Pub Date : 2025-09-30DOI: 10.1038/s41573-025-01291-5
Adrian Bot, Andrew Scharenberg, Kevin Friedman, Lin Guey, Robert Hofmeister, James I. Andorko, Michael Klichinsky, Frank Neumann, Jagesh V. Shah, Andrew J. Swayer, Kyle Trudeau, Drew Weissman, Matthias T. Stephan, Christian J. Buchholz, Carl H. June
Chimeric antigen receptor (CAR)-T cell therapy has transformed the outcomes of patients with haematological malignancies, yet its use is limited by labour-intensive manufacturing, constrained production capacity and variable clinical performance. In vivo CAR-T cell engineering, in which CAR-T cells are generated directly inside the patient’s body, seeks to overcome these challenges by eliminating the need for ex vivo cell processing and complex logistics, as well as improve clinical performance. Recent advances in virology, RNA medicines and nanotechnology have catalysed a radical overhaul of this approach, which uses targeted delivery systems such as lentiviral vectors and lipid nanoparticles to introduce CAR-encoding genetic material into endogenous T cells. Early clinical studies have shown efficient transduction, sustained CAR expression and initial signs of antitumour activity, establishing proof of concept. This Review explores the underlying technologies — including RNA delivered by lipid nanoparticles and engineered viral vectors — and discusses how they are being adapted to develop more broadly applicable, scalable, safe and effective CAR-T cell therapies. By removing the need for ex vivo manipulation and chemotherapeutic conditioning, this strategy could enable the wider application of CAR-T cell therapies not just to blood cancers but to autoimmune diseases for which ex vivo CAR-T cell therapies have shown strong promise, such as systemic lupus erythematosus. In vivo chimeric antigen receptor (CAR)-T cell engineering uses targeted delivery systems to generate CAR-T cells directly in patients, bypassing ex vivo manufacturing. This Review examines emerging viral and lipid nanoparticle platforms, early clinical proof of concept and potential applications beyond cancer.
{"title":"In vivo chimeric antigen receptor (CAR)-T cell therapy","authors":"Adrian Bot, Andrew Scharenberg, Kevin Friedman, Lin Guey, Robert Hofmeister, James I. Andorko, Michael Klichinsky, Frank Neumann, Jagesh V. Shah, Andrew J. Swayer, Kyle Trudeau, Drew Weissman, Matthias T. Stephan, Christian J. Buchholz, Carl H. June","doi":"10.1038/s41573-025-01291-5","DOIUrl":"10.1038/s41573-025-01291-5","url":null,"abstract":"Chimeric antigen receptor (CAR)-T cell therapy has transformed the outcomes of patients with haematological malignancies, yet its use is limited by labour-intensive manufacturing, constrained production capacity and variable clinical performance. In vivo CAR-T cell engineering, in which CAR-T cells are generated directly inside the patient’s body, seeks to overcome these challenges by eliminating the need for ex vivo cell processing and complex logistics, as well as improve clinical performance. Recent advances in virology, RNA medicines and nanotechnology have catalysed a radical overhaul of this approach, which uses targeted delivery systems such as lentiviral vectors and lipid nanoparticles to introduce CAR-encoding genetic material into endogenous T cells. Early clinical studies have shown efficient transduction, sustained CAR expression and initial signs of antitumour activity, establishing proof of concept. This Review explores the underlying technologies — including RNA delivered by lipid nanoparticles and engineered viral vectors — and discusses how they are being adapted to develop more broadly applicable, scalable, safe and effective CAR-T cell therapies. By removing the need for ex vivo manipulation and chemotherapeutic conditioning, this strategy could enable the wider application of CAR-T cell therapies not just to blood cancers but to autoimmune diseases for which ex vivo CAR-T cell therapies have shown strong promise, such as systemic lupus erythematosus. In vivo chimeric antigen receptor (CAR)-T cell engineering uses targeted delivery systems to generate CAR-T cells directly in patients, bypassing ex vivo manufacturing. This Review examines emerging viral and lipid nanoparticle platforms, early clinical proof of concept and potential applications beyond cancer.","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"25 2","pages":"116-137"},"PeriodicalIF":101.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194819","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}
Pub Date : 2025-09-23DOI: 10.1038/d41573-025-00160-5
Sarah Crunkhorn
