Molecular Therapy最新文献_第8页

Structure and sequence engineering approaches to improve in vivo expression of nucleic acid-delivered antibodies. 改善核酸递送抗体体内表达的结构和序列工程方法。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.030

Michaela Helble, Jacqueline Chu, Kaitlyn Flowers, Abigail R Trachtman, Alana Huynh, Amber Kim, Nicholas Shupin, Casey E Hojecki, Ebony N Gary, Shahlo Solieva, Elizabeth M Parzych, David B Weiner, Daniel W Kulp, Ami Patel

{"title":"Structure and sequence engineering approaches to improve in vivo expression of nucleic acid-delivered antibodies.","authors":"Michaela Helble, Jacqueline Chu, Kaitlyn Flowers, Abigail R Trachtman, Alana Huynh, Amber Kim, Nicholas Shupin, Casey E Hojecki, Ebony N Gary, Shahlo Solieva, Elizabeth M Parzych, David B Weiner, Daniel W Kulp, Ami Patel","doi":"10.1016/j.ymthe.2024.11.030","DOIUrl":"10.1016/j.ymthe.2024.11.030","url":null,"abstract":"Monoclonal antibodies are an important class of biologics with over 160 Food and Drug Administration/European Union-approved drugs. A significant bottleneck to global accessibility of recombinant monoclonal antibodies stems from complexities related to their production, storage, and distribution. Recently, gene-encoded approaches such as mRNA, DNA, or viral delivery have gained popularity, but ensuring biologically relevant levels of antibody expression in the host remains a critical issue. Using a synthetic DNA platform, we investigated the role of antibody structure and sequence toward in vivo expression. SARS-CoV-2 antibody 2196 was recently engineered as a DNA-encoded monoclonal antibody (DMAb-2196). Utilizing an immunoglobulin heavy and light chain \"chain-swap\" methodology, we interrogated features of DMAb-2196 that can modulate in vivo expression through rational design and structural modeling. Comparing these results to natural variation of antibody sequences resulted in development of an antibody frequency score that aids in the prediction of expression-improving mutations by leveraging antibody repertoire datasets. We demonstrate that a single amino acid mutation identified through this score increases in vivo expression up to 2-fold and that combinations of mutations can also enhance expression. This analysis has led to a generalized pipeline that can unlock the potential for in vivo delivery of therapeutic antibodies across many indications.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676189","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

ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma. ARI0003：共同转导的 CD19/BCMA 双靶向 CAR-T 细胞用于治疗非霍奇金淋巴瘤。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.028

Mireia Bachiller, Nina Barceló-Genestar, Alba Rodriguez-Garcia, Leticia Alserawan, Cèlia Dobaño-López, Marta Giménez-Alejandre, Joan Castellsagué, Salut Colell, Marc Otero-Mateo, Asier Antoñana-Vildosola, Marta Español-Rego, Noelia Ferruz, Mariona Pascal, Beatriz Martín-Antonio, Xavier M Anguela, Cristina Fillat, Eulàlia Olesti, Gonzalo Calvo, Manel Juan, Julio Delgado, Patricia Pérez-Galán, Álvaro Urbano-Ispizua, Sonia Guedan

{"title":"ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma.","authors":"Mireia Bachiller, Nina Barceló-Genestar, Alba Rodriguez-Garcia, Leticia Alserawan, Cèlia Dobaño-López, Marta Giménez-Alejandre, Joan Castellsagué, Salut Colell, Marc Otero-Mateo, Asier Antoñana-Vildosola, Marta Español-Rego, Noelia Ferruz, Mariona Pascal, Beatriz Martín-Antonio, Xavier M Anguela, Cristina Fillat, Eulàlia Olesti, Gonzalo Calvo, Manel Juan, Julio Delgado, Patricia Pérez-Galán, Álvaro Urbano-Ispizua, Sonia Guedan","doi":"10.1016/j.ymthe.2024.11.028","DOIUrl":"10.1016/j.ymthe.2024.11.028","url":null,"abstract":"CD19 CAR-T therapy has achieved remarkable responses in relapsed/refractory non-Hodgkin lymphoma (NHL). However, challenges persist, with refractory responses or relapses after CAR-T administration linked to CD19 loss or downregulation. Given the co-expression of CD19 and BCMA in NHL, we hypothesized that dual targeting could enhance long-term efficacy. We optimized different dual-targeting approaches, including co-transduction of two lentiviral vectors, bicistronic, tandem, and loop and pool strategies, based on our academic anti-CD19 (ARI0001) and anti-BCMA (ARI0002h) CAR-T cells. Comparison with anti-CD19/CD20 or anti-CD19/CD22 dual targeting was also performed. We demonstrate that anti-CD19/BCMA CAR-T cells can be effectively generated through the co-transduction of two lentiviral vectors after optimization to minimize competition for cellular resources. Co-transduced T cells, called ARI0003, effectively targeted NHL tumor cells with high avidity, outperforming anti-CD19 CAR-T cells and other dual-targeting approaches both in vitro and in vivo, particularly in low CD19 antigen density models. ARI0003 maintained effectiveness post-CD19 CAR-T treatment in xenograft models and in spheroids from relapsed CART-treated patients. ARI0003 CAR-T cells were effectively manufactured under Good Manufacturing Practice conditions, with a reduced risk of genotoxicity compared to other dual-targeting approaches. A first-in-human phase 1 clinical trial (CARTD-BG-01; this study was registered at ClinicalTrials.gov [NCT06097455]) has been initiated to evaluate the safety and efficacy of ARI0003 in NHL.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676016","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

