Molecular Therapy最新文献_第3页

CAR T cell therapy for glioblastoma: A review of the first decade of clinical trials. CAR - T细胞治疗胶质母细胞瘤：前十年临床试验回顾

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-03-08 DOI: 10.1016/j.ymthe.2025.03.004

Sabrina L Begley, Donald M O'Rourke, Zev A Binder

{"title":"CAR T cell therapy for glioblastoma: A review of the first decade of clinical trials.","authors":"Sabrina L Begley, Donald M O'Rourke, Zev A Binder","doi":"10.1016/j.ymthe.2025.03.004","DOIUrl":"10.1016/j.ymthe.2025.03.004","url":null,"abstract":"Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis and few effective treatment options. Focus has shifted toward using immunotherapies, such as chimeric antigen receptor (CAR) T cells, to selectively target tumor antigens and mediate cytotoxic activity within an otherwise immunosuppressive tumor microenvironment. Between 2015 and 2024, the results of eight completed and two ongoing phase I clinical trials have been published. The majority of studies have treated recurrent GBM patients, although the inter- and intra-patient tumor heterogeneity has been historically challenging to overcome. Molecular targets have included EGFR, HER2, and IL13Rα2 and there has been continued development in improving receptor constructs, identifying novel targets, and adding adjuvant enhancers to increase efficacy. CAR T cells have been safely administered through both peripheral and locoregional routes but with variable clinical and radiographic efficacy. Most trials utilized autologous T cell products to avoid immune rejection yet were unable to consistently show robust engraftment and persistence within patients. Nonetheless, targeted immunotherapies such as CAR T cell therapy remain the next frontier for GBM treatment, and the popularity and complexity of this undertaking is evident in the past, present, and future landscape of clinical trials.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2454-2461"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Autologous CD7 CAR-T cells generated without T cell pre-selection in pediatric patients with relapsed/refractory T-ALL: A phase I trial. 在复发/难治性 T-ALL 儿科患者中未进行 T 细胞预选而生成的自体 CD7 CAR T 细胞：I 期试验。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2024-09-07 DOI: 10.1016/j.ymthe.2024.09.006

Liping Zhao, Chuo Li, Shiyu Zuo, Yajing Han, Biping Deng, Zhuojun Ling, Yanlei Zhang, Shuixiu Peng, Jinlong Xu, Jiajia Duan, Zelin Wang, Xinjian Yu, Qinlong Zheng, Xiuwen Xu, Ying Yuan, Zhenglong Tian, Kaiting Tang, Yibing Zhang, Qing Niu, Jiecheng Zhang, Alex H Chang, Yuechen Luo, Xiaoming Feng, Jing Pan

{"title":"Autologous CD7 CAR-T cells generated without T cell pre-selection in pediatric patients with relapsed/refractory T-ALL: A phase I trial.","authors":"Liping Zhao, Chuo Li, Shiyu Zuo, Yajing Han, Biping Deng, Zhuojun Ling, Yanlei Zhang, Shuixiu Peng, Jinlong Xu, Jiajia Duan, Zelin Wang, Xinjian Yu, Qinlong Zheng, Xiuwen Xu, Ying Yuan, Zhenglong Tian, Kaiting Tang, Yibing Zhang, Qing Niu, Jiecheng Zhang, Alex H Chang, Yuechen Luo, Xiaoming Feng, Jing Pan","doi":"10.1016/j.ymthe.2024.09.006","DOIUrl":"10.1016/j.ymthe.2024.09.006","url":null,"abstract":"Chimeric antigen receptor (CAR)-T cell therapy showed preliminary activity in patients with refractory or relapsed T cell acute lymphoblastic leukemia (r/r T-ALL). However, many obstacles remain, including manufacturing difficulties and risk of infections. This phase I study (NCT04840875) evaluated autologous CD7 CAR-T cells manufactured without pre-selection of healthy T cells in r/r T-ALL. Thirty patients (29 children and one adult) with a median of two lines of prior therapy but without detectable peripheral leukemia were enrolled. Excluding three cases of manufacturing failures, a total of 27 (90%) patients received infusions after products were confirmed free of leukemia contamination, including 16 (59%) meeting planned target doses. Common adverse events within 30 days included grade 3-4 cytopenias (100%), grade 1-2 (70%) and 3-4 (7%, including one dose-limiting toxicity) cytokine release syndrome, grade 1 neurotoxicity (7%), grade 2 infection (4%), and grade 2 graft-versus-host disease (4%). Two patients developed grade 2 infections after day 30. At day 30, 96% responded and 85% achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi). Seventy-four percent underwent transplantation. Twelve-month progression-free survival with and without censoring transplantation was 22% (95% confidence interval 4%-100%) and 57% (41%-81%), respectively. These results support that autologous CD7 CAR-T therapy without T cell pre-selection is feasible in patients with r/r T-ALL.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2753-2767"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Emerging combined CAR-NK cell therapies in cancer treatment: Finding a dancing partner. 新出现的CAR-NK细胞联合疗法在癌症治疗中：寻找一个舞伴。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-01-03 DOI: 10.1016/j.ymthe.2024.12.057

