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Telomeres, telomerase, and cancer: mechanisms, biomarkers, and therapeutics.
IF 9.4 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-01-27 DOI: 10.1186/s40164-025-00597-9
Songting Shou, Ayidana Maolan, Di Zhang, Xiaochen Jiang, Fudong Liu, Yi Li, Xiyuan Zhang, En Geer, Zhenqing Pu, Baojin Hua, Qiujun Guo, Xing Zhang, Bo Pang

Telomeres and telomerase play crucial roles in the initiation and progression of cancer. As biomarkers, they aid in distinguishing benign from malignant tissues. Despite the promising therapeutic potential of targeting telomeres and telomerase for therapy, translating this concept from the laboratory to the clinic remains challenging. Many candidate drugs remain in the experimental stage, with only a few advancing to clinical trials. This review explores the relationship between telomeres, telomerase, and cancer, synthesizing their roles as biomarkers and reviewing the outcomes of completed trials. We propose that changes in telomere length and telomerase activity can be used to stratify cancer stages. Furthermore, we suggest that differential expression of telomere and telomerase components at the subcellular level holds promise as a biomarker. From a therapeutic standpoint, combining telomerase-targeted therapies with drugs that mitigate the adverse effects of telomerase inhibition may offer a viable strategy.

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引用次数: 0
Structural basis of FpGalNase and its combination with FpGalNAcDeAc for efficient A-to-O blood group conversion. FpGalNase 的结构基础及其与 FpGalNAcDeAc 的结合可实现 A 至 O 血型的高效转换。
IF 9.4 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-01-24 DOI: 10.1186/s40164-025-00599-7
Meiling Zhou, Kaishan Luo, Chao Su, Yan Sun, Zuyan Huang, Shuo Ma, Xun Gao, Jiwei Wang, Chen Zhang, Pengcheng Han, Guoqiu Wu

Transfusion safety and blood typing continue to present significant challenges in clinical practice, including risks of incorrect blood transfusions and blood shortages. One promising solution is the enzymatic conversion of all red blood cell (RBC) types into universal O-type RBCs. However, the major obstacle to this strategy is the relatively low catalytic efficiency of the enzymes involved. In this study, we investigated two enzymes from Flavonifractor plautii, N-acetylgalactosamine deacetylase (FpGalNAcDeAc) and galactosaminidase (FpGalNase), which demonstrate synergistic activity in efficiently converting A-type RBCs to O-type. We optimized treatment conditions, achieving over 99% conversion in just five minutes using phosphate buffer saline and a 16 nM enzyme concentration. Additionally, we engineered two fusion proteins, FpGalNAcDeAc-FpGalNase and FpGalNase-FpGalNAcDeAc, which showed a 28-fold increase in catalytic efficiency compared to the enzyme mixture. Using cryo-electron microscopy, we resolved the full-length structure of FpGalNase, identifying critical active site residues involved in its catalytic mechanism. This study provides essential structural and biochemical insights for clinical applications in blood group conversion, offering a promising approach for producing universal O-type RBCs.

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引用次数: 0
Construction and characterization of chimeric FcγR T cells for universal T cell therapy. 用于通用T细胞治疗的嵌合fc - γ r T细胞的构建和表征。
IF 9.4 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-01-15 DOI: 10.1186/s40164-025-00595-x
Juanjuan Zhao, Manling Chen, Xudong Li, Zhaoqi Chen, Wei Li, Rongqun Guo, Min Wang, Zhongxing Jiang, Yongping Song, Jianxiang Wang, Delong Liu

Background: Several approaches are being explored for engineering off-the-shelf chimeric antigen receptor (CAR) T cells. In this study, we engineered chimeric Fcγ receptor (FcγR) T cells and tested their potential as a versatile platform for universal T cell therapy.

Methods: Chimeric FcγR (CFR) constructs were generated using three distinct forms of FcγR, namely CD16A, CD32A, and CD64. The functionality of CFR T cells was evaluated through degranulation assays, specific target lysis experiments, in vitro cytokine production analysis, and assessment of tumor xenograft destruction specificity in mouse models using different monoclonal antibodies (MoAbs).

Results: Three types of CFR T cells were engineered, 16s3, 32-8a, 64-8a CFR T cells. In the presence of rituximab (RTX), cytotoxicity of all three types of CFR T cells against CD20+ Raji-wt, K562-CD20+, and primary tumor cells was significantly higher than that of the mock T cells (P < 0.001). When herceptin was used, all three types of CFR T cells exhibited significant cytotoxicity against HER2+ cell lines of SK-BR-3, SK-OV-3, and HCC1954 (P < 0.001). The cytotoxicity of 64-8a CFR T cells was significantly inhibited by free human IgG at a physiological dose (P < 0.001), which was not observed in 16s3, 32-8a CFR T cells. Compared to 32-8a CFR T cells, 16s3 CFR T cells exhibited more prolonged cytotoxicity than 32-8a CFR T cells (P < 0.01). In in vivo assays using xenograft models, 16s3 CFR T cells significantly prolonged the survival of mice xenografted with Raji-wt cells in the presence of RTX (P < 0.001), and effectively reduced tumor burden in mice xenografted with SK-OV-3 cells in the presence of herceptin (P < 0.05). No significant non-specific cytotoxicity of CFR T cells was found in vivo.

