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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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Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphomaupon anti-CD19 chimeric antigen receptor T therapy

《医学前沿（英文）》 2023年第17卷第4期页码 699-713 doi: 10.1007/s11684-022-0972-8

摘要： Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%–50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

关键词： anti-CD19 chimeric antigen receptor T immunotherapy diffuse large B cell lymphoma tumor microenvironment tumor-associated macrophage metabolism

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Platelet membrane-based and tumor-associated platelet- targeted drug delivery systems for cancer therapy

Yinlong Zhang, Guangna Liu, Jingyan Wei, Guangjun Nie

《医学前沿（英文）》 2018年第12卷第6期页码 667-677 doi: 10.1007/s11684-017-0583-y

摘要： Platelets have long been known to play critical roles in hemostasis by clumping and clotting blood vessel injuries. Recent experimental evidence strongly indicates that platelets can also interact with tumor cells by direct binding or secreting cytokines. For example, platelets have been shown to protect circulating cancer cells in blood circulation and to promote tumor metastasis. In-depth understanding of the role of platelets in cancer progression and metastasis provides promising approaches for platelet biomimetic drug delivery systems and functional platelet-targeting strategies for effective cancer treatment. This review highlights recent progresses in platelet membrane-based drug delivery and unique strategies that target tumor-associated platelets for cancer therapy. The paper also discusses future development opportunities and challenges encountered for clinical translation.

关键词： platelet-mimicking delivery systems tumor-associated platelets cancer therapy EPR effect

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Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications

null

《医学前沿（英文）》 2016年第10卷第1期页码 33-40 doi: 10.1007/s11684-016-0431-5

摘要：

Breast cancer is the most common malignant tumor in women, and the incidence of this disease has increased in recent years because of changes in diet, living environment, gestational age, and other unknown factors. Previous studies focused on cancer cells, but an increasing number of recent studies have analyzed the contribution of cancer microenvironment to the initiation and progression of breast cancer. Cancer-associated fibroblasts (CAFs), the most abundant cells in tumor stroma, secrete various active biomolecules, including extracellular matrix components, growth factors, cytokines, proteases, and hormones. CAFs not only facilitate the initiation, growth, angiogenesis, invasion, and metastasis of cancer but also serve as biomarkers in the clinical diagnosis, therapy, and prognosis of breast cancer. In this article, we reviewed the literature and summarized the research findings on CAFs in breast cancer.

关键词： cancer-associated fibroblast breast cancer progression prognosis

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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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Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of

《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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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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肿瘤特异性环状RNA来源抗原肽被证实存在于肝胆肿瘤中 Article

王文闻, 马莉丽 , 邢政, 苑廷淦, 包金霞, 朱妍静, 赵晓芳, 赵燕, 宗雅丽, 张雅妮, 莘似韵, 邱辛瑶, 杨帅, 王红阳, 高栋, 王鹏, 陈磊

《工程（英文）》 2023年第22卷第3期页码 159-170 doi: 10.1016/j.eng.2022.06.008

摘要：

由于缺乏经证实具备免疫原性的多肽，基于肿瘤抗原的免疫治疗应用受到限制。在本研究中，利用肝胆肿瘤类器官分析了环状RNA（circRNA）作为肿瘤抗原肽新来源的潜力。使用RNA测序（RNA-seq）和基于算法的评分工具，预测出27 个类器官中3950 个肿瘤特异性circRNA 可翻译18 971 条抗原肽。抗原图谱显示，11 个氨基酸长度（mer）的肽和人类白细胞抗原（HLA）-A结合肽的免疫原性相关评分最高。通过对5 个类器官进行基于质谱的免疫肽组学分析，直接证实其中三个类器官的13 条抗原肽为HLA-A、HLA-B 和HLA-C（HLA-ABC）结合肽。通过流式细胞仪和酶联免疫分析发现，HLA-ABC 呈递的cricRNA来源肿瘤特异性肽可以刺激CD8 T细胞，使其CD107a 和干扰素γ（IFNγ）共表达提高、IFNγ分泌增加。细胞杀伤实验证实，经circRNA 来源免疫原性肽活化的T 细胞可杀伤类器官细胞。值得注意的是，来自circTBC1D15 的抗原肽YGFNEILKK不仅可以被HLA-ABC呈递，还能活化T细胞，显著降低肿瘤类器官活率。本研究的发现提供了一种产生肿瘤抗原的重要来源，提示肿瘤特异性circRNA 可作为抗肿瘤靶点。

关键词：肿瘤抗原患者来源肝胆肿瘤类器官环状RNA 基于质谱的免疫肽组学

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Inhibition of TNF-alpha secretion from peripheral blood monocular cells by triptolid is associated with