Hamed Hosseinalizadeh, Li-Shu Wang, Hamed Mirzaei, Zohreh Amoozgar, Lei Tian, Jianhua Yu

{"title":"Emerging combined CAR-NK cell therapies in cancer treatment: Finding a dancing partner.","authors":"Hamed Hosseinalizadeh, Li-Shu Wang, Hamed Mirzaei, Zohreh Amoozgar, Lei Tian, Jianhua Yu","doi":"10.1016/j.ymthe.2024.12.057","DOIUrl":"10.1016/j.ymthe.2024.12.057","url":null,"abstract":"In recent decades, immunotherapy with chimeric antigen receptors (CARs) has revolutionized cancer treatment and given hope where other cancer therapies have failed. CAR-natural killer (NK) cells are NK cells that have been engineered ex vivo with a CAR on the cell membrane with high specificity for specific target antigens of tumor cells. The impressive results of several studies suggest that CAR-NK cell therapy has significant potential and successful performance in cancer treatment. Despite its effectiveness, CAR-NK cell therapy can have significant challenges when it comes to treating cancer. These challenges include tumor heterogeneity, antigen escape, an immunosuppressive tumor microenvironment, limited tissue migration from blood, exhaustion of CAR-NK cells, and inhibition by immunosuppressive checkpoint molecule signaling, etc. In CAR-T cell therapy, the use of combined approaches has shown encouraging outcomes for tumor regression and improved cancer treatment compared to single therapies. Therefore, to overcome these significant challenges in CAR-NK cells, innovative combination therapies of CAR-NK cells with other conventional therapies (e.g., chemotherapy and radiotherapy) or other immunotherapies are needed to counteract the above challenges and thereby increase the activity of CAR-NK cells. This review comprehensively discusses various cancer-treatment approaches in combination with CAR-NK cell therapy in the hope of providing valuable insights that may improve cancer treatment in the near future.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2406-2425"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering resilient CAR T cells for immunosuppressive environment. 免疫抑制环境下的工程弹性CAR - T细胞

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-01-25 DOI: 10.1016/j.ymthe.2025.01.035

Malak Khalifeh, Huda Salman

{"title":"Engineering resilient CAR T cells for immunosuppressive environment.","authors":"Malak Khalifeh, Huda Salman","doi":"10.1016/j.ymthe.2025.01.035","DOIUrl":"10.1016/j.ymthe.2025.01.035","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment and is now being explored for other diseases, such as autoimmune disorders. While the tumor microenvironment (TME) in cancer is often immunosuppressive, in autoimmune diseases, the environment is typically inflammatory. Both environments can negatively impact CAR T cell survival: the former through direct suppression, hypoxia, and nutrient deprivation, and the latter through chronic T cell receptor (TCR) engagement, risking exhaustion. Mechanisms of resistance include T cell exhaustion, dysfunction, and the impact of the TME. Chronic antigenic stimulation leads to CAR T cell exhaustion. CAR construct design, including co-stimulatory domains, hinge, transmembrane regions, promoters, the affinity of the binder site, and on/off rate plays a crucial role in modulating CAR T cell function and resistance. This review discusses the impact of the in vitro development of CAR T cells, albeit in relation to the TME, on therapeutic outcomes. The use of alternative cell sources, multi-antigen targeting, and reengineering the TME, are discussed. The review emphasizes the need for continued innovation in CAR T cell design and manufacturing to optimize therapeutic efficacy and durability, especially in the face of varying environmental challenges.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2391-2405"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting human plasma cells using regulated BCMA CAR T cells eliminates circulating antibodies in humanized mice. 利用小分子调节的BCMA CAR - T细胞靶向人浆细胞，消除人源化小鼠体内的循环抗体。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2024-12-12 DOI: 10.1016/j.ymthe.2024.12.018

Yuchi Honaker, David Gruber, Chester Jacobs, Rene Yu-Hong Cheng, Shivani Patel, Christopher Zavala Galvan, Iram F Khan, Kevin Zhou, Karen Sommer, Alexander Astrakhan, Peter J Cook, Richard G James, David J Rawlings