Conclusion: The anti-tumor effects of the CFR T cells in vitro and in xenograft mouse models are mediated by specific MoAbs such as RTX and herceptin. The CFR T cells therefore have the features of universal T cells with specificity directed by MoAbs. 16s3 CFR T cells are chosen for clinical trials.

背景:目前正在探索几种方法来设计现成的嵌合抗原受体(CAR) T细胞。在这项研究中,我们设计了嵌合Fcγ受体(Fcγ r) T细胞,并测试了它们作为通用T细胞治疗的通用平台的潜力。方法:利用CD16A、CD32A和CD64三种不同形式的FcγR构建嵌合FcγR (CFR)。使用不同的单克隆抗体(MoAbs),通过脱颗粒实验、特异性靶点裂解实验、体外细胞因子产生分析和评估小鼠模型中肿瘤异种移植物破坏特异性来评估CFR T细胞的功能。结果:共获得3种CFR T细胞:16s3、32-8a、64-8a。在利妥昔单抗(RTX)作用下,三种类型的CFR T细胞对CD20+ Raji-wt、K562-CD20+和原发肿瘤细胞的细胞毒性均显著高于模拟T细胞(SK-BR-3、SK-OV-3和HCC1954的P +细胞系)(P)。结论:CFR T细胞在体外和异种移植小鼠模型中的抗肿瘤作用是由RTX和赫赛汀等特异性MoAbs介导的。因此,CFR T细胞具有通用T细胞的特征,并具有由MoAbs定向的特异性。16s3选择CFR T细胞用于临床试验。
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引用次数: 0
Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer. 组合功能鉴定hdac6依赖的放射耐药头颈癌分子易损性。
IF 9.4 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-01-12 DOI: 10.1186/s40164-024-00590-8
Sharon Pei Yi Chan, Celestia Pei Xuan Yeo, Boon Hao Hong, Evelyn Mui Cheng Tan, Chaw Yee Beh, Eugenia Li Ling Yeo, Dennis Jun Jie Poon, Pek Lim Chu, Khee Chee Soo, Melvin Lee Kiang Chua, Edward Kai-Hua Chow

Background: Radiotherapy is the primary treatment modality for most head and neck cancers (HNCs). Despite the addition of chemotherapy to radiotherapy to enhance its tumoricidal effects, almost a third of HNC patients suffer from locoregional relapses. Salvage therapy options for such recurrences are limited and often suboptimal, partly owing to divergent tumor and microenvironmental factors underpinning radioresistance. In this study, we utilized a combinatorial functionomics approach, the Quadratic Phenotypic Optimization Platform (QPOP), to rationally design drug pairings that exploit the molecular fingerprint and vulnerability of established in vitro isogenic radioresistant (RR)-HNC models.

Methods: A QPOP-specific protocol was applied to RR-HNC models to rank and compare all possible drug combinations from a 12-drug set comprising standard chemotherapy, small molecule inhibitors and targeted therapies specific to HNC. Drug combination efficacy was evaluated by computing combination index scores, and by measuring apoptotic response. Drug targeting was validated by western blot analyses, and the Comet assay was used to quantify DNA damage. Enhanced histone deacetylase inhibitor (HDACi) efficacy in RR models was further examined by in vivo studies, and genetic and chemical inhibition of major Class I/II HDACs. Regulatory roles of HDAC6/SP1 axis were investigated using immunoprecipitation, gel shift and ChIP-qPCR assays. Comparative transcriptomic analyses were employed to determine the prognostic significance of targeting HDAC6.

Results: We report the therapeutic potential of combining panobinostat (pan-HDAC inhibitor) with AZD7762 (CHK1/2 inhibitor; AstraZeneca) or ionizing radiation (IR) to re-sensitize RR-HNC cells and showed increased DNA damage underlying enhanced synergy. We further refined this RR-specific drug combination and prioritized HDAC6 as a targetable dependency in reversing radioresistance. We provide mechanistic insights into HDAC6-mediated regulation via a crosstalk involving SP1 and oncogenic and repair genes. From two independent patient cohorts, we identified a four-gene signature that may have discriminative ability to predict for radioresistance and amenable to HDAC6 inhibition.

Conclusion: We have uncovered HDAC6 as a promising molecular vulnerability that should be explored to treat RR-HNC.