Xiu-Liang TAO MM, Sheng-Hao TU MD, Ri-Bo XIONG MM, Yong-Hong HU BM,

《医学前沿（英文）》 2010年第4卷第2期页码 220-224 doi: 10.1007/s11684-010-0025-6

摘要： This study examined the inhibitory effect of triptolid (TP) on tumor necrosis factor-α (TNF-α) secreted from peripheral blood monocular cells (PBMCs) and the association of the inhibitory effect with TNF-α-308 gene polymorphisms in rheumatoid arthritis (RA) patients. Gene polymorphism at A-G site 308 in the promoter region of TNF-α gene was detected in 42 RA patients by using allele specific polymerase chain reaction (AS-PCR) assay. PBMCs were harvested from these patients and treated first with lipopolysaccharides (LPS) and then with different doses of TP (1, 5.4 and 15 ng/mL). The TNF-α level in the supernatants was measured by enzyme-linked immunosorbent assay (ELISA). The results showed that TNF-α level in the supernatants of TP (1 ng/mL)-treated PBMCs was decreased by 3.80% and 4.91%, respectively, in the patients with AA and AG genotypes, when compared with those treated with LPS alone (>0.05). Moreover, the TNF-α level in the patients with GG genotype was reduced by 20.74% (<0.05). When PBMCs were treated with TP at 5.4 ng/mL, TNF-α levels in the patients with AA, AG, and GG genotypes were decreased by 20.42%, 34.73%, and 41.69%, respectively (<0.05). The TNF-α level was slightly higher in the PBMCs treated with 15 ng/mL of TP than those in the two TP groups in the patients carrying AA, AG, and GG genotypes (>0.05). It was concluded that gene polymorphism at TNF-α-308 sites may relate to the secretion of TNF-α in RA patients. TP has different inhibitory effects on the secretion of TNF-α in the patients harboring different genotypes, which may be one of the reasons for individual variation in response to TP.

关键词： arthritis rheumatoid molonuclear cells tumor necrosis factor gene polymorphisms triptolid

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Heterogeneity of the tumor immune microenvironment and clinical interventions

《医学前沿（英文）》 2023年第17卷第4期页码 617-648 doi: 10.1007/s11684-023-1015-9

摘要： Heterogeneity of the tumor immune microenvironment and clinical interventions

关键词： Heterogeneity tumor immune

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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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Advancement of human leukocyte antigen-partially matched related hematopoietic stem cell transplantation

null

《医学前沿（英文）》 2013年第7卷第3期页码 306-315 doi: 10.1007/s11684-013-0279-x

摘要：

Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the most effective options for hematological malignancies, and human leukocyte antigen-partially matched related donors (PMRDs) are a valuable option for HSCT. Several protocols (with or without ex vivo T-cell depletion (TCD)) have been established worldwide. TCD including CD34⁺positive selection and CD3/CD19 depletion has successfully overcome the human leukocyte antigen disparity. However, TCD is associated with prolonged immune deficiencies, increased risks of infectious complications, and high transplantation-related mortality. PMRD HSCT without ex vivo TCD is well developed, and numerous patients have benefitted from it. Here, we review the literature on PMRD HSCT.

关键词： partially matched related donor hematopoietic stem cell transplantation allogeneic

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Proteins moonlighting in tumor metabolism and epigenetics

Lei Lv, Qunying Lei

《医学前沿（英文）》 2021年第15卷第3期页码 383-403 doi: 10.1007/s11684-020-0818-1

摘要： Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signal−moonlighting protein−metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.

关键词： moonlighting function tumor metabolism epigenetics

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Complex interplay between tumor microenvironment and cancer therapy

null

《医学前沿（英文）》 2018年第12卷第4期页码 426-439 doi: 10.1007/s11684-018-0663-7

摘要：

Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.

关键词： tumor microenvironment therapy response treatment resistance

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Crk-associated substrate, vascular smooth muscle and hypertension

TANG Dale

《医学前沿（英文）》 2008年第2卷第4期页码 323-331 doi: 10.1007/s11684-008-0062-6

摘要： Hypertension is characterized by vascular smooth muscle constriction and vascular remodeling involving cell migration, hypertrophy and growth. Crk-associated substrate (CAS), the first discovered member of the adapter protein CAS family, has been shown to be a critical cellular component that regulates various smooth muscle functions. In this review, the molecular structure and protein interactions of the CAS family members are summarized. Evidence for the role of CAS in the regulation of vascular smooth muscle contractility is presented. Contraction stimulation induces CAS phosphorylation on Tyr-410 in arterial smooth muscle, creating the binding site for the Src homology (SH) 2/SH3 protein CrkII, which activates neuronal Wiskott-Aldrich syndrome protein (N-WASP)-mediated actin assembly and force development. The functions of CAS in cell migration, hypertrophy and growth are also summarized. Abelson tyrosine kinase (Abl), c-Src, focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (PYK2), protein tyrosine phosphatase-proline, glutamate, serine and threonine sequence protein (PTP-PEST) and SHP-2 have been documented to coordinate the phosphorylation and dephosphorylation of CAS. The downstream signaling partners of CAS in the context of cell motility, hypertrophy, survival and growth are also discussed. These new findings establish the important role of CAS in the modulation of vascular smooth muscle functions. Furthermore, the upstream regulators of CAS may be new biologic targets for the development of more effective and specific treatment of cardiovascular diseases such as hypertension.

关键词： Contraction stimulation phosphatase-proline molecular structure discovered hypertension

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标题作者时间类型操作

CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a

期刊论文

Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphomaupon anti-CD19 chimeric antigen receptor T therapy

期刊论文

Platelet membrane-based and tumor-associated platelet- targeted drug delivery systems for cancer therapy

Yinlong Zhang, Guangna Liu, Jingyan Wei, Guangjun Nie

期刊论文

Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications

null

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

Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of

期刊论文