Molecular Therapy最新文献_第4页

Use of CD19-targeted immune modulation to eradicate AAV-neutralizing antibodies. 利用cd19靶向免疫调节根除AAV中和抗体。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-07-02 Epub Date: 2025-03-08 DOI: 10.1016/j.ymthe.2025.03.003

Bhavya S Doshi, Caroline A Markmann, Noelle Novak, Silvia Juarez Rojas, Robert Davidson, Julia Q Chau, Wei Wang, Sean Carrig, Cristina Martos Rus, Benjamin J Samelson-Jones, Juliana C Small, Vijay G Bhoj, Lindsey A George

{"title":"Use of CD19-targeted immune modulation to eradicate AAV-neutralizing antibodies.","authors":"Bhavya S Doshi, Caroline A Markmann, Noelle Novak, Silvia Juarez Rojas, Robert Davidson, Julia Q Chau, Wei Wang, Sean Carrig, Cristina Martos Rus, Benjamin J Samelson-Jones, Juliana C Small, Vijay G Bhoj, Lindsey A George","doi":"10.1016/j.ymthe.2025.03.003","DOIUrl":"10.1016/j.ymthe.2025.03.003","url":null,"abstract":"Neutralizing antibodies (NAbs) against adeno-associated virus (AAV) represent a significant obstacle to the efficacy of systemic recombinant AAV vector administration or re-administration. While there are some promising preclinical immunomodulation strategies in development, insights into which B cell subsets and compartments maintain persistent AAV NAb may define the optimal eradication strategy. Given the limited success of CD20-directed monotherapy in previous studies, we hypothesized that CD19-directed approaches that extend targeting into the plasma cell compartments may improve AAV NAb eradication. We tested this approach in mice using chimeric antigen receptor T (CAR-T) cells or monoclonal antibodies (mAbs). We observed that combination mAbs targeting CD19, CD22, CD20, or B220 in mice did not eliminate tissue-resident B cells and, correspondingly, did not deplete pre-existing high titer AAV8 NAb. In contrast, CD19 CAR-T therapy eliminated peripheral and tissue-resident B cells and plasma cells and resulted in a marked reduction or eradication of high titer AAV8 NAb that permitted successful transgene expression following systemic AAV8 re-administration in mice. This successful therapeutic approach in mice identifies the population and location of B cells necessary to reduce or eradicate AAV NAb sufficiently to permit successful transgene expression with systemic AAV vector administration.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3073-3085"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586366","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

Bispecific receptor decoy proteins block ocular neovascularization via simultaneous blockade of vascular endothelial growth factor A and C. 双特异性受体诱骗蛋白通过同时阻断血管内皮生长因子A和C抑制眼部新生血管。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-07-02 Epub Date: 2025-03-25 DOI: 10.1016/j.ymthe.2025.03.027

Paul R Sargunas, Emily Ariail, Raquel Lima E Silva, Akash Patil, Mingliang Zhang, Jikui Shen, Beatriz Silva Lopes, Yuseong Oh, Amelia C McCue, Ranjani Ramasubramanian, A Carson Stephenson, Aleksander S Popel, Peter A Campochiaro, Jamie B Spangler

