Scientific Reports
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2022
·Vol. 12
·期 1
·1-12
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IF 4.996
Zhang Shangkun,Gu Chaojiang,Huang Lifang,Wu Han,Shi Jiangzhou,Zhang Zijian,Zhou Yong,Zhou Jingjiao,Gao Yang,Liu Jiaxing,Leng Yingqi,Liu Xiyu,Zhang Qinxing,Huang Liang,Tong Xiqin,Young Ken H.,Li Jiapeng,Zhu Haichuan,Zhang Tongcun
CAR T-cell therapy is well tolerated and effective in patients with Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). However, even second- generation anti-CD30 CAR T-cells with CD28 (28z) costimulatory domains failed to achieve the desired rate of complete responses. In the present study, we developed second-generation (CD28z) and third-generation (CD28BBz) CAR T-cells targeting CD30 and investigated their efficacy in vitro and in vivo. Both of CD28z and CD28BBz anti-CD30 CAR T cells were similar regarding amplification, T cell subsets distribution, T cell activity, effector/memory and exhaustion. However, we found that the 28BBz anti-CD30 CAR T-cells persist long-term, specifically homing to the tumor and mediating powerful antitumor activity in tumor xenograft models. Subsequently, we also demonstrated that the third generation anti-CD30 CAR T-cells have miner side effects or potential risks of tumorigenesis. Thus, anti-CD30 CAR T-cells represent a safe and effective treatment for Hodgkin lymphoma.
研究领域:
免疫疗法
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肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
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2025
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IF 4
Yue Gao,Chenghui Cai,Wanyu Zheng,Shicheng Fan,Yifei Zhang,Yanying Zhou,Huilin Li,Jie Yang,Shaoxing Guan,Huichang Bi
Constitutive androstane receptor (CAR, NR1I3), a nuclear receptor superfamily member, plays a pivotal role in liver size regulation. Murine CAR agonist TCPOBOP was reported to induce hepatomegaly in mice, accompanied by hepatocyte hypertrophy and proliferation. However, whether CAR activation-induced hepatomegaly is reversible and the histological changes during reversal process remain elusive. In the current study, C57BL/6 mice were administered TCPOBOP for 5 days and sacrificed at different time points after drug withdrawal. The results showed that TCPOBOP-induced hepatomegaly required a long time to reverse, as evidenced by the liver-to-body weight ratio in the TCPOBOP group remained significantly higher than that in the Vehicle group even 120 days after withdrawal. CTNNB1 and CCND1 staining indicated a reduction in hepatocyte size and proliferating cells. To investigate the involved mechanisms, we measured proteins associated with hepatomegaly and liver regeneration termination. The results suggested that YAP, C-MYC, CTNNB1, FOXM1 and HNF4α changed significantly after TCPOBOP withdrawal and functioned at different stages during reversal. Furthermore, we established a UPLC-MS/MS method to quantify TCPOBOP concentration. The results indicated a long-term hepatic retention of TCPOBOP, which constantly activated CAR and led to sustained hepatomegaly after TCPOBOP withdrawal. Overall, these findings revealed the reversibility of CAR activation-induced hepatomegaly and provided new insights into the safety of CAR as a drug target. Additionally, the results highlighted the importance of considering long-term TCPOBOP accumulation in the liver to avoid potential adverse effects and experimental biases.