背景:放疗是大多数头颈癌(HNCs)的主要治疗方式。尽管在放疗的基础上增加化疗以增强其杀瘤效果,但近三分之一的HNC患者出现局部复发。这种复发的挽救治疗选择是有限的,而且往往是次优的,部分原因是肿瘤分化和微环境因素支持放射耐药。在这项研究中,我们利用组合函数学方法,二次型表型优化平台(QPOP),合理设计药物配对,利用已建立的体外等基因辐射耐药(RR)-HNC模型的分子指纹和脆弱性。方法:将qpop特异性方案应用于RR-HNC模型,对包括标准化疗、小分子抑制剂和HNC特异性靶向治疗在内的12种药物组合中的所有可能的药物组合进行排名和比较。通过计算联合指数得分和测定细胞凋亡反应来评价药物联合疗效。通过western blot分析验证药物靶向性,并使用Comet测定定量DNA损伤。组蛋白去乙酰化酶抑制剂(HDACi)在RR模型中的有效性通过体内研究和主要的I/II类hdac的遗传和化学抑制进一步得到验证。采用免疫沉淀、凝胶移位和ChIP-qPCR检测HDAC6/SP1轴的调控作用。采用比较转录组学分析来确定靶向HDAC6的预后意义。结果:我们报道了panobinostat (pan-HDAC抑制剂)联合AZD7762 (CHK1/2抑制剂;阿斯利康(AstraZeneca)或电离辐射(IR)对RR-HNC细胞进行再敏化,结果显示协同作用增强导致DNA损伤增加。我们进一步完善了这种rr特异性药物组合,并优先考虑HDAC6作为逆转放射耐药的靶向依赖性。我们通过SP1与致癌和修复基因的串扰,提供了hdac6介导的调控机制。从两个独立的患者队列中,我们确定了一个四基因标记,该标记可能具有预测放射耐药的判别能力,并且适合HDAC6抑制。结论:我们发现HDAC6是一个有希望的分子易感性,值得探索治疗RR-HNC。
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引用次数: 0
Biomechanics in the tumor microenvironment: from biological functions to potential clinical applications. 肿瘤微环境中的生物力学:从生物学功能到潜在的临床应用。
IF 9.4 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-01-11 DOI: 10.1186/s40164-024-00591-7
Hao Peng, Zheng Chao, Zefeng Wang, Xiaodong Hao, Zirui Xi, Sheng Ma, Xiangdong Guo, Junbiao Zhang, Qiang Zhou, Guanyu Qu, Yuan Gao, Jing Luo, Zhihua Wang, Jing Wang, Le Li

Immune checkpoint therapies have spearheaded drug innovation over the last decade, propelling cancer treatments toward a new era of precision therapies. Nonetheless, the challenges of low response rates and prevalent drug resistance underscore the imperative for a deeper understanding of the tumor microenvironment (TME) and the pursuit of novel targets. Recent findings have revealed the profound impacts of biomechanical forces within the tumor microenvironment on immune surveillance and tumor progression in both murine models and clinical settings. Furthermore, the pharmacological or genetic manipulation of mechanical checkpoints, such as PIEZO1, DDR1, YAP/TAZ, and TRPV4, has shown remarkable potential in immune activation and eradication of tumors. In this review, we delved into the underlying biomechanical mechanisms and the resulting intricate biological meaning in the TME, focusing mainly on the extracellular matrix, the stiffness of cancer cells, and immune synapses. We also summarized the methodologies employed for biomechanical research and the potential clinical translation derived from current evidence. This comprehensive review of biomechanics will enhance the understanding of the functional role of biomechanical forces and provide basic knowledge for the discovery of novel therapeutic targets.

免疫检查点疗法在过去十年中引领了药物创新,将癌症治疗推向了精准治疗的新时代。然而,低反应率和普遍耐药的挑战强调了深入了解肿瘤微环境(TME)和追求新靶点的必要性。最近的研究结果揭示了在小鼠模型和临床环境中,肿瘤微环境中的生物力学力对免疫监测和肿瘤进展的深远影响。此外,机械检查点的药理学或遗传学操作,如PIEZO1, DDR1, YAP/TAZ和TRPV4,在免疫激活和肿瘤根除方面显示出显着的潜力。在这篇综述中,我们深入研究了TME的潜在生物力学机制及其复杂的生物学意义,主要集中在细胞外基质、癌细胞的刚度和免疫突触上。我们还总结了生物力学研究中使用的方法以及从现有证据中获得的潜在临床转化。这篇生物力学的综合综述将增强对生物力学力的功能作用的理解,并为发现新的治疗靶点提供基础知识。
{"title":"Biomechanics in the tumor microenvironment: from biological functions to potential clinical applications.","authors":"Hao Peng, Zheng Chao, Zefeng Wang, Xiaodong Hao, Zirui Xi, Sheng Ma, Xiangdong Guo, Junbiao Zhang, Qiang Zhou, Guanyu Qu, Yuan Gao, Jing Luo, Zhihua Wang, Jing Wang, Le Li","doi":"10.1186/s40164-024-00591-7","DOIUrl":"10.1186/s40164-024-00591-7","url":null,"abstract":"<p><p>Immune checkpoint therapies have spearheaded drug innovation over the last decade, propelling cancer treatments toward a new era of precision therapies. Nonetheless, the challenges of low response rates and prevalent drug resistance underscore the imperative for a deeper understanding of the tumor microenvironment (TME) and the pursuit of novel targets. Recent findings have revealed the profound impacts of biomechanical forces within the tumor microenvironment on immune surveillance and tumor progression in both murine models and clinical settings. Furthermore, the pharmacological or genetic manipulation of mechanical checkpoints, such as PIEZO1, DDR1, YAP/TAZ, and TRPV4, has shown remarkable potential in immune activation and eradication of tumors. In this review, we delved into the underlying biomechanical mechanisms and the resulting intricate biological meaning in the TME, focusing mainly on the extracellular matrix, the stiffness of cancer cells, and immune synapses. We also summarized the methodologies employed for biomechanical research and the potential clinical translation derived from current evidence. This comprehensive review of biomechanics will enhance the understanding of the functional role of biomechanical forces and provide basic knowledge for the discovery of novel therapeutic targets.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"4"},"PeriodicalIF":9.4,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A cohort-based multi-omics identifies nuclear translocation of eIF5B /PD-L1/CD44 complex as the target to overcome Osimertinib resistance of ARID1A-deficient lung adenocarcinoma. 一项基于队列的多组学研究发现,eIF5B /PD-L1/CD44复合物的核易位是克服arid1a缺陷肺腺癌奥西替尼耐药的靶点。
IF 9.4 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-01-07 DOI: 10.1186/s40164-024-00594-4
Dantong Sun, Helei Hou, Feiyue Feng, Weizheng Wu, Jingyu Tan, Tongji Xie, Jiayu Liu, Jinsong Wang, Haili Qian, Junling Li, Puyuan Xing