{"title":"Designing new antibiotics","authors":"Sarah Crunkhorn","doi":"10.1038/d41573-025-00160-5","DOIUrl":"10.1038/d41573-025-00160-5","url":null,"abstract":"","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 11","pages":"827-827"},"PeriodicalIF":101.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131638","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}
Pub Date : 2025-09-22DOI: 10.1038/s41573-025-01290-6
Alvar Agusti, Dave Singh, Rosa Faner
Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder of the lungs that affects about 10% of the adult population and is currently the third leading global cause of death. COPD is the result of multiple, repeated and dynamic gene–environment interactions, starting early in life, that determine the lung function trajectory that a given individual follows over a lifetime. Increasing understanding of COPD pathogenesis has opened many new opportunities for drug development, including recently approved monoclonal antibodies that reduce inflammatory cytokine signalling by targeting the IL-4α receptor or the eosinophil-activating IL-5. Drugs targeting a range of other culprits involved in COPD, including neutrophils, alarmins and kinases, are also in clinical development. As the current pipeline of drugs in development for COPD matures, potential areas for novel therapies continue to emerge while lessons from ongoing trials such as patient stratification can be used to refine the design of future trials in this disease. Chronic obstructive pulmonary disease (COPD) is a progressive and severe respiratory disease featuring airway obstruction and recurrent exacerbations, driven by a complex network of inflammatory processes. In their Review, Agusti and co-authors appraise drugs in development for COPD including recently approved antibodies targeting IL-4 and IL-5 signalling. They discuss opportunities to improve the success of future interventions, including considerations to optimize clinical trial design.
{"title":"Treatment of chronic obstructive pulmonary disease: current pipeline and new opportunities","authors":"Alvar Agusti, Dave Singh, Rosa Faner","doi":"10.1038/s41573-025-01290-6","DOIUrl":"10.1038/s41573-025-01290-6","url":null,"abstract":"Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder of the lungs that affects about 10% of the adult population and is currently the third leading global cause of death. COPD is the result of multiple, repeated and dynamic gene–environment interactions, starting early in life, that determine the lung function trajectory that a given individual follows over a lifetime. Increasing understanding of COPD pathogenesis has opened many new opportunities for drug development, including recently approved monoclonal antibodies that reduce inflammatory cytokine signalling by targeting the IL-4α receptor or the eosinophil-activating IL-5. Drugs targeting a range of other culprits involved in COPD, including neutrophils, alarmins and kinases, are also in clinical development. As the current pipeline of drugs in development for COPD matures, potential areas for novel therapies continue to emerge while lessons from ongoing trials such as patient stratification can be used to refine the design of future trials in this disease. Chronic obstructive pulmonary disease (COPD) is a progressive and severe respiratory disease featuring airway obstruction and recurrent exacerbations, driven by a complex network of inflammatory processes. In their Review, Agusti and co-authors appraise drugs in development for COPD including recently approved antibodies targeting IL-4 and IL-5 signalling. They discuss opportunities to improve the success of future interventions, including considerations to optimize clinical trial design.","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"25 2","pages":"98-115"},"PeriodicalIF":101.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117125","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}
Pub Date : 2025-09-22DOI: 10.1038/d41573-025-00155-2
Carles Recasens-Alvarez, Gideon Heap, Graeme Green
{"title":"The evolution of the obesity drug market","authors":"Carles Recasens-Alvarez, \u0000 Gideon Heap, \u0000 Graeme Green","doi":"10.1038/d41573-025-00155-2","DOIUrl":"10.1038/d41573-025-00155-2","url":null,"abstract":"","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 12","pages":"902-903"},"PeriodicalIF":101.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/d41573-025-00155-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117124","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}
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