研究领域:
药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Qianqian Wang,Xin Yuan,Cuijuan Liu,Ying Huang,Lin Li,Yimin Zhu
CAR-T cell therapy has been proven to be effective on hematological tumors, although graft-versus-host disease and cytokine release syndrome(CRS) limit its application to a certain extent. However, CAR-T therapy for solid tumors met challenges, among which the lack of tumor-specific antigens (TSA) and immunosuppressive tumor microenvironment (TME) are the most important factors. CAR-NK could be a good alternative to CAR-T in some ways since they can induce mild CRS and are independent of HLA-matching, but the efficacy of CAR-NKs remains limited in solid tumors. CAR cells armed with multiple tumor targeting molecules may obtain higher therapeutic efficacy against solid tumors. Due to large molecular weight, multivalent scFvs cannot be displayed efficiently on T cells and the high affinity of scFv to the target makes it easy to cause on-target, off-tumor(OTOT) toxicity. Peptides with low molecular weight and slightly lower affinity than scFvs allow immune cells to display multiple peptides to increase killing ability and reduce OTOT toxicity. In our study, peptide-based CAR-NK cells were designed to solve the dilemma of CAR-T in solid tumors. Firstly, the peptide-based CAR-NK92MI cells with A1 peptide were constructed and their inhibitory effects on the growth of A549 tumor cells were identified. Secondly, the tri-specific CAR-NK92MI cells with peptides that simultaneously targeted PD-L1, EGFR and VEGFR2 were developed for the combinatory therapy. Tri-specific CAR-NK92MI exhibited comparable killing activities to scFv-based CAR-NK92MI. Moreover, peptide-based CAR NK92MI mitigated OTOT toxicity. Our study implied that peptide-based CAR-NKs could behave as promising tools in solid tumor
研究领域:
免疫学
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肿瘤学
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细胞治疗
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产品关联
DOI
PubMed
高影响因子
BMC CANCER
·
2025
·Vol. 25
·期 1
·1-10
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IF 3.4
Liu Shiyuan,Guan Tian,Yang Futian,Zhang Honglei,Yao Yao,Huang Jiman,Zhao Pengfei,Huang Wei,Wu Tailiang,Lin Hui,Fu Ting,Chen Shaoyu,Dai Pengzhan,Ding Zhechun,Chen Dongmei,Li Wei,Zeng Haoyu,Zhang Xianjun
Human oral tongue squamous cell carcinoma (OTSCC) is a prevalent form of head and neck squamous cell carcinoma (HNSCC), often presenting at an advanced stage with a grim prognosis. Traditional therapeutic approaches such as surgery, adjuvant radiotherapy, and chemoradiotherapy have shown limited efficacy in treating advanced OTSCC, underscoring the urgent need for innovative treatment strategies. Our bioinformatics analysis identified CD276 as a significant biomarker in OTSCC, with high protein expression levels correlating to a markedly reduced survival rate in late-stage patients. This discovery has led us to develop chimeric antigen receptor-natural killer (CAR-NK) cells derived from umbilical cord blood cells (UCBCs), specifically targeting CD276. Our aim is to investigate this novel therapeutic approach for its potential to combat OTSCC under pre-clinical conditions. Our in vitro and ex vivo studies have demonstrated that CD276-targeted CAR-NK cells exhibit remarkable efficacy in lysing OTSCC cell lines and primary cells, as well as in eliminating OTSCC organoids. These promising results underscore the pivotal role of CD276 in OTSCC pathogenesis and highlight the potential of CAR-NK cell therapy as a groundbreaking treatment option for advanced-stage OTSCC, offering new hope for translational medicine in the field of stomatology.