Background: Osimertinib has emerged as a critical element in the treatment landscape following recent clinical trials. Further investigation into the mechanisms driving resistance to Osimertinib is necessary to address the restricted treatment options and survival advantages that are compromised by resistance in patients with EGFR-mutated lung adenocarcinoma (LUAD).

Methods: Spatial transcriptomic and proteomic analyses were utilized to investigate the mechanisms of Osimertinib resistance. Co-IP, MS, RNA-seq, ChIP-seq, RIP-seq, and ATAC-seq were performed in cell lines to further explore the mechanism. To validate the findings, in vitro and in vivo molecular experiments were conducted.

Results: We found that the ARID1A deficiency results in resistance to Osimertinib by hindering programmed cell death through the EZH2/PTEN/E2F1 axis. This altered axis influences PD-L1 transcription through E2F1-mediated promoter activation and PD-L1 translation via the MDM2/eIF5B/PD-L1 axis. Subsequently, ARID1A deficiency results in increased expression of eIF5B and Importin-β1, promoting PD-L1 nuclear-translocation. The nuclear PD-L1 (nPD-L1) interacts with CD44, leading to nPD-L1 complex formation, activation of the RASGEF1A promoter, initiation of the Ras pathway, and contributing to Osimertinib resistance. Targeting the transcription, translation and nuclear-translocation of PD-L1 using lipid nanoparticles (LNPs) overcomes ARID1A deficiency-induced resistance.

Conclusion: ARID1A deficiency promotes PD-L1 nuclear translocation and induces Osimertinib resistance.

背景:在最近的临床试验之后,奥西替尼已经成为治疗领域的一个关键因素。有必要进一步研究驱动奥西替尼耐药的机制,以解决egfr突变肺腺癌(LUAD)患者耐药所损害的有限治疗选择和生存优势。方法:利用空间转录组学和蛋白质组学分析方法,探讨奥西替尼耐药机制。在细胞系中进行Co-IP、MS、RNA-seq、ChIP-seq、RIP-seq和ATAC-seq,进一步探讨其机制。为了验证这些发现,我们进行了体外和体内分子实验。结果:我们发现ARID1A缺陷通过EZH2/PTEN/E2F1轴阻碍程序性细胞死亡,从而导致对奥西替尼的耐药性。这种改变的轴通过e2f1介导的启动子激活和MDM2/eIF5B/PD-L1轴的PD-L1翻译影响PD-L1的转录。随后,ARID1A缺陷导致eIF5B和Importin-β1的表达增加,促进PD-L1核易位。核PD-L1 (nPD-L1)与CD44相互作用,导致nPD-L1复合物形成,激活RASGEF1A启动子,启动Ras通路,并促进奥西替尼耐药。利用脂质纳米颗粒(LNPs)靶向PD-L1的转录、翻译和核易位,克服了ARID1A缺陷诱导的耐药性。结论:ARID1A缺陷促进PD-L1核易位,诱导奥西替尼耐药。
{"title":"A cohort-based multi-omics identifies nuclear translocation of eIF5B /PD-L1/CD44 complex as the target to overcome Osimertinib resistance of ARID1A-deficient lung adenocarcinoma.","authors":"Dantong Sun, Helei Hou, Feiyue Feng, Weizheng Wu, Jingyu Tan, Tongji Xie, Jiayu Liu, Jinsong Wang, Haili Qian, Junling Li, Puyuan Xing","doi":"10.1186/s40164-024-00594-4","DOIUrl":"https://doi.org/10.1186/s40164-024-00594-4","url":null,"abstract":"<p><strong>Background: </strong>Osimertinib has emerged as a critical element in the treatment landscape following recent clinical trials. Further investigation into the mechanisms driving resistance to Osimertinib is necessary to address the restricted treatment options and survival advantages that are compromised by resistance in patients with EGFR-mutated lung adenocarcinoma (LUAD).</p><p><strong>Methods: </strong>Spatial transcriptomic and proteomic analyses were utilized to investigate the mechanisms of Osimertinib resistance. Co-IP, MS, RNA-seq, ChIP-seq, RIP-seq, and ATAC-seq were performed in cell lines to further explore the mechanism. To validate the findings, in vitro and in vivo molecular experiments were conducted.</p><p><strong>Results: </strong>We found that the ARID1A deficiency results in resistance to Osimertinib by hindering programmed cell death through the EZH2/PTEN/E2F1 axis. This altered axis influences PD-L1 transcription through E2F1-mediated promoter activation and PD-L1 translation via the MDM2/eIF5B/PD-L1 axis. Subsequently, ARID1A deficiency results in increased expression of eIF5B and Importin-β1, promoting PD-L1 nuclear-translocation. The nuclear PD-L1 (nPD-L1) interacts with CD44, leading to nPD-L1 complex formation, activation of the RASGEF1A promoter, initiation of the Ras pathway, and contributing to Osimertinib resistance. Targeting the transcription, translation and nuclear-translocation of PD-L1 using lipid nanoparticles (LNPs) overcomes ARID1A deficiency-induced resistance.</p><p><strong>Conclusion: </strong>ARID1A deficiency promotes PD-L1 nuclear translocation and induces Osimertinib resistance.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"3"},"PeriodicalIF":9.4,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prominent efficacy and good safety of sequential CD19 and CD22 CAR-T therapy in relapsed/refractory adult B-cell acute lymphoblastic leukemia. 序贯CD19和CD22 CAR-T治疗复发/难治性成人b细胞急性淋巴细胞白血病疗效突出,安全性好。
IF 9.4 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-01-03 DOI: 10.1186/s40164-024-00593-5
Tingting Yang, Yetian Dong, Mingming Zhang, Jingjing Feng, Shan Fu, Pingnan Xiao, Ruimin Hong, Huijun Xu, Jiazhen Cui, Simao Huang, Guoqing Wei, Delin Kong, Jia Geng, Alex H Chang, He Huang, Yongxian Hu