{"title":"Bispecific receptor decoy proteins block ocular neovascularization via simultaneous blockade of vascular endothelial growth factor A and C.","authors":"Paul R Sargunas, Emily Ariail, Raquel Lima E Silva, Akash Patil, Mingliang Zhang, Jikui Shen, Beatriz Silva Lopes, Yuseong Oh, Amelia C McCue, Ranjani Ramasubramanian, A Carson Stephenson, Aleksander S Popel, Peter A Campochiaro, Jamie B Spangler","doi":"10.1016/j.ymthe.2025.03.027","DOIUrl":"10.1016/j.ymthe.2025.03.027","url":null,"abstract":"Several debilitating eye diseases that lead to vision loss are driven by ocular neovascularization, which entails abnormal blood vessel growth in the eye. Neovascularization is often induced by the upregulation of vascular endothelial growth factor (VEGF) ligands, which activate angiogenesis through engagement of VEGF receptor (VEGFR) proteins on endothelial cells. Therapeutic interventions that block ocular neovascularization by targeting VEGF ligands, particularly VEGF-A, have revolutionized eye disease treatment. However, a significant population of patients are either non-responders or develop resistance, which can be driven by the upregulation of other VEGF family ligands such as VEGF-C. Here, we engineered two bispecific receptor decoy fusion proteins that incorporate domains of VEGFR-1 and VEGFR-2 for more effective and comprehensive inhibition of VEGF ligands. We demonstrated that our engineered proteins bind all VEGF ligands and can sequester two ligands simultaneously. We further showed that these molecules block VEGF activity to potently inhibit proliferation, migration, and survival of human endothelial cells. Moreover, these receptor decoy proteins significantly reduced ocular neovascularization in two mouse models at doses wherein the current standard-of-care anti-VEGF therapy is ineffective. Collectively, our engineered receptor decoy proteins present a new architecture for VEGF pathway inhibition, offering a promising treatment paradigm for ocular diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3128-3146"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720362","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

Gene delivery of SUMO1-derived peptide rescues neuronal degeneration and motor deficits in a mouse model of Parkinson's disease. 在rAAV-α-synuclein-A53T帕金森病小鼠模型中，sumo1衍生肽的基因传递可拯救神经元变性和运动缺陷。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-07-02 Epub Date: 2025-04-05 DOI: 10.1016/j.ymthe.2025.04.005

Zhaohui Liang, Suresh Kanna Murugappan, Yuxuan Li, Man Nga Lai, Yajing Qi, Yi Wang, Ho Yin Edwin Chan, Marianne M Lee, Michael K Chan

{"title":"Gene delivery of SUMO1-derived peptide rescues neuronal degeneration and motor deficits in a mouse model of Parkinson's disease.","authors":"Zhaohui Liang, Suresh Kanna Murugappan, Yuxuan Li, Man Nga Lai, Yajing Qi, Yi Wang, Ho Yin Edwin Chan, Marianne M Lee, Michael K Chan","doi":"10.1016/j.ymthe.2025.04.005","DOIUrl":"10.1016/j.ymthe.2025.04.005","url":null,"abstract":"Developing α-synuclein aggregation inhibitors is challenging because its aggregation process involves several microscopic steps and heterogeneous intermediates. Previously, we identified a SUMO1-derived peptide, SUMO1(15-55), that exhibits tight binding to monomeric α-synuclein via SUMO-SUMO-interacting motif (SIM) interactions, and effectively blocks the initiation of aggregation and formation of toxic aggregates in vitro. In cellular and Drosophila models, SUMO1(15-55) was efficacious in protecting neuronal cells from α-synuclein-induced neurotoxicity and neuronal degeneration. Given the demonstrated ability of SUMO1(15-55) to sequester α-synuclein monomers thereby blocking oligomer formation, we sought to evaluate whether it could be equally effective against the aggregation-prone familial mutant α-synuclein-A53T. Herein, we show that SUMO1(15-55) selectively binds to monomeric α-synuclein-A53T, inhibits primary nucleation, and prevents the formation of structured protofibrils in vitro, thereby protecting neuronal cells from protofibril-induced cell death. We further demonstrate that larval feeding of a designed His10-SUMO1(15-55) that exhibits enhanced sub-stoichiometric suppression of α-synuclein-A53T aggregation in vitro can ameliorate Parkinson's disease (PD)-related symptoms in α-synuclein-A53T transgenic Drosophila models, while its rAAV-mediated gene delivery can relieve the PD-related histological and behavioral deficiencies in an rAAV-α-synuclein-A53T mouse PD model. Our findings suggest that gene delivery of His10-SUMO1(15-55) may serve as a clinical therapy for a spectrum of α-synuclein-aggregation associated synucleinopathies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3056-3072"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795762","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

