10 doi: 10.1007/s11684-020-0741-5

摘要： Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a heterogeneous genetic profile. Chemotherapy exhibits substantial activity in a small subset of these patients. Drug resistance is inevitable. Major progress has been made in the genetic analysis of TNBC to identify novel targets and increase the precision of therapeutic intervention. Such progress has translated into major advances in treatment strategies, including modified chemotherapy approaches, immune checkpoint inhibitors, and targeted therapeutic drugs. All of these strategies have been evaluated in clinical trials. Nevertheless, patient selection remains a considerable challenge in clinical practice.

关键词： triple-negative breast cancer immunotherapy targeted therapy

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Chimeric antigen receptor T cell targeting EGFRvIII for metastatic lung cancer therapy

Zhao Zhang, Jun Jiang, Xiaodong Wu, Mengyao Zhang, Dan Luo, Renyu Zhang, Shiyou Li, Youwen He, Huijie Bian, Zhinan Chen

《医学前沿（英文）》 2019年第13卷第1期页码 57-68 doi: 10.1007/s11684-019-0683-y

摘要：

Lung cancer is the most common incident cancer and the leading cause of cancer death. In recent years, the development of tumor immunotherapy especially chimeric antigen receptor T (CAR-T) cell has shown a promising future. Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation expressed in various types of tumors and has been detected in non-small cell lung cancer with a mutation rate of 10%. Thus, EGFRvIII is a potential antigen for targeted lung cancer therapy. In this study, CAR vectors were constructed and transfected into virus-packaging cells. Then, activated T cells were infected with retrovirus harvested from stable virus-producing single clone cell lines. CAR expression on the surfaces of the T cells was detected by flow cytometry and Western blot. The function of CAR-T targeting EGFRvIII was then evaluated. The EGFRvIII-CAR vector was successfully constructed and confirmed by DNA sequencing. A stable virus-producing cell line was produced from a single clone by limited dilution. The culture conditions for the cell line, including cell density, temperature, and culture medium were optimized. After infection with retrovirus, CAR was expressed on more than 90% of the T cells. The proliferation of CAR-T cells were induced by cytokine and specific antigen in vitro. More importantly, EGFRvIII-CART specifically and efficiently recognized and killed A549-EGFRvIII cells with an effector/target ratio of 10:1 by expressing and releasing cytokines, including perforin, granzyme B, IFN-g, and TNF-α. The in vivo study indicated that the metastasis of A549-EGFRvIII cells in mice were inhibited by EGFRvIII-CART cells, and the survival of the mice was significantly prolonged with no serious side effects. EGFRvIII-CART showed significantly efficient antitumor activity against lung cancer cells expressing EGFRvIII in vivo and in vitro. Therefore, CAR-T targeting EGFRvIII is a potential therapeutic strategy in preventing recurrence and metastasis of lung cancer after surgery.

关键词： chimeric antigen receptor T cells epidermal growth factor receptor lung cancer immunotherapy tumor immunology

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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-1_157–165 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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Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status

Chenfei Zhou, Jun Zhang

《医学前沿（英文）》 2019年第13卷第1期页码 12-23 doi: 10.1007/s11684-019-0685-9

摘要：

Strategies in comprehensive therapy for gastrointestinal (GI) cancer have been optimized in the last decades to improve patients’ outcomes. However, treatment options remain limited for late-stage or refractory diseases. The efficacy of immune checkpoint inhibitors (ICIs) for treatment of refractory GI cancer has been confirmed by randomized clinical trials. In 2017, pembrolizumab was approved by the US Food and Drug Administration as the first agent for treatment of metastatic solid tumors with mismatch repair deficiency, especially for colorectal cancer. Given the different mechanisms, oncologists have focused on determining whether ICIs-based combination strategies could achieve higher efficacy than conventional therapy alone in late-stage or even front-line treatment of GI cancer. This review discusses the current status of combining immune checkpoint inhibitors with molecular targeted therapy, chemotherapy, or radiotherapy in GI cancer in terms of mechanisms, safety, and efficacy to provide basis for future research.

关键词： gastrointestinal cancer immune checkpoint inhibitor combination therapy

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Advances on immune-related adverse events associated with immune checkpoint inhibitors

Yong Fan, Yan Geng, Lin Shen, Zhuoli Zhang

《医学前沿（英文）》 2021年第15卷第1期页码 33-42 doi: 10.1007/s11684-019-0735-3

摘要： Immunotherapy has recently led to a paradigm shift in cancer therapy, in which immune checkpoint inhibitors (ICIs) are the most successful agents approved for multiple advanced malignancies. However, given the nature of the non-specific activation of effector T cells, ICIs are remarkably associated with a substantial risk of immune-related adverse events (irAEs) in almost all organs or systems. Up to 90% of patients who received ICIs combination therapy experienced irAEs, of which majority were low-grade toxicity. Cytotoxic lymphocyte antigen-4 and programmed cell death protein-1/programmed cell death ligand 1 inhibitors usually display distinct features of irAEs. In this review, the mechanisms of action of ICIs and how they may cause irAEs are described. Some unsolved challenges, however really engrossing issues, such as the association between irAEs and cancer treatment response, tumor response to irAEs therapy, and ICIs in challenging populations, are comprehensively summarized.

关键词： cancer immunotherapy immune checkpoint inhibitors immune-related adverse events review