{"title":"Targeting human plasma cells using regulated BCMA CAR T cells eliminates circulating antibodies in humanized mice.","authors":"Yuchi Honaker, David Gruber, Chester Jacobs, Rene Yu-Hong Cheng, Shivani Patel, Christopher Zavala Galvan, Iram F Khan, Kevin Zhou, Karen Sommer, Alexander Astrakhan, Peter J Cook, Richard G James, David J Rawlings","doi":"10.1016/j.ymthe.2024.12.018","DOIUrl":"10.1016/j.ymthe.2024.12.018","url":null,"abstract":"Pathogenic long-lived plasma cells (LLPCs) secrete autoreactive antibodies, exacerbating autoimmune diseases and complicating solid organ transplantation. Targeted elimination of the autoreactive B cell pool represents a promising therapeutic strategy, yet current treatment modalities fall short in depleting mature PCs. Here, we demonstrate that chimeric antigen receptor (CAR) T cells, targeting B cell maturation antigen (BCMA) utilizing a split-receptor design, offer a controlled and effective therapeutic strategy against LLPCs. Dimerizing agent-regulated immune-receptor complex (DARIC) T cells demonstrated robust rapamycin-dependent targeting of tumor and PCs. Notably, in humanized mouse models, DARIC T cells regulated peripheral human immunoglobulin levels through specific elimination of human LLPCs from the bone marrow. Furthermore, DARIC constructs were efficiently integrated into the T cell receptor α constant (TRAC) locus while maintaining potent antigen-specific cytotoxicity. These findings underscore the potential of split-receptor CAR T cells in autoimmune and transplant medicine, highlighting their versatility in applications beyond oncology.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2819-2833"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The high efficacy of claudin18.2-targeted CAR-T cell therapy in advanced pancreatic cancer with an antibody-dependent safety strategy. claudin18.2靶向CAR-T细胞治疗晚期胰腺癌的高疗效，并确保患者的安全性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-01-10 DOI: 10.1016/j.ymthe.2025.01.012

Guocheng Zhong, Xiaomin Zhang, Ruocong Zhao, Zheng Guo, Chenguang Wang, Chuan Yu, Dongzhe Liu, Ke Hu, Yujie Gao, Bochen Zhao, Xianhao Liu, Xuanren Shi, Lei Chen, Yisheng Li, Li Yu

{"title":"The high efficacy of claudin18.2-targeted CAR-T cell therapy in advanced pancreatic cancer with an antibody-dependent safety strategy.","authors":"Guocheng Zhong, Xiaomin Zhang, Ruocong Zhao, Zheng Guo, Chenguang Wang, Chuan Yu, Dongzhe Liu, Ke Hu, Yujie Gao, Bochen Zhao, Xianhao Liu, Xuanren Shi, Lei Chen, Yisheng Li, Li Yu","doi":"10.1016/j.ymthe.2025.01.012","DOIUrl":"10.1016/j.ymthe.2025.01.012","url":null,"abstract":"Pancreatic cancer (PC) is one of the most lethal digestive system tumors. Claudin18.2 is highly expressed in PC tissue and could serve as a suitable target for CAR-T therapy. In the present study, we reported the utilization of tEGFR-expressing claudin18.2-targeted CAR-T cells to treat 3 patients with advanced PC. Intriguingly, all 3 patients achieved disease remission after CAR-T cell infusion, with 1 complete remission (CR) and 2 partial remissions (PRs). However, gastric mucosal injury was observed, which was recognized as on-target off-tumor toxicity (OTOT) and may be due to the expression of claudin18.2 on normal gastric tissues. To control the severe OTOT in patient 3, cyclophosphamide and cetuximab were administered to deplete CAR-T cells, and they successfully controlled OTOT. Single-cell transcriptome and T cell receptor sequencing revealed the objective alterations of CAR-T cell clones after cetuximab treatment. Collectively, the present study showed the robust anti-tumor activity of claudin18.2-targeted CAR-T cells against PC and reported the feasibility of the antibody-dependent safety switch strategy to control the OTOT caused by CAR-T cells in patients. Our study may pave the way for the development of a novel strategy to treat patients with advanced PC in the future.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2778-2788"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clinical development of therapeutic mRNA applications. mRNA治疗应用的临床发展。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-03-25 DOI: 10.1016/j.ymthe.2025.03.034