TNFAIP8L2 maintains hair cell function and regulates age-related hearing loss via mTORC1 signaling. TNFAIP8L2维持毛细胞功能并通过mTORC1信号调节年龄相关性听力损失

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-07-02 Epub Date: 2025-03-30 DOI: 10.1016/j.ymthe.2025.03.046

Wen Li, Yu Li, Min Wang, Hao Liu, Guodong Hong, Luhan Jiang, Ziyi Liu, Yunhao Wu, Liangjie Yuan, Xiaoxu Zhao, Zuhong He, Siwei Guo, Yu Xiao, Xiuli Bi, Ming Xia, Guichang Zou, Lining Zhang, Jiangang Gao, Xiaolong Fu

{"title":"TNFAIP8L2 maintains hair cell function and regulates age-related hearing loss via mTORC1 signaling.","authors":"Wen Li, Yu Li, Min Wang, Hao Liu, Guodong Hong, Luhan Jiang, Ziyi Liu, Yunhao Wu, Liangjie Yuan, Xiaoxu Zhao, Zuhong He, Siwei Guo, Yu Xiao, Xiuli Bi, Ming Xia, Guichang Zou, Lining Zhang, Jiangang Gao, Xiaolong Fu","doi":"10.1016/j.ymthe.2025.03.046","DOIUrl":"10.1016/j.ymthe.2025.03.046","url":null,"abstract":"Age-related hearing loss (ARHL) is one of the most prevalent and complex disorders. Our previous study demonstrated that abnormal activation of mammalian target of rapamycin complex 1 (mTORC1) signaling in the cochlear neurosensory epithelium causes auditory hair cell (HC) damage and contributes to ARHL. However, the underlying mechanism of mTORC1 activation remains unclear. In this study, we identified tumor necrosis factor-alpha-induced protein 8-like 2 (TNFAIP8L2), an immune regulatory gene, as a potential candidate. To elucidate the effect of TNFAIP8L2 on mTORC1 signaling in the neurosensory epithelium and on hearing function, we generated a Tnfaip8l2-deficient (Tnfaip8l2-/-) mouse model. We discovered that Tnfaip8l2 deficiency led to features of oxidative stress in cochlear HCs and age-related hearing degeneration, exhibiting a similar phenotype to the mTORC1-over-activated Tsc1-cKO mice described previously. Furthermore, rapamycin, a well-known mTORC1 inhibitor, significantly mitigated the hearing dysfunction caused by Tnfaip8l2-deficiency. Mechanistically, we found that TNFAIP8L2 regulates mTORC1 signaling by simultaneously inhibiting the GTPase activity of Ras homolog enriched in brain (RHEB) and Ras-related C3 botulinum toxin substrate 1 (RAC1). Notably, both RHEB and RAC1 inhibitors alleviated the hearing phenotype observed in Tnfaip8l2-/- mice by inhibiting mTORC1 signaling. Collectively, our results provide insights into the activation of the mTORC1 pathway in aged mouse cochleae and positions TNFAIP8L2 as a valuable theoretical strategy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3036-3055"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753682","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

Living myocardial slices as a model for testing cardiac pro-reparative gene therapies. 活体心肌切片作为检测心脏促修复基因疗法的模型。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-07-02 Epub Date: 2025-03-25 DOI: 10.1016/j.ymthe.2025.03.033

Rocco Caliandro, Azra Husetić, Merel L Ligtermoet, Arie R Boender, Lorena Zentilin, Gerard J J Boink, Mauro Giacca, Monika M Gladka

