Tang and Zheng et al. developed a drug delivery system comprising a protein of interest (e.g., cytokine) cross-linked with a reversible disulfide linker, forming a nanogel that is anchored to the T cell surface via CD45, which allows for prolonged surface retention. Upon TCR stimulation, T cells increase cell surface reduction activity, which triggers the release of the protein via cross-link cleavage. In vivo, adoptive transfer of T cells with IL-15-loaded nanogels significantly slowed tumor growth, improved survival, and lessened toxicity (due to tumor-targeted release) in mice with melanoma, compared to transfer of T cells combined with free IL-15.
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.
Author Info: (1) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. Department of Materials Science and Enginee
Author Info: (1) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. (2) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. (3) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. (4) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. (5) Cellular Immunotherapy Program, Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA. (6) Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland. (7) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. (8) Vaccine Center, Wistar Institute, Philadelphia, Pennsylvania, USA. (9) Altor BioScience Corporation, Miramar, Florida, USA. (10) Altor BioScience Corporation, Miramar, Florida, USA. (11) Cellular Immunotherapy Program, Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. (12) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