Background: Sequential CD19 and CD22 chimeric antigen receptor (CAR)-T cell therapy offers a promising approach to antigen-loss relapse in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL); however, research in adults remains limited.

Methods: This study aimed to evaluate the efficacy and safety of sequential CD19 and CD22 CAR-T cell therapy in adult patients with R/R B-ALL between November 2020 and November 2023 (ChiCTR2100053871). Key endpoints included the adverse event incidence, overall survival (OS), and leukemia-free survival (LFS).

Results: Twenty-three patients with a median age of 58.1 years (range 25.9-75.0) were enrolled. High-risk cytogenetic and genomic aberrations were identified in 43.5% of patients, and five patients had baseline extramedullary disease (EMD). The median interval between the two infusions was 3.8 months. Grade ≥ 3 hematological adverse events occurred at comparable rates after both infusions. Cytokine release syndrome was observed in 78.3% and 39.1% of patients after CD19 and CD22 CAR-T therapy, respectively. Two patients experienced grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) during CD19 CAR-T, and no ICANS was reported during CD22 CAR-T. The median OS was not reached with a median follow-up of 19.4 months (range 8.7-45.6), while the median LFS was 20.8 months. OS and LFS rates were 91.3% and 67.1% at 1 year and 58.6% and 47.0% at 2 years, respectively. Eight patients experienced relapse, with the cumulative incidence of relapse being 28.6% at 1 year and 42.5% at 2 years. Higher baseline leukemia burden (≥ 64% bone marrow blasts) and the presence of EMD were significant risk factors for inferior OS and LFS, respectively.

Conclusions: Sequential CAR-T cell therapy demonstrated durable efficacy and a manageable safety profile in R/R B-ALL, providing a viable option to address antigen-loss relapse and improve long-term outcomes in high-risk adult patients.