Longitudinal imaging of therapeutic enzyme expression after gene therapy for Fabry disease using positron emission tomography and the radiotracer [¹⁸F]AGAL. 利用正电子发射断层扫描和放射性示踪剂 [18F]AGAL 对法布里病基因治疗后的治疗酶表达进行纵向成像。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.021

Charalambos Kaittanis, Tyler Teceno, Ashley Knight, Yoann Petibon, Phil Sandoval, Lawrence Cohen, Shin Hye Ahn, Anthony P Belanger, Louise M Clark, Quang-De Nguyen, Wanida Ruangsiriluk, Shreya Mukherji, Cristian C Constantinescu, Amy Llopis Amenta, Sarav Narayanan, Mugdha Deshpande, Rizwana Islam, Shipeng Yuan, Paul McQuade, Christopher T Winkelmann, Talakad G Lohith

{"title":"Longitudinal imaging of therapeutic enzyme expression after gene therapy for Fabry disease using positron emission tomography and the radiotracer [18F]AGAL.","authors":"Charalambos Kaittanis, Tyler Teceno, Ashley Knight, Yoann Petibon, Phil Sandoval, Lawrence Cohen, Shin Hye Ahn, Anthony P Belanger, Louise M Clark, Quang-De Nguyen, Wanida Ruangsiriluk, Shreya Mukherji, Cristian C Constantinescu, Amy Llopis Amenta, Sarav Narayanan, Mugdha Deshpande, Rizwana Islam, Shipeng Yuan, Paul McQuade, Christopher T Winkelmann, Talakad G Lohith","doi":"10.1016/j.ymthe.2024.11.021","DOIUrl":"10.1016/j.ymthe.2024.11.021","url":null,"abstract":"Longitudinal, non-invasive, in vivo monitoring of therapeutic gene expression is an unmet need for gene therapy (GT). Positron emission tomography (PET) radiotracers designed to bind to therapeutic proteins may provide a sensitive imaging platform to guide treatment response and dose optimization in GT. Herein, we evaluate a novel PET tracer ([18F]AGAL) for targeting α-galactosidase A (GLA), an enzyme deficient in Fabry disease. Gla knockout mice were subjected to either GT with an adeno-associated virus encoding the human GLA (AAVGLA) or recombinant GLA for enzyme replacement studies. PET imaging, ex vivo autoradiography, biochemical analyses and radiation dosimetry were performed. [18F]AGAL exhibited pH-dependent binding to GLA, suggesting recognition of the active enzyme residing within the acidified lysosomes. Imaging studies in the Fabry mouse model showed quick renal clearance with high radioactive uptake in the heart at 6 weeks that was sustained for 26 weeks after a single administration of AAVGLA, indicating effective and durable transgene expression from GT. Good concordance was achieved between in vivo PET imaging and ex vivo quantification of GLA levels in biofluids and tissues. Biodistribution and dosimetry in non-human primate showed acceptable radiation exposure for multiple injections, demonstrating its potential for translation to clinical trial use.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676172","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

Orthogonal transcriptional modulation and gene editing using multiple CRISPR-Cas systems. 使用多个 CRISPR/Cas 系统进行正交转录调节和基因编辑。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.024

Amalie Dyrelund Broksø, Louise Bendixen, Simon Fammé, Kasper Mikkelsen, Trine Ilsø Jensen, Rasmus O Bak