研究领域:
肿瘤学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
Nature Nanotechnology
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2025
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IF 34.9
Zhao Zhipeng,Li Qian,Qu Chenghao,Jiang Zeyu,Jia Guoqing,Lan Gongde,Luan Yuxia
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of haematological malignancies. Challenges in overcoming physical barriers however greatly limit CAR-T cell efficacy in solid tumours. Here we show that an approach based on collagenase nanogel generally improves the outcome of T cell-based therapies, and specifically of CAR-T cell therapy. The nanogels are created by cross-linking collagenase and subsequently modifying them with a CXCR4 antagonist peptide. These nanogels can bind CAR-T cells via receptor–ligand interaction, resulting in cellular backpack delivery systems. The nanogel backpacks modulate tumoural infiltration and localization of CAR-T cells by surmounting physical barriers and disrupting chemokine-mediated CAR-T cell imprisonment, thereby addressing their navigation deficiency within solid tumours. Our approach offers a promising strategy for pancreatic cancer therapy and holds potential for advancing CAR-T cell therapy towards clinical applications.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2021
·Vol. 11
·期 1
·1-9
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IF 4.38
Yang Xin,Yu Qiuxia,Xu Hao,Zhou Jianfeng
Treatment failure or relapse due to tumor escape caused by reduction in target antigen expression has become a challenge in the field of CART therapy. Target antigen density is closely related to the effectiveness of CART therapy, and reduced or lost target antigen expression limits the efficacy of CART therapy and hinders the durability of CAR T cells. Epigenetic drugs can regulate histones for molecular modifications to regulate the transcriptional, translational and post-translational modification processes of target agents, and we demonstrated for the first time the role in regulating CD22 expression and its effect on the efficacy of CD22 CART. In this paper, we found that Chidamide promoted the expression of CD22 on the surface of B-cell tumor cells in vitro and in vivo, and enhanced the function of CD22 CART. As for mechanisms, we demonstrated that Chidamide did not affect CD22 mRNA transcription, but significantly increased the expression of total CD22 protein, indicating that Chidamide may upregulate cell surface CD22 expression by affecting the distribution of CD22 protein. In summary, our results suggest that Chidamide may enhance the efficacy of CD22 CART by inhibiting histone deacetylases to regulate post-transcriptional modifications that affect protein distribution to increase the expression of CD22 on the cell surface.
研究领域:
肿瘤学
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免疫疗法
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
MICROCHEMICAL JOURNAL
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2025
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IF 5.1
Siyu Wu,Xiaojuan Niu,Jiali Chen,Wangni Meng,Han Tao,Jianli Zhou,Yuangen Wu
Kanamycin (KAN) can generate a serious threat to human health due to its tendency to accumulate in food. Current colorimetric strategy for KAN detection still faces some challenges, and nanozyme-based colorimetry is an ideal alternative approach. Herein, a non‑copper-based multivalent laccase mimic named Mn-Car is first synthesized through a self-assembly of manganese ions and the endogenous biomolecule carnosine, which is further used to develop a novel colorimetric method for ultrasensitive and selective detection of KAN. The laccase-like catalytic center is formed through the multidentate chelation bonds between manganese ions and imidazolium groups of histidine as well as carboxyl groups of β-alanine in carnosine. The multivalent oxidation states of manganese dynamically regulate electron transfer pathways through synergistic coordination. The unique Mn-Car architecture drives the efficient generation of superoxide radicals (O 2 · − ) and semiquinone radicals (SQ· − ). Leveraging the excellent laccase-like activity of Mn-Car , a highly sensitive colorimetric method for KAN detection is developed. Mn-Car forms polydentate chelation with the amino and hydroxyl groups in KAN, which can trigger multi-step cascade oxidation reactions that disrupt the structural core of Mn-Car and lead to reduced colorimetric signals. The colorimetric method achieves a limit of detection (LOD) of 0.102 μM and is successfully applied for on-site detection of KAN in water samples and honey, providing a novel platform for antibiotic residue analysis.
研究领域:
分析化学
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纳米技术
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生物传感
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产品关联
DOI
高影响因子
Future Science OA
·
2024
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IF 2.4
Yan Zhu,Luanhong Wang,Biyu Jiang,Yini Wang,Qing Wu,Sihua Hong,Xiaojing Wang,Yuancheng Li,Tian Guan,Haoyu Zeng,Congzhu Li
Aim: This study aimed to explore using peripheral blood mononuclear cell (PBMC)-derived chimeric antigen receptor (CAR) NK cells targeting ROBO1 as a personalized medicine approach for ovarian cancer. Methods: A two-step strategy generated ROBO1-targeted CAR NK cells from PBMCs of ovarian cancer patients. Efficacy was evaluated using xCELLigence RTCA, CCK-8 and Live/Dead fluorescence assays. Results: ROBO1-NK cells exhibited higher efficiency in eradicating primary ovarian cancer cells and lysing ovarian tumor organoids compared with primary NK cells without ROBO1-CAR modification. Conclusion: These findings highlight the potential of developing ROBO1-targeted CAR-NK cells from patients' PBMCs as a personalized treatment option for ovarian cancer.
