Cancer vaccines may unlock the full potential of immune checkpoint inhibitors and increase the still suboptimal response rates obtainable by these drugs. Nevertheless, the potency and antigen-specificity of available cancer vaccines is still unsatisfactory. To overcome these limitations, we developed an innovative and effective nanoparticle targeting platform to leverage the superior antigen presenting capacity of cross-presenting dendritic cells (DCs), which selectively targets tumour antigens to Clec9A+ cross-presenting DCs in vivo, both in mice and in humans. In a mouse model of HPV-driven carcinoma, Clec9A-targeting Tailored Nanoemulsions (TNEs) loaded with recombinant E6/E7 viral oncoproteins showed a markedly superior efficacy as compared to a standard vaccination protocol. To exploit the tumour “mutanome” with our TNE platform, we 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 with the induction of potent epitope-specific T-cell immunity. The treatment resulted in high rate of tumour eradication and tumour-free mice were protected by a subsequent re-challenge with B16F10 cells, consistent with the induction of strong memory responses.
With the aim to enhance the efficacy of CAR-T cell therapy for solid tumours, we also explored the possibility that Clec9A-TNE could prime DCs for antigen presentation to CAR-T cells through their TCR, thereby enhancing the expansion and activation of adoptively transferred dual-specific T cells. To address this, dual-receptor CAR-T cells, expressing a CAR against the human Her2 antigen, and TCRs specific for Ovalbumin (OVA) peptides SIINFEKL (CAROTI) or OVA323-339 (CAROTII) were combined with an OVA-carrying Clec9A-TNE (OVA-Clec9A-TNE). Combined treatment of mice bearing established Her2+ tumours with CAROT cells and OVA-Clec9A-TNE vaccine led to significant tumour regression and rejection...