{"title":"Living myocardial slices as a model for testing cardiac pro-reparative gene therapies.","authors":"Rocco Caliandro, Azra Husetić, Merel L Ligtermoet, Arie R Boender, Lorena Zentilin, Gerard J J Boink, Mauro Giacca, Monika M Gladka","doi":"10.1016/j.ymthe.2025.03.033","DOIUrl":"10.1016/j.ymthe.2025.03.033","url":null,"abstract":"Available models currently adopted for preclinical studies in the cardiovascular field either fail to recapitulate human cardiac physiology or are extremely expensive and time-consuming. Translational research would greatly benefit from the development of novel models that reflect the native mature phenotype of the human heart while being cost and time effective. Living myocardial slices (LMSs) have emerged as a novel, powerful ex vivo tool for translational research. Although the number of studies adopting LMSs is rapidly increasing, this model remains largely under-characterized. In this study, we make use of LMSs and compare them to a murine model to deliver the cardioprotective factor zinc finger E box-binding homeobox 2 (ZEB2), a transcription factor known to exert cardioprotective effects after ischemic injury and promote the secretion of pro-angiogenetic factors thymosin beta-4 (TMSB4) and prothymosin alpha (PTMA). Our data show that viral-mediated delivery of these factors induced similar cardiomyocyte gene expression changes in LMS and mouse models. We also show that the delivery of these pro-angiogenic factors enhances an angiogenic response in both models, indicating that LMSs are a suitable alternative to mice for studying the effects of gene transfer in various cardiac cell types.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2990-2996"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720640","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

Intranasal replicon SARS-CoV-2 vaccine produces protective respiratory and systemic immunity and prevents viral transmission. 鼻内复制子SARS-CoV-2疫苗产生保护性呼吸道和全身免疫，并防止病毒传播。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-07-02 Epub Date: 2025-04-09 DOI: 10.1016/j.ymthe.2025.04.007

Madeleine F Jennewein, Michael D Schultz, Samuel Beaver, Peter Battisti, Julie Bakken, Derek Hanson, Jobaida Akther, Fen Zhou, Raodoh Mohamath, Jasneet Singh, Noah Cross, Darshan N Kasal, Matthew R Ykema, Sierra Reed, Davies Kalange, Isabella R Cheatwood, Jennifer L Tipper, Jeremy B Foote, R Glenn King, Aaron Silva-Sanchez, Kevin S Harrod, Davide Botta, Alana Gerhardt, Corey Casper, Troy D Randall, Frances E Lund, Emily A Voigt

{"title":"Intranasal replicon SARS-CoV-2 vaccine produces protective respiratory and systemic immunity and prevents viral transmission.","authors":"Madeleine F Jennewein, Michael D Schultz, Samuel Beaver, Peter Battisti, Julie Bakken, Derek Hanson, Jobaida Akther, Fen Zhou, Raodoh Mohamath, Jasneet Singh, Noah Cross, Darshan N Kasal, Matthew R Ykema, Sierra Reed, Davies Kalange, Isabella R Cheatwood, Jennifer L Tipper, Jeremy B Foote, R Glenn King, Aaron Silva-Sanchez, Kevin S Harrod, Davide Botta, Alana Gerhardt, Corey Casper, Troy D Randall, Frances E Lund, Emily A Voigt","doi":"10.1016/j.ymthe.2025.04.007","DOIUrl":"10.1016/j.ymthe.2025.04.007","url":null,"abstract":"While mRNA vaccines have been effective in combating SARS-CoV-2, the waning of vaccine-induced antibody responses and lack of vaccine-induced respiratory tract immunity contribute to ongoing infection and transmission. In this work, we compare and contrast intranasal (i.n.) and intramuscular (i.m.) administration of a SARS-CoV-2 replicon vaccine delivered by a nanostructured lipid carrier (NLC). Both i.m. and i.n. vaccines induce potent systemic serum neutralizing antibodies, bone marrow-resident immunoglobulin G-secreting cells, and splenic T cell responses. The i.n. vaccine additionally induces robust respiratory mucosal immune responses, including SARS-CoV-2-reactive lung-resident memory T cell populations. As a booster following previous i.m. vaccination, the i.n. vaccine also elicits the development of mucosal virus-specific T cells. Both the i.m.- and i.n.-administered vaccines durably protect hamsters from infection-associated morbidity upon viral challenge, significantly reducing viral loads and preventing challenged hamsters from transmitting virus to naive cagemates. This replicon-NLC vaccine's potent systemic immunogenicity, and additional mucosal immunogenicity when delivered i.n., may be key for combating SARS-CoV-2 and other respiratory pathogens.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3286-3306"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019281","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

