Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy

Hyunjoon Kim; Lin Niu; Peter Larson; Tamara A Kucaba; Katherine A Murphy; Britnie R James; David M Ferguson; Thomas S Griffith; Jayanth Panyam

doi:10.1016/j.biomaterials.2018.02.034

Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy

Biomaterials. 2018 May:164:38-53. doi: 10.1016/j.biomaterials.2018.02.034. Epub 2018 Feb 17.

Authors

Hyunjoon Kim¹, Lin Niu¹, Peter Larson², Tamara A Kucaba³, Katherine A Murphy³, Britnie R James⁴, David M Ferguson², Thomas S Griffith⁵, Jayanth Panyam⁶

Affiliations

¹ Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.
² Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
³ Department of Urology, University of Minnesota, Minneapolis, MN 55455, USA.
⁴ Department of Urology, University of Minnesota, Minneapolis, MN 55455, USA; Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN 55455, USA.
⁵ Department of Urology, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN 55455, USA.
⁶ Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: jpanyam@umn.edu.

PMID: 29482062
DOI: 10.1016/j.biomaterials.2018.02.034

Abstract

Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy because of their ability to directly kill tumor cells and secrete tumor suppressive cytokines. Anticancer vaccines aim to provoke tumor-specific CTL responses, which require activation of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Therefore, a potent immunostimulatory adjuvant capable of activating APCs is an essential component of anticancer vaccines. In this study, we introduce novel TLR 7/8 bi-specific agonists that significantly enhance cytokine secretion compared to TLR7 mono-selective compounds. Encapsulation of these TLR 7/8 agonists in poly(lactide-co-glycolide) (PLGA) nanoparticles increased the co-stimulatory molecule expression and antigen presentation via MHC I by DCs compared to the soluble agonist. When administered subcutaneously, these nanoparticles migrated to draining lymph node and triggered DC activation and expansion. This lead to expansion of antigen-specific CD8 T cells and enhanced CTL response, which resulted in significant prophylactic and therapeutic efficacy in melanoma, bladder and renal cell carcinoma tumor models. Importantly, our studies demonstrate significant reductions in systemic metastasis with the nanoparticle vaccine. Our results suggest novel TLR 7/8 agonist-encapsulated nanoparticles are potent immunostimulatory adjuvants for cancer immunotherapy.

Keywords: Cancer vaccine; Immunotherapy; Nanoparticle; TLR7/8 agonist.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adjuvants, Immunologic / pharmacology
Animals
Antineoplastic Agents / pharmacology
Drug Carriers* / chemistry
Female
Humans
Imidazoles / pharmacology*
Immunotherapy / methods
Mice, Inbred C57BL
Nanocapsules*
Neoplasms, Experimental / immunology
Neoplasms, Experimental / therapy
Polyglactin 910*
Quinolines / pharmacology*
T-Lymphocytes, Cytotoxic / drug effects
Toll-Like Receptor 7 / agonists*
Toll-Like Receptor 8 / agonists*

Substances

Adjuvants, Immunologic
Antineoplastic Agents
Drug Carriers
Imidazoles
Nanocapsules
Quinolines
Toll-Like Receptor 7
Toll-Like Receptor 8
Polyglactin 910