Magdalena M Żak, Lior Zangi

{"title":"Clinical development of therapeutic mRNA applications.","authors":"Magdalena M Żak, Lior Zangi","doi":"10.1016/j.ymthe.2025.03.034","DOIUrl":"10.1016/j.ymthe.2025.03.034","url":null,"abstract":"mRNA therapeutics are emerging as a transformative approach in modern medicine, providing innovative, highly adaptable solutions for a wide range of diseases, from viral infections to cancer. Since the approval of the first mRNA therapeutic-the coronavirus disease 2019 vaccines in 2021-we have identified more than 70 current clinical trials utilizing mRNA for various diseases. We propose classifying mRNA therapeutics into four main categories: vaccines, protein replacement therapies, antibodies, and mRNA-based cell and gene therapies. Each category can be further divided into subcategories. Vaccines include those targeting viral antigens, bacterial or parasitic antigens, general and individualized cancer antigens, and self-antigens. Protein replacement therapies include maintenance therapeutics designed to treat genetic disorders and interventional therapeutics, where delivering therapeutic proteins could improve patient outcomes, such as vascular endothelial growth factor A for ischemic heart disease or proinflammatory cytokines in cancer. Therapeutic antibodies are based on mRNA sequences encoding the heavy and light chains of clinically relevant antibodies, enabling patient cells to produce them directly, bypassing the costly and complex process of manufacturing protein-ready antibodies. Another category of mRNA-based therapeutics encompasses cell and gene therapies, including CRISPR with mRNA-mediated delivery of Cas9 and the in vivo generation of cells expressing CAR through mRNA. We discuss examples of mRNA therapeutics currently in clinical trials within each category, providing a comprehensive overview of the field's progress and highlighting key advancements as of the end of 2024.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2583-2609"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CAR-T cell therapy for treatment of acute myeloid leukemia, advances and outcomes. CAR - T细胞疗法治疗急性髓性白血病，进展和结果。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-04-02 DOI: 10.1016/j.ymthe.2025.03.052

Malak Khalifeh, Emily Hopewell, Huda Salman

引用次数: 0

China's first approved gene therapy for hemophilia B: A new era for global AAV-based treatments. 中国首个获批的血友病B基因疗法：全球基于aav治疗的新时代

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-05-28 DOI: 10.1016/j.ymthe.2025.05.014

Hongying Wei, Weidong Xiao, Jing Dai

引用次数: 0

Long-term safety and efficacy of the fully human CAR-T therapy CT103A in relapsed/refractory multiple myeloma. 全人 CAR-T 疗法 CT103A 在复发性/难治性多发性骨髓瘤中的长期安全性和疗效。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2024-11-08 DOI: 10.1016/j.ymthe.2024.11.013

Qiuxia Yu, Di Wang, Zhe Li, Ning An, Chunhui Li, Yuhan Bao, Xinyu Wen, Xiaolu Long, Jue Wang, Lijun Jiang, Wei Mu, Peiling Zhang, Chang Shu, Huan Ye, Hongyu Gui, Songbai Cai, Guang Hu, Wen Wang, Aihua Du, Chunrui Li

{"title":"Long-term safety and efficacy of the fully human CAR-T therapy CT103A in relapsed/refractory multiple myeloma.","authors":"Qiuxia Yu, Di Wang, Zhe Li, Ning An, Chunhui Li, Yuhan Bao, Xinyu Wen, Xiaolu Long, Jue Wang, Lijun Jiang, Wei Mu, Peiling Zhang, Chang Shu, Huan Ye, Hongyu Gui, Songbai Cai, Guang Hu, Wen Wang, Aihua Du, Chunrui Li","doi":"10.1016/j.ymthe.2024.11.013","DOIUrl":"10.1016/j.ymthe.2024.11.013","url":null,"abstract":"CT103A is a fully human chimeric antigen receptor T cell (CAR-T) product for targeting B cell maturation antigen. This study presents the updated safety and efficacy profiles of CT103A in patients with relapsed/refractory multiple myeloma (RRMM) after long-term follow-up. As of July 31, 2023, the median follow-up time after CAR-T cell infusion was 45.0 months (range, 0.7-58.3 months). During long-term follow-up, the incidence of adverse events gradually decreased over time. One patient had a maximum duration of response of nearly 5 years. All 18 patients (100%) achieved partial remission or better; 77.8% (14 of 18) of patients eventually exhibited complete response or stringent complete response (sCR), with response increasing over time. At the time of data cutoff, nine patients were still alive and seven patients had an sCR status with negative minimal residual disease. The median progression-free survival was 22.6 months, and the median overall survival was 50.2 months for all 18 patients. The median CAR transgene persistence was 14.0 months (range, 0.7-57.3 months). Long-term follow-up demonstrated that CT103A confers durable clinical benefit for RRMM patients based on the sustained presence of fully human CAR-T cells.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2768-2777"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0