In utero genetic therapy: Treatment of early onset neurological disorders before they start. 子宫内基因治疗：在发病前治疗早发性神经系统疾病。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-07-02 Epub Date: 2025-06-26 DOI: 10.1016/j.ymthe.2025.06.012

Beltran Borges, Stephen M Brown, Tippi C MacKenzie, Charlotte J Sumner

引用次数: 0

An engineered antibody-lectin conjugate targeting the HIV glycan shield protects humanized mice against HIV challenge. 一种针对HIV聚糖屏蔽的工程抗体-凝集素偶联物保护人源化小鼠免受HIV攻击。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-07-02 Epub Date: 2025-03-27 DOI: 10.1016/j.ymthe.2025.03.039

Rashmi Kumariya, Jiadong Sun, Sabrina Lusvarghi, Sijy O'Dell, Gengxiang Zhao, Nicole A Doria-Rose, Carole A Bewley

{"title":"An engineered antibody-lectin conjugate targeting the HIV glycan shield protects humanized mice against HIV challenge.","authors":"Rashmi Kumariya, Jiadong Sun, Sabrina Lusvarghi, Sijy O'Dell, Gengxiang Zhao, Nicole A Doria-Rose, Carole A Bewley","doi":"10.1016/j.ymthe.2025.03.039","DOIUrl":"10.1016/j.ymthe.2025.03.039","url":null,"abstract":"Enveloped viruses responsible for global health pandemics often display a glycan shield on their surface envelope glycoproteins. In HIV, the glycan shield is formed by clusters of high-mannose glycans and plays essential roles in viral fitness and immune evasion. A few mannose-binding lectins potently inactivate HIV but have not been fully exploited due to poor pharmacokinetics and short serum half-lives. To address this, we engineered an antibody-lectin conjugate comprising the anti-HIV lectin griffithsin (GRFT) to the Fc region of human IgG1, with the aim of extending its serum half-life and augmenting anti-HIV activity by inducing immune effector responses. Engineered mGRFT-Fc produced in bacteria exhibited picomolar anti-HIV activity and an extended serum half-life, and mGRFT-Fc produced in mammalian cells (mGRFT-Fcglyc) elicited immune effector responses. In HIV-infected CD34+-humanized mice, both GRFT and mGRFT-Fcglyc effectively suppressed viral loads for up to 8 weeks after a single dose. Significantly, mGRFT-Fcglyc prevented HIV infection by neutralizing HIV and provided sustained protection from break-through infections via Fc-mediated immune effector responses, exhibiting a dual mode of protection. This study demonstrates the successful engineering of a lectin-based biologic and provides early evidence that a glycan-targeting agent alone can confer protection from viral infection in vivo.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3147-3162"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743059","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

Myeloma cell-intrinsic ANXA1 elevation and T cell dysfunction contribute to BCMA-negative relapse after CAR-T therapy. 骨髓瘤细胞内生性ANXA1升高和T细胞功能障碍导致CAR-T治疗后bcma阴性复发。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-07-02 Epub Date: 2025-03-08 DOI: 10.1016/j.ymthe.2025.03.001

Shuangshuang Yang, Guixiang Wang, Jiahuan Chen, Wu Zhang, Jing Wu, Weiqing Liu, Ling Bai, Peide Huang, Jianqing Mi, Jie Xu

