Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy.
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.
Department of Biomedical and Environmental Engineering, Yale University School of Engineering and Applied Sciences, New Haven, Connecticut 06511, USA.
Jason
J
Park
Stephen H
SH
Wrzesinski
Eric
E
Stern
Michael
M
Look
Jason
J
Criscione
Ragy
R
Ragheb
Steven M
SM
Jay
Stacey L
SL
Demento
Atu
A
Agawu
Paula
P
Licona Limon
Anthony F
AF
Ferrandino
David
D
Gonzalez
Ann
A
Habermann
Richard A
RA
Flavell
Tarek M
TM
Fahmy
D056704:Adaptive Immunity; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D003505:Cyclodextrins; D004339:Drug Compounding; D005782:Gels; D007113:Immunity, Innate; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000378:metabolism; D008081:Liposomes; D051379:Mice; D008815:Mice, Inbred Strains; D049329:Nanostructures; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects
D000970:Antineoplastic Agents; D003505:Cyclodextrins; D005782:Gels; D007376:Interleukin-2; D008081:Liposomes; D016212:Transforming Growth Factor beta