期刊
ADVANCED MATERIALS
卷 30, 期 25, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adma.201706098
关键词
cancer immunotherapy; checkpoint inhibitor; combination therapy; polymeric nanoparticle; T-cell agonist
类别
资金
- National Institutes of Health/National Cancer Institute [U54CA198999, R01 CA178748]
- Department of Defense Congressionally Directed Medical Research Programs-Peer Reviewed Cancer Research Program Idea Award [CA150391]
- UNC University Cancer Research Fund
- Paul Calabresi Oncology K12 Award
- UNC CCNE Pilot Grant
Combination immunotherapy has recently emerged as a powerful cancer treatment strategy. A promising treatment approach utilizes coadministration of antagonistic antibodies to block checkpoint inhibitor receptors, such as antiprogrammed cell death-1 (aPD1), alongside agonistic antibodies to activate costimulatory receptors, such as antitumor necrosis factor receptor superfamily member 4 (aOX40). Optimal T-cell activation is achieved when both immunomodulatory agents simultaneously engage T-cells and promote synergistic proactivation signaling. However, standard administration of these therapeutics as free antibodies results in suboptimal T-cell binding events, with only a subset of the T-cells binding to both aPD1 and aOX40. Here, it is shown that precise spatiotemporal codelivery of aPD1 and aOX40 using nanoparticles (NP) (dual immunotherapy nanoparticles, DINP) results in improved T-cell activation, enhanced therapeutic efficacy, and increased immunological memory. It is demonstrated that DINP elicits higher rates of T-cell activation in vitro than free antibodies. Importantly, it is demonstrated in two tumor models that combination immunotherapy administered in the form of DINP is more effective than the same regimen administered as free antibodies. This work demonstrates a novel strategy to improve combination immunotherapy using nanotechnology.
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