{"title":"Myeloma cell-intrinsic ANXA1 elevation and T cell dysfunction contribute to BCMA-negative relapse after CAR-T therapy.","authors":"Shuangshuang Yang, Guixiang Wang, Jiahuan Chen, Wu Zhang, Jing Wu, Weiqing Liu, Ling Bai, Peide Huang, Jianqing Mi, Jie Xu","doi":"10.1016/j.ymthe.2025.03.001","DOIUrl":"10.1016/j.ymthe.2025.03.001","url":null,"abstract":"Multiple myeloma (MM) relapse still occurs after a durable response to anti-B cell maturation antigen (BCMA) chimeric antigen receptor-engineered T (CAR-T) cell therapy with less-defined factors. Herein, we investigated a CAR-T-exposed MM patient who relapsed after 12 months of remission by single-cell transcriptome sequencing. The bone marrow CAR-T population at relapse exhibited exhaustion and proliferation attenuation. The recurrent myeloma cells were deficient in or weakly expressed TNFRSF17 (BCMA) but possessed an identical immunoglobulin clonality to the baseline tumor. Interestingly, combined with the transcriptome profile of the myeloma strains, MM cells with BCMA negativity featured high ANXA1 expression that was identified as an inferior prognostic indicator for MM patients. At a single-cell resolution, BCMA-negative myeloma could be present in the MM patients without CAR-T cell exposure and displayed an increased level of intrinsic ANXA1 transcripts. In vitro assays unveiled that Annexin A1 (ANXA1) elevation conferred growth capacity to BCMA-negative myeloma cells via AMPKα signaling activation and disturbed CAR-T cell fitness. Blockade of Annexin A1 reduced BCMA-negative myeloma cell proliferation. Murine models further demonstrated that Annexin A1 inhibition could effectively diminish BCMA-negative myeloma that escaped from CAR-T's attack. Together, our data identified ANXA1 as a potential target for BCMA-negative myeloma clearance. The ANXA1-targeting strategy might be helpful for CAR-T treatment optimization.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3375-3391"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586363","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

Genetically engineered macrophages reverse the immunosuppressive tumor microenvironment and improve immunotherapeutic efficacy in TNBC. 基因工程巨噬细胞逆转免疫抑制肿瘤微环境，提高TNBC的免疫治疗效果。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-07-02 Epub Date: 2025-03-20 DOI: 10.1016/j.ymthe.2025.03.024

Ranran Jiang, Liechi Yang, Xin Liu, Yujun Xu, Lulu Han, Yuxin Chen, Ge Gao, Meng Wang, Tong Su, Huizhong Li, Lin Fang, Nan Sun, Hongwei Du, Junnian Zheng, Gang Wang

{"title":"Genetically engineered macrophages reverse the immunosuppressive tumor microenvironment and improve immunotherapeutic efficacy in TNBC.","authors":"Ranran Jiang, Liechi Yang, Xin Liu, Yujun Xu, Lulu Han, Yuxin Chen, Ge Gao, Meng Wang, Tong Su, Huizhong Li, Lin Fang, Nan Sun, Hongwei Du, Junnian Zheng, Gang Wang","doi":"10.1016/j.ymthe.2025.03.024","DOIUrl":"10.1016/j.ymthe.2025.03.024","url":null,"abstract":"The main challenges in current immunotherapy for triple-negative breast cancer (TNBC) lie in the immunosuppressive tumor microenvironment (TME). Considering tumor-associated macrophages (TAMs) are the most abundant immune cells in the TME, resetting TAMs is a promising strategy for ameliorating the immunosuppressive TME. Here, we developed genetically engineered macrophages (GEMs) with gene-carrying adenoviruses, to maintain the M1-like phenotype and directly deliver the immune regulators interleukin-12 and CXCL9 into local tumors, thereby reversing the immunosuppressive TME. In tumor-bearing mice, GEMs demonstrated targeted enrichment in tumors and successfully reprogramed TAMs to M1-like macrophages. Moreover, GEMs significantly enhanced the accumulation, proliferation, and activation of CD8+ T cells, mature dendritic cells, and natural killer cells within tumors, while diminishing M2-like macrophages, immunosuppressive myeloid-derived suppressor cells, and regulatory T cells. This treatment efficiently suppressed tumor growth. In addition, combination therapy with GEMs and anti-programmed cell death protein 1 further improved interferon-γ+CD8+ T cell percentages and tumor inhibition efficacy in an orthotopic murine TNBC model. Therefore, this study provides a novel strategy for reversing the immunosuppressive TME and improving immunotherapeutic efficacy through live macrophage-mediated gene delivery.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3339-3359"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676603","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