{"title":"Orthogonal transcriptional modulation and gene editing using multiple CRISPR-Cas systems.","authors":"Amalie Dyrelund Broksø, Louise Bendixen, Simon Fammé, Kasper Mikkelsen, Trine Ilsø Jensen, Rasmus O Bak","doi":"10.1016/j.ymthe.2024.11.024","DOIUrl":"10.1016/j.ymthe.2024.11.024","url":null,"abstract":"CRISPR-Cas-based transcriptional activation (CRISPRa) and interference (CRISPRi) enable transient programmable gene regulation by recruitment or fusion of transcriptional regulators to nuclease-deficient Cas (dCas). Here, we expand on the emerging area of transcriptional engineering and RNA delivery by benchmarking combinations of RNA-delivered dCas and transcriptional modulators. We utilize dCas9 from Staphylococcus aureus and Streptococcus pyogenes for orthogonal transcriptional modulation to upregulate one set of genes while downregulating another. We also establish trimodal genetic engineering by combining orthogonal transcriptional regulation with gene knockout by Cas12a (Acidaminococcus; AsCas12a) ribonucleoprotein delivery. To simplify trimodal engineering, we explore optimal parameters for implementing truncated single guide RNAs (sgRNAs) to make use of SpCas9 for knockout and CRISPRa. We find the Cas9 protein/sgRNA ratio to be crucial for avoiding sgRNA cross-complexation and for balancing knockout and activation efficiencies. We demonstrate high efficiencies of trimodal genetic engineering in primary human T cells while preserving basic T cell health and functionality. This study highlights the versatility and potential of complex genetic engineering using multiple CRISPR-Cas systems in a simple one-step process yielding transient transcriptome modulation and permanent DNA changes. We believe such elaborate engineering can be implemented in regenerative medicine and therapies to facilitate more sophisticated treatments.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676185","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

C-reactive protein promotes diabetic kidney disease via Smad3-mediated NLRP3 inflammasome activation. C 反应蛋白通过 Smad3 介导的 NLRP3 炎症小体激活促进糖尿病肾病的发生。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-13 DOI: 10.1016/j.ymthe.2024.11.018

Yifan Wang, Yong-Ke You, Jianbo Guo, Jianan Wang, Baoyi Shao, Haidi Li, Xiaoming Meng, Hui-Yao Lan, Haiyong Chen

{"title":"C-reactive protein promotes diabetic kidney disease via Smad3-mediated NLRP3 inflammasome activation.","authors":"Yifan Wang, Yong-Ke You, Jianbo Guo, Jianan Wang, Baoyi Shao, Haidi Li, Xiaoming Meng, Hui-Yao Lan, Haiyong Chen","doi":"10.1016/j.ymthe.2024.11.018","DOIUrl":"10.1016/j.ymthe.2024.11.018","url":null,"abstract":"Diabetic kidney disease (DKD) is the leading cause of end-stage kidney diseases resulting in enormous socio-economic burden. Accumulated evidence has indicated that C-reactive protein (CRP) exacerbates DKD by enhancing renal inflammation and fibrosis through TGF-β/Smad3 signaling. NLRP3 inflammasome is the key sensor contributing to renal inflammation. However, whether CRP enhances inflammation in DKD via NLRP3 inflammasome-related pathway remains unknown. In this study, we demonstrate that CRP promotes DKD via Smad3-mediated NLRP3 inflammasome activation as mice overexpressing human CRP gene exhibits accelerated renal inflammation in diabetic kidneys, which is associated with the activation of Smad3 and NLRP3 inflammasomes. In contrast, blockade of CPR signaling with a neutralizing anti-CD32 antibody attenuates CRP-induced activation of Smad3 and NLRP3 in vitro. Importantly, genetic deletion or pharmacological inhibition of Smad3 also mitigates CRP-induced activation of NLRP3 in diabetic kidneys or in high glucose-treated cells. Mechanistically, we reveal that Smad3 binds to the NLRP3 gene promoter, which is enhanced by CRP. Taken together, we conclude that CRP induces renal inflammation in DKD via a Smad3-NLRP3 inflammasome-dependent mechanism. Thus, targeting CRP or Smad3-NLRP3 pathways may be a new therapeutic potential for DKD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624234","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

Optimizing CAR-T treatment: A T²EVOLVE guide to raw and starting material selection. 优化 CAR-T 治疗：T2EVOLVE 原料和起始材料选择指南》。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-12 DOI: 10.1016/j.ymthe.2024.11.017

