Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery.
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Tang L
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
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Zheng Y
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
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Melo MB
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
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Mabardi L
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
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Castaño AP
Cellular Immunotherapy Program, Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
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Xie YQ
Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
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Li N
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
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Kudchodkar SB
Vaccine Center, Wistar Institute, Philadelphia, Pennsylvania, USA.
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Wong HC
Altor BioScience Corporation, Miramar, Florida, USA.
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Jeng EK
Altor BioScience Corporation, Miramar, Florida, USA.
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Maus MV
Cellular Immunotherapy Program, Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
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Irvine DJ
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
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Published in:
- Nature biotechnology. - 2018
English
Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to 'backpack' large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface-conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo.
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Language
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Open access status
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green
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Identifiers
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Persistent URL
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https://sonar.ch/global/documents/105718
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