α-Galactosylceramide and nano-vaccine induced a strong anti-tumor effect

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α-Galactosylceramide and nano-vaccine induced a strong anti-tumor effect

Segunda, 30.07.2018

Combination of α-galactosylceramide (GalCer), a Natural Killer T (NKT) cell agonist, with melanoma-associated antigens presented by MHC class I (Melan-A:26) and MHC class II (gp100:44) molecules, and Toll-like Receptor (TLR) ligands (MPLA and CpG), within nanoparticle matrix induced a prominent anti-tumor immune response able to restrict melanoma growth. An enhanced infiltration of NKT and NK cells into tumor site was only achieved when the combination GalCer, antigens and TLR ligands were co-delivered by the nanovaccine.


Vanessa Sainz1,2,3, Liane I. F. Moura1,3, Carina Peres1, Ana I Matos1, Ana S. Viana4, Angela M. Wagner5,7, Julia E. Vela Ramirez6,7, Teresa Barata2, Manuela Gaspar1, Steve Brocchini2, Mire Zloh3, Nicholas A. Peppas5,6,7,8,9, Ronit Satchi-Fainaro10,11, Helena F. Florindo1 

1 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, Lisbon 1649-003, Portugal

2 Department of Pharmaceutics, The School of Pharmacy, University College London, 29/39 Brunswick Square, London WC1N 1AX, UK

3 School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK

4 Chemistry and Biochemistry Center, Sciences Faculty, Universidade de Lisboa, 1749-016 Lisbon, Portugal

5 McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA

6 Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA

7 Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, TX 78712, USA

8 Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA

9 Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA

10 Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

11 Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel


alpha-Galactosylceramide (GalCer) is a glycolipid widely known as an activator of Natural killer T (NKT) cells, constituting a promising adjuvant against cancer, including melanoma. However, limited clinical outcomes have been obtained so far. This study evaluated the synergy between GalCer and major histocompatibility complex (MHC) class I and MHC class II melanoma-associated peptide antigens and the Toll-Like Receptor (TLR) ligands CpG and monophosphoryl lipid A (MPLA), which we intended to maximize following their co-delivery by a nanoparticle (NP). This is expected to improve GalCer capture by dendritic cells (DCs) and subsequent presentation to NKT cells, and simultaneously induce an anti-tumor specific T-cell mediated immunity. The combination of GalCer with melanoma peptides and TLR ligands successfully restrained tumor growth. The tumor volume in these animals was 5-fold lower than the ones presented by mice immunized with NPs not containing GalCer. However, tumor growth was controlled at similar levels by GalCer entrapped or in its soluble form, when mixed with antigens and TLR ligands. Those two groups showed an improved infiltration of T lymphocytes into the tumor, but only GalCer-loaded nano-vaccine induced a prominent and enhanced infiltration of NKT and NK cells. In addition, splenocytes of these animals secreted levels of IFN-γ and IL-4 at least 1.5-fold and 2-fold higher, respectively, than those treated with the mixture of antigens and adjuvants in solution. Overall, the combined delivery of the NKT agonist with TLR ligands and melanoma antigens via this multivalent nano-vaccine displayed a synergistic anti-tumor immune-mediated efficacy in B16F10 melanoma mouse model.

Acta Biomaterialia

https://www.sciencedirect.com/science/article/pii/S1742706118303751?via%3Dihub