Sergio Navarro, Carole Moukheiber, Susana Inogés Sancho, Marta Ruiz Guillén, Ascensión López-Díaz de Cerio, Carmen Sanges, Toshimitsu Tanaka, Sylvain Arnould, Javier Briones, Harry Dolstra, Michael Hudecek, Rashmi Choudhary, Inga Schapitz, Manel Juan, Nina Worel, Delphine Ammar, Maik Luu, Mirko Müller, Bernd Schroeder, Hélène Negre, Paul Franz

{"title":"Optimizing CAR-T treatment: A T2EVOLVE guide to raw and starting material selection.","authors":"Sergio Navarro, Carole Moukheiber, Susana Inogés Sancho, Marta Ruiz Guillén, Ascensión López-Díaz de Cerio, Carmen Sanges, Toshimitsu Tanaka, Sylvain Arnould, Javier Briones, Harry Dolstra, Michael Hudecek, Rashmi Choudhary, Inga Schapitz, Manel Juan, Nina Worel, Delphine Ammar, Maik Luu, Mirko Müller, Bernd Schroeder, Hélène Negre, Paul Franz","doi":"10.1016/j.ymthe.2024.11.017","DOIUrl":"10.1016/j.ymthe.2024.11.017","url":null,"abstract":"Chimeric antigen receptor (CAR)-T cell products, classified as Advanced Therapy Medicinal Products (ATMPs), have shown promising outcomes in cancer immunotherapy. The quality of raw and starting materials used in manufacturing is critical to ensure the efficacy and safety of CAR-T cell products and depends primarily on the selection of the right materials and the right suppliers. It is essential to consider a long-term strategy when selecting raw and starting materials to prevent delays in the supply of innovative, high-quality, and safe therapies to patients. A thorough assessment will allow developers not only to select suppliers who comply with regulatory requirements but also to ensure a sustainable supply of materials throughout the development and the commercial phases. A careful selection of materials and suppliers can avoid the need of comparability studies due to changes in the supply of materials, impacting costs and causing significant delays in development and treatment readiness for patients. This work, coordinated by the T2EVOLVE IMI consortium, provides guidance for the selection and handling of raw and starting materials. By following these suggestions, developers can ensure that they use high quality raw and starting materials through the product development and life cycle, resulting in safe and effective CAR-T therapies for patients.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624260","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

SNRK modulates mTOR-autophagy pathway for liver lipid homeostasis in MAFLD. SNRK调节mTOR-自噬通路，促进MAFLD患者的肝脂稳态。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-09 DOI: 10.1016/j.ymthe.2024.11.016

Shan Lin, Xiusheng Qiu, Xiaoying Fu, Shuting Zhang, Changyong Tang, Jian Kuang, Haixia Guan, Shuiqing Lai

{"title":"SNRK modulates mTOR-autophagy pathway for liver lipid homeostasis in MAFLD.","authors":"Shan Lin, Xiusheng Qiu, Xiaoying Fu, Shuting Zhang, Changyong Tang, Jian Kuang, Haixia Guan, Shuiqing Lai","doi":"10.1016/j.ymthe.2024.11.016","DOIUrl":"10.1016/j.ymthe.2024.11.016","url":null,"abstract":"Metabolism-related fatty liver disease (MAFLD) is associated with abnormal fat accumulation in the liver. The exact mechanism underlying the occurrence and development of MAFLD remains to be elucidated. Here, we discovered that the expression of sucrose non-fermenting-related kinase (SNRK) is elevated in the liver of the MAFLD population. Mice deficient in SNRK exhibited damage to fatty acid oxidation and persistent accumulation of lipids in the liver. Pharmacological inhibition of the mTOR pathway in SNRK-deficient mice restored autophagy and improved lipid accumulation. In terms of mechanism, we observed that SNRK binds to the raptor component of mTOR complex 1, promoting fatty acid oxidation in the liver by activating autophagy. Overexpression of SNRK in high-fat diet-induced obese mice restored autophagy and ameliorated lipid accumulation. Notably, we also demonstrated that overexpression of SNRK significantly enhanced fatty acid oxidation in the mouse liver. We further confirmed that SNRK is essential for the liver to regulate autophagy and fatty acid oxidation. These findings underscore the importance of the potential of SNRK in the treatment of MAFLD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624268","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

In this issue. 本期内容

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-09 DOI: 10.1016/j.ymthe.2024.11.015

引用次数: 0

The rise of cochlear gene therapy. 人工耳蜗基因疗法的崛起

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-08 DOI: 10.1016/j.ymthe.2024.11.012

Lukas D Landegger, Ellen Reisinger, François Lallemend, Steffen R Hage, Dirk Grimm, Christopher R Cederroth

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 : 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":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-08","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