研究领域:
肿瘤学
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免疫治疗
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2023
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IF 7.3
Xi Zhang,Tiaoxia Wang,Xiaona Zhu,Yong Lu,Mingpeng Li,Zhihong Huang,Deping Han,Longzhen Zhang,Yang Wu,Liantao Li,Frank Klawonn,Renata Stripecke
Introduction Epstein-Barr virus (EBV) is a widely spread pathogen associated with lymphoproliferative diseases, B/ T/ NK cell lymphomas, nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). EBV lytic reactivations contribute to the genomic instability, inflammation and tumorigenesis of NPC, promoting cancer progression. Patients with NPC refractory to standard therapies show dismal survival. EBV gp350 is an envelope protein detectable in NPC specimens intracellularly and on the cell membrane of malignant cells, and is a potential viral antigen for T cell-directed immunotherapies. The potency of T cells engineered with a chimeric antigen receptor (CAR) targeting gp350 against EBV + lymphoproliferative disease was previously shown. Methods Here, we advanced towards preclinical and non-clinical developments of this virus-specific CAR-T cell immunotherapy against NPC. Different gp350CAR designs were inserted into a lentiviral vector (LV) backbone. Results A construct expressing the scFv 7A1-anti−gp350 incorporating the CD8 transmembrane and CD28.CD3ζ signaling domain (ZT002) was selected. High titer ZT002 (~1x10 8 TU/ml) was manufactured in HEK 293T/17 suspension cells in serum free media as large-scale production under good manufacturing practices (GMP). A LV multiplicity of infection (MOI) of 1 resulted in high frequencies of functional gp350CAR + T cells (>70%) at a low (<2) vector copy numbers in the genome. ZT002 was therefore used to establish gp350CAR-T batch run production methods. GMP upscaling and validation of T cell transduction and expansion in several runs resulted in average 3x10 9 gp350CAR-T cells per batch. >80% CD3 + gp350CAR-T cells bound to purified gp350 protein. In vitro cytotoxicity and cytokine secretion assays (IFN-γ and TNF-α) confirmed the specificity of gp350CAR-T cells against gp350 + NPC, GC and lymphoma cell targets. Immunocompromised B-NDG mice (NOD.CB17- PrkdcscidIl2rgtm1 /Bcgen) were challenged s.c. with a EBV + NPC C666.1 cell line expressing gp350 and then treated with escalating doses of gp350CAR-T cells or with non-transduced T cells. gp350CAR-T cells promoted antitumor responses, bio-distributed in several tissues, infiltrated in tumors and rejected gp350 + tumor cells. Discussion These results support the use of gp350CAR-T cells generated with ZT002 as an Innovative New Drug to treat patients with solid and liquid EBV-associated malignancies.
研究领域:
免疫治疗
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肿瘤学
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分子生物学
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病毒学
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临床前研究
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2024
·
IF 18
Zilin Tan,Liangjie Tian,Yang Luo,Kexin Ai,Xuehua Zhang,Haitao Yuan,Jinfan Zhou,Guangyao Ye,Shuofei Yang,Ming Zhong,Gaohua Li,Yanan Wang
Colorectal cancer (CRC) recurrence post-surgery remains a major challenge. While Chimeric Antigen Receptor (CAR)-engineered natural killer (NK) cells hold immense therapeutic potential, their intratumoral infiltration ability remains limited, hampering efficacy. Building upon prior research suggesting that chemokines like C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10) recruit CAR-NK cells, we hypothesized that tumor cell m6A methylation, regulated by Methyltransferase-like 3 (METTL3), influences chemokine secretion. This study aims to elucidate the underlying mechanisms and improve METTL3 inhibition efficiency. We designed an adhesive hemostasis hydrogel loaded with STM2457, a METTL3 inhibitor, aimed at sustained release in the acidic tumor microenvironment. In vitro, the hydrogel promoted CAR-NK cell recruitment and tumor killing via sustained METTL3 inhibition. The hydrogel's Schiff base bonds further enabled intestinal adhesion and hemostasis in an incomplete tumor resection model of CRC. Combining the hydrogel with CAR-NK cell therapy significantly reduced CRC recurrence in vivo. Overall, our study reveals the crucial role of METTL3 in CRC recurrence and proposes a promising, multimodal strategy using STM2457-loaded hydrogel and CAR-NK cells for enhanced therapeutic efficacy.