背景:序贯CD19和CD22嵌合抗原受体(CAR)-T细胞治疗为复发/难治性(R/R) b细胞急性淋巴细胞白血病(B-ALL)的抗原丢失复发提供了一种有希望的方法;然而,对成人的研究仍然有限。方法:本研究旨在评估2020年11月至2023年11月期间,CD19和CD22 CAR-T细胞序贯治疗成人R/R B-ALL患者的疗效和安全性(ChiCTR2100053871)。主要终点包括不良事件发生率、总生存期(OS)和无白血病生存期(LFS)。结果:23例患者入组,中位年龄为58.1岁(25.9-75.0岁)。43.5%的患者存在高危细胞遗传学和基因组畸变,5例患者基线为髓外疾病(EMD)。两次输注的中位间隔为3.8个月。两次输注后发生≥3级血液学不良事件的发生率相当。CD19和CD22 CAR-T治疗后分别有78.3%和39.1%的患者出现细胞因子释放综合征。2例患者在CD19 CAR-T过程中出现2级免疫效应细胞相关神经毒性综合征(ICANS),而在CD22 CAR-T过程中没有ICANS的报道。中位OS未达到,中位随访19.4个月(范围8.7-45.6),而中位LFS为20.8个月。1年OS和LFS分别为91.3%和67.1%,2年OS和LFS分别为58.6%和47.0%。8例患者复发,1年和2年的累计复发率分别为28.6%和42.5%。较高的基线白血病负担(≥64%骨髓母细胞)和EMD的存在分别是不良OS和LFS的重要危险因素。结论:序贯CAR-T细胞疗法在R/R B-ALL中表现出持久的疗效和可管理的安全性,为解决抗原丢失复发和改善高风险成人患者的长期预后提供了可行的选择。
{"title":"Prominent efficacy and good safety of sequential CD19 and CD22 CAR-T therapy in relapsed/refractory adult B-cell acute lymphoblastic leukemia.","authors":"Tingting Yang, Yetian Dong, Mingming Zhang, Jingjing Feng, Shan Fu, Pingnan Xiao, Ruimin Hong, Huijun Xu, Jiazhen Cui, Simao Huang, Guoqing Wei, Delin Kong, Jia Geng, Alex H Chang, He Huang, Yongxian Hu","doi":"10.1186/s40164-024-00593-5","DOIUrl":"https://doi.org/10.1186/s40164-024-00593-5","url":null,"abstract":"<p><strong>Background: </strong>Sequential CD19 and CD22 chimeric antigen receptor (CAR)-T cell therapy offers a promising approach to antigen-loss relapse in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL); however, research in adults remains limited.</p><p><strong>Methods: </strong>This study aimed to evaluate the efficacy and safety of sequential CD19 and CD22 CAR-T cell therapy in adult patients with R/R B-ALL between November 2020 and November 2023 (ChiCTR2100053871). Key endpoints included the adverse event incidence, overall survival (OS), and leukemia-free survival (LFS).</p><p><strong>Results: </strong>Twenty-three patients with a median age of 58.1 years (range 25.9-75.0) were enrolled. High-risk cytogenetic and genomic aberrations were identified in 43.5% of patients, and five patients had baseline extramedullary disease (EMD). The median interval between the two infusions was 3.8 months. Grade ≥ 3 hematological adverse events occurred at comparable rates after both infusions. Cytokine release syndrome was observed in 78.3% and 39.1% of patients after CD19 and CD22 CAR-T therapy, respectively. Two patients experienced grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) during CD19 CAR-T, and no ICANS was reported during CD22 CAR-T. The median OS was not reached with a median follow-up of 19.4 months (range 8.7-45.6), while the median LFS was 20.8 months. OS and LFS rates were 91.3% and 67.1% at 1 year and 58.6% and 47.0% at 2 years, respectively. Eight patients experienced relapse, with the cumulative incidence of relapse being 28.6% at 1 year and 42.5% at 2 years. Higher baseline leukemia burden (≥ 64% bone marrow blasts) and the presence of EMD were significant risk factors for inferior OS and LFS, respectively.</p><p><strong>Conclusions: </strong>Sequential CAR-T cell therapy demonstrated durable efficacy and a manageable safety profile in R/R B-ALL, providing a viable option to address antigen-loss relapse and improve long-term outcomes in high-risk adult patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"2"},"PeriodicalIF":9.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Safety and efficacy of CD33-targeted CAR-NK cell therapy for relapsed/refractory AML: preclinical evaluation and phase I trial. cd33靶向CAR-NK细胞治疗复发/难治性AML的安全性和有效性:临床前评估和I期试验
IF 9.4 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-01-02 DOI: 10.1186/s40164-024-00592-6
Ruihao Huang, Xiaoqi Wang, Hongju Yan, Xu Tan, Yingying Ma, Maihong Wang, Xiao Han, Jia Liu, Li Gao, Lei Gao, Guangjun Jing, Cheng Zhang, Qin Wen, Xi Zhang

Background: Due to the lack of effective treatment options, the prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) remains poor. Although chimeric antigen receptor (CAR)-T-cell therapy has shown promising effects in acute lymphoblastic leukemia (ALL) and lymphoma, its application in R/R AML is limited by "off-target" effects, which lead to severe bone marrow suppression and limit its clinical application. CAR-natural killer (NK) cells not only exhibit antitumor effects but also demonstrate increased safety and universality. We have developed a new CAR construct that targets CD33 and modified NK cells, specifically eliminating AML cells while reducing severe side effects on stem cells.

Methods: The CD33-targeting domain was selected by CAR-T cells, and this optimized CAR construct was subsequently transduced into umbilical cord-derived NK cells via a retroviral vector. Preclinical efficacy and safety studies were conducted both in vitro and in vivo. Ten eligible patients with R/R AML aged 18-65 years who received one or more infusions of anti-CD33 CAR-NK cells following the preconditioning regimen were enrolled. We assessed the response rates and treatment-related side effects post-infusion, while also documenting the long-term efficacy of the therapy.

Results: The CD33 sequence was selected on the basis of its antitumor efficacy and safety in CAR-T-cell studies conducted both in vitro and in vivo. CD33 CAR-NK cells demonstrated efficacy comparable to that of CD33 CAR-T cells but showed limited toxicity to hematopoietic stem cells (HSCs). Ten patients, with a median of five prior lines of treatment, completed the efficacy evaluation (range, 3-8). No grade 3-4 adverse events were observed, except bone marrow suppression, which was relieved within one month. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GVHD) were reported following CAR-NK cell infusion. Only one patient experienced grade 2 cytokine release syndrome (CRS) and presented with persistent fever. By day 28, six of ten patients had achieved minimal residual disease (MRD)-negative complete remission.

Conclusions: Our preclinical and clinical data demonstrated the primary efficacy and safety of CD33 CAR-NK cells for patients with R/R AML. Expanded samples and longer follow-up periods are needed to provide further efficacy data.

Trial registration: NCT05008575 ( https://clinicaltrials.gov/study/NCT05008575 ).

