Journal
NATURE MATERIALS
Volume 11, Issue 10, Pages 895-905Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NMAT3355
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Funding
- NIH [R01-HL085416, R01-EB008260]
- NIH Autoimmunity Center of Excellence Pilot Award [U19AI082713]
- Public Health Grant [HL-55397]
- NSF CAREER grant
- Yale Skin SPORE Career Development Award
- Howard Hughes Medical Institute
- Yale Cancer Center
- Pew Charitable Trust: Pew Latin American Fellow Program in Biomedical Sciences
- Yale Rheumatologic Disease Research Core Center [P30AR053495]
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [747577] Funding Source: National Science Foundation
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The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-beta (TGF-beta), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-beta inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8(+) T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.
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