Poster Presentation Eradicate Cancer 2018

New strategies to improve the efficacy of personalized cancer immunotherapy (#105)

Riccardo Dolcetti 1 2 , Bijun Zeng 2 , Anton Midelberg 3 , Adrian Gemiarto 4 , Kelli MacDonald 5 , Alan Baxter 4 , Meghna Talekar 2 , Davide Moi 2 , Irina Caminschi 6 , Roberta Mazzieri 2 , Mireille Lahoud 6 , Ranjeny Thomas 2
  1. The University of Queensland, Woolloongabba, QLD, Australia
  2. The University of Queensland Diamantina Institute, Woolloongabba, QLD, Australia
  3. Australia Institute for Bioengineering and Nanotechnology, Brisbane, QLD, Australia
  4. James Cook University, Townsville, QLD, Australia
  5. QIMR Berghofer, Brisbane, QLD, Australia
  6. Department of Biochemistry and Molecular Biology, Monash University , Melbourne, VIC, Australia

    To overcome the limitations current cancer vaccines and improve their efficacy, we have developed a versatile antigen delivery platform targeting cross-presenting dendritic cells (DCs) in vivo. By preparing of a solid-in-oil-in-water double emulsion through sequential reagent addition, we developed a tailored nanoemulsion (TNE), which was functionalized to target Clec9A (Clec9A-TNE), a DC-specific endocytic receptor expressed by cross-presenting CD103+ and CD8+ DCs and plasmacytoid (p)DCs in mice and BDCA3+/CD141+ DCs in humans. Clec9A-targeting TNEs are stable in physiological environments and after i.v. injection in mice, they are selectively taken up by CD8+ DCs and pDCs in spleen and tumor bed. TNEs traffic to both early endosomes and lysosomes, essential prerequisite for an efficient antigen processing and presentation through MHC class I and II pathways. Clec9A-targeting TNE encapsulating a reference antigen (ovalbumin, OVA) without adjuvant targeted and activated cross-presenting DCs and promoted antigen-specific CD4+ and CD8+ T-cell proliferation, cytotoxic T-cell activity and antibody responses in vivo. To exploit the tumour “mutanome” with our TNE platform, we have developed a functional assay to rank immunogenicity of individual neo-epitopes using the murine B16-F10 melanoma as a model. Four weekly i.v. injections of Clec9A-targeting TNEs loaded with a functionally selected pool of neo-epitopes strongly inhibited the in vivo growth of the highly aggressive and poorly immunogenic B16F10 melanoma cells and induced strong epitope-specific IFN-g T-cell immunity. Similar findings were also observed in a mouse model of HPV-driven carcinoma in which Clec9A-targeting TNEs loaded with recombinant E6/E7 viral oncoproteins showed a markedly superior efficacy as compared to a standard vaccination protocol.

     Versatile, personalized, antigen-specific cancer vaccines are a long-sought therapeutic strategy in cancer immunotherapy. Clec9A-targeting nanoemulsions represent such a platform to deliver recombinant tumour protein or neo-epitope antigens specifically to cross-presenting DCs in vivo. This platform can fully exploit the neo-epitope target repertoire of individual tumours thereby improving the feasibility and efficacy of personalized cancer immunotherapy.