背景:由于缺乏有效的治疗方案,复发/难治性急性髓性白血病(R/R AML)患者的预后仍然很差。虽然嵌合抗原受体(CAR)- t细胞治疗在急性淋巴细胞白血病(ALL)和淋巴瘤中显示出良好的效果,但其在R/R AML中的应用受到“脱靶”效应的限制,导致严重的骨髓抑制,限制了其临床应用。car -自然杀伤(NK)细胞不仅具有抗肿瘤作用,而且具有更高的安全性和普遍性。我们已经开发出一种新的靶向CD33和修饰NK细胞的CAR结构,特异性地消除AML细胞,同时减少对干细胞的严重副作用。方法:利用CAR- t细胞选择cd33靶向结构域,并通过逆转录病毒载体将优化后的CAR构建体导入脐带NK细胞。体外和体内均进行了临床前疗效和安全性研究。10名年龄在18-65岁的符合条件的R/R AML患者在预处理方案后接受一次或多次抗cd33 CAR-NK细胞输注。我们评估了输注后的反应率和治疗相关的副作用,同时也记录了治疗的长期疗效。结果:CD33序列的选择是基于其在体外和体内car - t细胞研究中的抗肿瘤功效和安全性。CD33 CAR-NK细胞显示出与CD33 CAR-T细胞相当的疗效,但对造血干细胞(hsc)显示出有限的毒性。10例患者完成了疗效评估(范围3-8),其中中位数为5条既往治疗线。除骨髓抑制在1个月内缓解外,未见3-4级不良事件。CAR-NK细胞输注后无免疫效应细胞相关神经毒性综合征(ICANS)或移植物抗宿主病(GVHD)病例报道。仅有1例患者出现2级细胞因子释放综合征(CRS)并表现为持续发热。到第28天,10名患者中有6名达到了最小残留病(MRD)阴性的完全缓解。结论:我们的临床前和临床数据证明了CD33 CAR-NK细胞治疗R/R AML患者的主要有效性和安全性。需要扩大样本和延长随访时间来提供进一步的疗效数据。试验注册:NCT05008575 (https://clinicaltrials.gov/study/NCT05008575)。
{"title":"Safety and efficacy of CD33-targeted CAR-NK cell therapy for relapsed/refractory AML: preclinical evaluation and phase I trial.","authors":"Ruihao Huang, Xiaoqi Wang, Hongju Yan, Xu Tan, Yingying Ma, Maihong Wang, Xiao Han, Jia Liu, Li Gao, Lei Gao, Guangjun Jing, Cheng Zhang, Qin Wen, Xi Zhang","doi":"10.1186/s40164-024-00592-6","DOIUrl":"10.1186/s40164-024-00592-6","url":null,"abstract":"<p><strong>Background: </strong>Due to the lack of effective treatment options, the prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) remains poor. Although chimeric antigen receptor (CAR)-T-cell therapy has shown promising effects in acute lymphoblastic leukemia (ALL) and lymphoma, its application in R/R AML is limited by \"off-target\" effects, which lead to severe bone marrow suppression and limit its clinical application. CAR-natural killer (NK) cells not only exhibit antitumor effects but also demonstrate increased safety and universality. We have developed a new CAR construct that targets CD33 and modified NK cells, specifically eliminating AML cells while reducing severe side effects on stem cells.</p><p><strong>Methods: </strong>The CD33-targeting domain was selected by CAR-T cells, and this optimized CAR construct was subsequently transduced into umbilical cord-derived NK cells via a retroviral vector. Preclinical efficacy and safety studies were conducted both in vitro and in vivo. Ten eligible patients with R/R AML aged 18-65 years who received one or more infusions of anti-CD33 CAR-NK cells following the preconditioning regimen were enrolled. We assessed the response rates and treatment-related side effects post-infusion, while also documenting the long-term efficacy of the therapy.</p><p><strong>Results: </strong>The CD33 sequence was selected on the basis of its antitumor efficacy and safety in CAR-T-cell studies conducted both in vitro and in vivo. CD33 CAR-NK cells demonstrated efficacy comparable to that of CD33 CAR-T cells but showed limited toxicity to hematopoietic stem cells (HSCs). Ten patients, with a median of five prior lines of treatment, completed the efficacy evaluation (range, 3-8). No grade 3-4 adverse events were observed, except bone marrow suppression, which was relieved within one month. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GVHD) were reported following CAR-NK cell infusion. Only one patient experienced grade 2 cytokine release syndrome (CRS) and presented with persistent fever. By day 28, six of ten patients had achieved minimal residual disease (MRD)-negative complete remission.</p><p><strong>Conclusions: </strong>Our preclinical and clinical data demonstrated the primary efficacy and safety of CD33 CAR-NK cells for patients with R/R AML. Expanded samples and longer follow-up periods are needed to provide further efficacy data.</p><p><strong>Trial registration: </strong>NCT05008575 ( https://clinicaltrials.gov/study/NCT05008575 ).</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"1"},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition. AOH1996通过抑制线粒体PCNA靶向白血病干细胞的线粒体动力学和代谢。
IF 9.4 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-28 DOI: 10.1186/s40164-024-00586-4
HyunJun Kang, Melissa Valerio, Jia Feng, Long Gu, Dinh Hoa Hoang, Amanda Blackmon, Shawn Sharkas, Khyatiben Pathak, Jennifer Jossart, Zhuo Li, Hongyu Zhang, Bin Zhang, Patrick Pirrotte, J Jefferson P Perry, Robert J Hickey, Linda Malkas, Guido Marcucci, Le Xuan Truong Nguyen

