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In vivo CAR T cell generation to treat cancer and autoimmune disease.

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Title: In vivo CAR T cell generation to treat cancer and autoimmune disease.
Authors: Hunter, Theresa L., Bao, Yanjie, Zhang, Yan, Matsuda, Daiki, Riener, Romina, Wang, Annabel, Li, John J., Soldevila, Ferran, Chu, David S. H., Nguyen, Duy P., Yong, Qian-Chen, Ross, Brittany, Nguyen, Michelle, Vestal, James, Roberts, Scott, Galvan, Diana, Vega, Jerel Boyd, Jhung, Donald, Butcher, Matthew, Nguyen, Josephine
Source: Science. 6/19/2025, Vol. 388 Issue 6753, p1311-1317. 7p.
Subjects: T cells, Autoimmune diseases, Cancer treatment, Chimeric antigen receptors, Immunotherapy
Abstract: Chimeric antigen receptor (CAR) T cell therapies have transformed treatment of B cell malignancies. However, their broader application is limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility. We present an in vivo engineering strategy using targeted lipid nanoparticles (tLNPs) for messenger RNA delivery to specific T cell subsets. These tLNPs reprogrammed CD8+ T cells in both healthy donor and autoimmune patient samples, and in vivo dosing resulted in tumor control in humanized mice and B cell depletion in cynomolgus monkeys. In cynomolgus monkeys, the reconstituted B cells after depletion were predominantly naïve, suggesting an immune system reset. By eliminating the requirements for complex ex vivo manufacturing, this tLNP platform holds the potential to make CAR T cell therapies more accessible and applicable across additional clinical indications. Editor's summary: Chimeric antigen receptor (CAR)–T cell therapies have been highly successful for treating B cell malignancies and also have potential for the treatment of autoimmune disease. However, complex manufacturing and conditioning regimens have limited their accessibility and scalability. Hunter et al. report a gene-delivery system to generate CAR-T cells in vivo by dosing of a CD8-targeted lipid nanoparticle carrying anti-CD19 CAR mRNA (see the Perspective by Peche and Gottschalk). Data from rodent and nonhuman primate (NHP) models demonstrated tumor control. In autoimmune models, deep and transient depletion of B cells was observed in the blood and tissues of NHPs, resulting in an "immune reset." Such a strategy may provide an off-the-shelf, nonviral, and scalable alternative to ex vivo CAR-T cell immunotherapy. —Priscilla N. Kelly [ABSTRACT FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: In vivo CAR T cell generation to treat cancer and autoimmune disease.
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  Data: <searchLink fieldCode="AR" term="%22Hunter%2C+Theresa+L%2E%22">Hunter, Theresa L.</searchLink><br /><searchLink fieldCode="AR" term="%22Bao%2C+Yanjie%22">Bao, Yanjie</searchLink><br /><searchLink fieldCode="AR" term="%22Zhang%2C+Yan%22">Zhang, Yan</searchLink><br /><searchLink fieldCode="AR" term="%22Matsuda%2C+Daiki%22">Matsuda, Daiki</searchLink><br /><searchLink fieldCode="AR" term="%22Riener%2C+Romina%22">Riener, Romina</searchLink><br /><searchLink fieldCode="AR" term="%22Wang%2C+Annabel%22">Wang, Annabel</searchLink><br /><searchLink fieldCode="AR" term="%22Li%2C+John+J%2E%22">Li, John J.</searchLink><br /><searchLink fieldCode="AR" term="%22Soldevila%2C+Ferran%22">Soldevila, Ferran</searchLink><br /><searchLink fieldCode="AR" term="%22Chu%2C+David+S%2E+H%2E%22">Chu, David S. H.</searchLink><br /><searchLink fieldCode="AR" term="%22Nguyen%2C+Duy+P%2E%22">Nguyen, Duy P.</searchLink><br /><searchLink fieldCode="AR" term="%22Yong%2C+Qian-Chen%22">Yong, Qian-Chen</searchLink><br /><searchLink fieldCode="AR" term="%22Ross%2C+Brittany%22">Ross, Brittany</searchLink><br /><searchLink fieldCode="AR" term="%22Nguyen%2C+Michelle%22">Nguyen, Michelle</searchLink><br /><searchLink fieldCode="AR" term="%22Vestal%2C+James%22">Vestal, James</searchLink><br /><searchLink fieldCode="AR" term="%22Roberts%2C+Scott%22">Roberts, Scott</searchLink><br /><searchLink fieldCode="AR" term="%22Galvan%2C+Diana%22">Galvan, Diana</searchLink><br /><searchLink fieldCode="AR" term="%22Vega%2C+Jerel+Boyd%22">Vega, Jerel Boyd</searchLink><br /><searchLink fieldCode="AR" term="%22Jhung%2C+Donald%22">Jhung, Donald</searchLink><br /><searchLink fieldCode="AR" term="%22Butcher%2C+Matthew%22">Butcher, Matthew</searchLink><br /><searchLink fieldCode="AR" term="%22Nguyen%2C+Josephine%22">Nguyen, Josephine</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 6/19/2025, Vol. 388 Issue 6753, p1311-1317. 7p.
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  Data: <searchLink fieldCode="DE" term="%22T+cells%22">T cells</searchLink><br /><searchLink fieldCode="DE" term="%22Autoimmune+diseases%22">Autoimmune diseases</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+treatment%22">Cancer treatment</searchLink><br /><searchLink fieldCode="DE" term="%22Chimeric+antigen+receptors%22">Chimeric antigen receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Immunotherapy%22">Immunotherapy</searchLink>
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  Data: Chimeric antigen receptor (CAR) T cell therapies have transformed treatment of B cell malignancies. However, their broader application is limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility. We present an in vivo engineering strategy using targeted lipid nanoparticles (tLNPs) for messenger RNA delivery to specific T cell subsets. These tLNPs reprogrammed CD8+ T cells in both healthy donor and autoimmune patient samples, and in vivo dosing resulted in tumor control in humanized mice and B cell depletion in cynomolgus monkeys. In cynomolgus monkeys, the reconstituted B cells after depletion were predominantly naïve, suggesting an immune system reset. By eliminating the requirements for complex ex vivo manufacturing, this tLNP platform holds the potential to make CAR T cell therapies more accessible and applicable across additional clinical indications. Editor's summary: Chimeric antigen receptor (CAR)–T cell therapies have been highly successful for treating B cell malignancies and also have potential for the treatment of autoimmune disease. However, complex manufacturing and conditioning regimens have limited their accessibility and scalability. Hunter et al. report a gene-delivery system to generate CAR-T cells in vivo by dosing of a CD8-targeted lipid nanoparticle carrying anti-CD19 CAR mRNA (see the Perspective by Peche and Gottschalk). Data from rodent and nonhuman primate (NHP) models demonstrated tumor control. In autoimmune models, deep and transient depletion of B cells was observed in the blood and tissues of NHPs, resulting in an "immune reset." Such a strategy may provide an off-the-shelf, nonviral, and scalable alternative to ex vivo CAR-T cell immunotherapy. —Priscilla N. Kelly [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1126/science.ads8473
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        Text: English
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      – SubjectFull: Cancer treatment
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      – SubjectFull: Chimeric antigen receptors
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