研究领域:
肿瘤学
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分子生物学
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免疫疗法
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2020
·
IF 8.724
Hong Pan,Wenjun Li,Ze Chen,Yingmei Luo,Wei He,Mengmeng Wang,Xiaofan Tang,Huamei He,Lanlan Liu,Mingbin Zheng,Xin Jiang,Ting Yin,Ruijing Liang,Yifan Ma,Lintao Cai
The adoptive transfer of chimeric antigen receptor-T (CAR-T) cells has shown remarkable clinical responses in hematologic malignancies. However, unsatisfactory curative results and side effects for tumor treatment are still unsolved problems. Herein we develop a click CAR-T cell engineering strategy via cell glycometabolic labeling for robustly boosting their antitumor effects and safety in vivo. Briefly, paired chemical groups (N 3 /BCN) are separately incorporated into CAR-T cell and tumor via nondestructive intrinsic glycometabolism of exogenous Ac 4 GalNAz and Ac 4 ManNBCN, serving as an artificial ligand-receptor. Functional groups anchored on cell surface strengthen the interaction of CAR-T cell and tumor via bioorthogonal click chemistry, further enhancing specific recognition, migration and selective antitumor effects of CAR-T cells. In vivo, click CAR-T cell completely removes lymphoma cells and minimizes off-target toxicity via selective and efficient bioorthogonal targeting in blood cancer. Surprisingly, compared to unlabeled cells, artificial bioorthogonal targeting significantly promotes the accumulation, deep penetration and homing of CAR-T cells into tumor tissues, ultimately improving its curative effect for solid tumor. Click CAR-T cell engineering robustly boosts selective recognition and antitumor capabilities of CAR T cells in vitro and in vivo, thereby holding a great potential for effective clinical cell immunotherapy with avoiding adverse events in patients.
研究领域:
免疫疗法
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肿瘤学
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化学生物学
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细胞工程
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
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2025
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IF 5.7
Huajin Zhang,Fujun Liu,Junyilang Zhao,Yong Wang,Yuge Shen,Qiqi Li,Hui Luo,Yu Chen,Rong Li,Fan Zhu,Shuo Xie,Yinhao Wei,Xupeng Gou,Danling Hu,Zhengji Li,Hanshuo Yang
Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable promise in treating hematological malignancies. However, the ex vivo expansion of CAR-T cells is time-consuming, potentially impairing CAR-T cells function. Physiologically, T cell activation and proliferation occur within the lymph node (LN) paracortex, a dynamic environment structured by a three-dimensional (3D) reticular network (RN) that promotes cell migration and mediator delivery. Mimicking this physiological niche offers a compelling strategy to improve CAR-T cell expansion. Inspired by the structure of RN, we developed a biomimetic RN-like poriferous microsphere (PM) to establish a 3D culture platform optimized for both T cell and CAR-T cell proliferation. This engineered system not only significantly enhanced the proliferation rates of human T cells and CAR-T cells compared to conventional methods, but also preserved a higher proportion of central memory T cells (TCM) and reduced the expression of exhaustion markers (PD-1, TIM-3, and LAG-3). Moreover, CAR-T cells expanded in PMs exhibited superior anti-tumor efficacy in both ex vivo and in vivo models, which correlated with the enrichment of pathways associated with robust T cell function at the RNA level. Over all, this biomimetic platform addresses critical limitations in human T/CAR-T cell expansion, preserving cell function and improving therapeutic outcomes.
研究领域:
免疫治疗
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生物工程
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癌症生物学
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细胞治疗
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）