Tondini and Reintjens et al. showed that covalent conjugation of adjuvant CRX-527, a TLR4 ligand comprised of a detoxified lipid A analog, to MHC-I and -II-restricted TH and CTL peptide antigens improved antigen uptake by and maturation of DCs and specific T cell activation in vitro. Intradermal injection of mice with peptide–CRX-527 conjugates stimulated DC migration and peptide-specific T cell priming and expansion, and enhanced tumor protection and host survival in prophylactic and therapeutic vaccination models. Antitumor activity was greatest when hosts were vaccinated with both MHC-I and -II-restricted peptide–CRX-527 conjugates.
Contributed by Paula Hochman
ABSTRACT: Adjuvants play a determinant role in cancer vaccination by optimally activating APCs and shaping the T cell response. Bacterial-derived lipid A is one of the most potent immune-stimulators known, and is recognized via Toll-like receptor 4 (TLR4). In this study, we explore the use of the synthetic, non-toxic, lipid A analog CRX-527 as an adjuvant for peptide cancer vaccines. This well-defined adjuvant was covalently conjugated to antigenic peptides as a strategy to improve vaccine efficacy. We show that coupling of this TLR4 agonist to peptide antigens improves vaccine uptake by dendritic cells (DCs), maturation of DCs and T cell activation in vitro, and stimulates DC migration and functional T cell priming in vivo. This translates into enhanced tumor protection upon prophylactic and therapeutic vaccination via intradermal injection against B16-OVA melanoma and HPV-related TC1 tumors. These results highlight the potential of CRX-527 as an adjuvant for molecularly defined cancer vaccines, and support the design of adjuvant-peptide conjugates as a strategy to optimize vaccine formulation.
Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (2) Bio-organic Synthesis, Leiden Institute of
Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (2) Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. (3) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (4) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (5) Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. (6) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (7) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (8) Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. (9) Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. (10) Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. jcodee@chem.leidenuniv.nl. (11) Department of Immunology, Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. f.a.ossendorp@lumc.nl.