Cytoplasmic proliferating cell nuclear antigen (PCNA) is highly expressed in acute myeloid leukemia (AML) cells, supporting oxidative metabolism and leukemia stem cell (LSC) growth. We report on AOH1996 (AOH), an oral compound targeting cancer-associated PCNA, which shows significant antileukemic activity. AOH inhibited growth in AML cell lines and primary CD34 + CD38 - blasts (LSC-enriched) in vitro while sparing normal hematopoietic stem cells (HSCs). In vivo, AOH-treated mice demonstrated prolonged survival compared to controls (50 vs. 35 days; p < 0.0001) with reduced LSC burden, as shown in secondary transplants (42 vs. 30 days, p < 0.0001). Mechanistically, AOH disrupted mitochondrial PCNA's binding to the OPA1 protein, enhancing OPA1's interaction with its E3 ligase, MARCH5, which led to OPA1 degradation. This process reduced mitochondrial length, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS), thereby inhibiting LSC expansion. The addition of venetoclax (VEN), an FDA-approved Bcl-2 inhibitor, further enhanced AOH's effects, reducing mitochondrial length, FAO, and OXPHOS while improving survival in AML models. While VEN is approved for AML, AOH is under clinical investigation for solid tumors, and our findings support its broader therapeutic potential.

细胞质增殖细胞核抗原(PCNA)在急性髓系白血病(AML)细胞中高表达,支持氧化代谢和白血病干细胞(LSC)的生长。我们报道了一种靶向癌症相关PCNA的口服化合物AOH1996 (AOH),它显示出显著的抗白血病活性。AOH在体外抑制AML细胞系和原代CD34 + CD38 -母细胞(lsc富集)的生长,同时保留正常的造血干细胞(hsc)。在体内,与对照组相比,aoh处理小鼠的生存时间延长(50天对35天;p
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引用次数: 0
Disrupting Notch signaling related HES1 in myeloid cells reinvigorates antitumor T cell responses. 破坏髓细胞中Notch信号相关的HES1可激活抗肿瘤T细胞反应。
IF 9.4 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-19 DOI: 10.1186/s40164-024-00588-2
Myung Sup Kim, Hyeokgu Kang, Jung-Hwan Baek, Moon-Gyu Cho, Eun Joo Chung, Seok-Jun Kim, Joon-Yong Chung, Kyung-Hee Chun

Background: Tumor-associated macrophages (TAMs) are immunosuppressive cells within the tumor microenvironment (TME) that hinder anti-tumor immunity. Notch signaling is a pathway crucial for TAM differentiation and function. Here, we investigate the role of HES1, a downstream target of Notch signaling, in TAM-mediated immunosuppression and explore its potential as a target for cancer immunotherapy.

Methods: In this work, we constructed conditional Hes1 knockout mice to selectively delete Hes1 in TAMs. We further analyzed the TME composition, T cell infiltration and activation, and anti-tumor effects in these mice, both alone and in combination with PD-1 checkpoint blockade.

Results: Our study showed that expression levels of Notch target Hes1 were increase in TAMs and mice with conditional knockout of Hes1 gene in TAMs exhibited decreased tumor growth, with increased infiltration and activation of cytotoxic T cells in tumors. Expression of tumor promoting factors was critically altered in Hes1-conditional KO TAMs, leading to the improved tumor microenvironment. Notably, arginase-1 expression was decreased in Hes1-conditional KO mice. Arg1 is known to deplete arginine and deactivate T cells in the TME. Administration of anti-PD-1 monoclonal antibody inhibited tumor growth to a greater extent in Hes1-conditional KO mice than in WT mice.

Conclusions: We identified a pivotal role for the Notch signaling pathway in shaping TAM function, suggesting that T-cell dysfunction in the TME is caused when the Notch target, HES1, in TAMs is upregulated by tumor-associated factors (TAFs), which, in turn, increases the expression of arginase-1. Targeting HES1 in TAMs appears to be a promising strategy for cancer immunotherapy.

背景:肿瘤相关巨噬细胞(tumor -associated macrophages, tam)是肿瘤微环境(tumor microenvironment, TME)中的免疫抑制细胞,可阻碍抗肿瘤免疫。Notch信号是TAM分化和功能的重要途径。在这里,我们研究了Notch信号的下游靶点HES1在tam介导的免疫抑制中的作用,并探索其作为癌症免疫治疗靶点的潜力。方法:构建条件Hes1敲除小鼠,选择性删除tam中的Hes1。我们进一步分析了单独和联合PD-1检查点阻断剂对这些小鼠的TME组成、T细胞浸润和活化以及抗肿瘤作用。结果:我们的研究表明,Notch靶基因Hes1在tam中表达水平升高,有条件敲除tam中Hes1基因的小鼠肿瘤生长下降,肿瘤中细胞毒性T细胞的浸润和活化增加。在hes1条件下的KO tam中,肿瘤促进因子的表达发生了严重改变,导致肿瘤微环境的改善。值得注意的是,精氨酸酶-1在hes1条件下的KO小鼠中表达降低。Arg1已知能消耗精氨酸并使TME中的T细胞失活。与WT小鼠相比,抗pd -1单克隆抗体对hes1条件下KO小鼠肿瘤生长的抑制作用更大。结论:我们确定了Notch信号通路在TAM功能形成中的关键作用,表明当TAM中的Notch靶点HES1被肿瘤相关因子(TAFs)上调,进而增加精氨酸酶-1的表达时,TME中的t细胞功能障碍就会发生。在tam中靶向HES1似乎是一种很有前途的癌症免疫治疗策略。
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引用次数: 0
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Experimental Hematology & Oncology
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