Tumour specific antigens (TSAs) have become interesting targets for cancer antigen targeting in the vaccine space. However, some of these antigens particularly aeTSAs are rarely presenting making them hard to target. Colleen Winstead, Director of Immunology at Epitopea, discussed how we can target antigens and deliver therapies if targets are not expressed on cancers.
Recent work from the University of Montreal uncovered that the most numerous classes of TSAs are non-canonical cryptic antigens derived from dysregulated splicing and epigenetic regulation. These aeTSAs offer high tumour specificity and are not prone to central immune tolerance, making them promising targets.
Epitopea is a new startup that has exclusively licensed a cutting-edge immunopeptidomics platform designed to discover these shared cryptic TSAs. The company is specifically focused on developing vaccines for acute myeloid leukaemia (AML) and ovarian cancer. Winstead explained that the platform is used to identify AML-specific targets by comparing peptides from (AML) blasts to a database of normal tissue expression. In simpler terms, the peptides extracted from the AML cells were analysed for their MHC-I presentation and compared to normal tissue databases to ensure tumour specificity.
Having secured seed funding and established its UK operations at the Milner Therapeutics Institute, Epitopea is validating aeTSAs in AML by using in vitro assays to confirm their presentation and immunogenicity. The targets are confirmed in vitro using prevalent HLA haplotypes and a select list of approximately 100 targets identified from AML samples. Winstead stated: “Our strategy (to rank candidates) combines three characteristics: high transcript ratio in AML (mTECs to MPCs), MHC binding affinity, and predicted TCR engagement and immunogenic potential ranked by the Repitope R package.”
Moreover, Epitopea is collaborating with 10X genomics BEAM technology to advance their next-generation screening (NGS) capabilities to profile TCR specificity. Furthermore, by screening healthy human donors the researchers have identified T cells that recognise the antigens, highlighting their potential for immunotherapy.
Beyond this project, Epitopea is designing mRNA-LNP vaccines for cancer immunotherapy. However, given that the target cells for the mRNA -LNP vaccines are splenocytes as opposed to typical liver cells, this could present challenges. Therefore, it is important to explore technologies that allow for endosomal escape and prolonged expression in the target cells according to Winstead. There are in vivo studies using mouse models (CT26 and MC38 colorectal cancer models) in development to test vaccine efficacy and immune response.
In conclusion, Epitopea’s research presents novel approaches towards cancer immunotherapy by revealing hidden tumour specific targets using their immunopeptidomics platform. Winstead
and her team seek to overcome existing limitations of TSA-based therapies, and their research shows great potential for developing more effective tumour specific treatments.