He et al. developed a peptide-binding vaccine carrier based on a cobalt porphyrin-phospholipid liposome containing QS-21 (a saponin adjuvant) and PHAD (a TLR4 agonist) (altogether, CPQ). CPQ readily bound the gp70 peptide A5 and improved in vitro APC uptake into MHC-I-containing endosomes, and in vivo DC accumulation in the dLN. Prophylactic A5-CPQ immunization induced robust A5-specific T cell responses, inhibited gp70-expressing tumors, and was nontoxic in CD-1 mice. In a therapeutic setting, A5/CPQ regressed CT26 tumors and eliminated lung metastases. Immunization with CPQ was used to functionally screen candidate neoantigen peptides.
Contributed by Alex Najibi
ABSTRACT: Short major histocompatibility complex (MHC) class I (MHC-I)-restricted peptides contain the minimal biochemical information to induce antigen (Ag)-specific CD8(+) cytotoxic T cell responses but are generally ineffective in doing so. To address this, we developed a cobalt-porphyrin (CoPoP) liposome vaccine adjuvant system that induces rapid particleization of conventional, short synthetic MHC-I epitopes, leading to strong cellular immune responses at nanogram dosing. Along with CoPoP (to induce particle formation of peptides), synthetic monophosphoryl lipid A (PHAD) and QS-21 immunostimulatory molecules were included in the liposome bilayer to generate the "CPQ" adjuvant system. In mice, immunization with a short MHC-I-restricted peptide, derived from glycoprotein 70 (gp70), admixed with CPQ safely generated functional, Ag-specific CD8(+) T cells, resulting in the rejection of multiple tumor cell lines, with durable immunity. When cobalt was omitted, the otherwise identical peptide and adjuvant components did not result in peptide binding and were incapable of inducing immune responses, demonstrating the importance of stable particle formation. Immunization with the liposomal vaccine was well-tolerated and could control local and metastatic disease in a therapeutic setting. Mechanistic studies showed that particle-based peptides were better taken up by antigen-presenting cells, where they were putatively released within endosomes and phagosomes for display on MHC-I surfaces. On the basis of the potency of the approach, the platform was demonstrated as a tool for in vivo epitope screening of peptide microlibraries comprising a hundred peptides.