QR Code
Park, Jason; Wrzesinski, Stephen H; Stern, Eric; Look, Michael; Criscione, Jason; Ragheb, Ragy; Jay, Steven M; Demento, Stacey L; Agawu, Atu; Limon, Paula Licona; Ferrandino, Anthony F; Gonzalez, David; Habermann, Ann; Flavell, Richard A; Fahmy, Tarek M (2012)

COMBINATION DELIVERY OF TGF-BETA INHIBITOR AND IL-2 BY NANOSCALE LIPOSOMAL POLYMERIC GELS ENHANCES TUMOUR IMMUNOTHERAPY

Nat Mater 11(10):895-905
full text

The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), 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-β 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.