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IMMUNOWATCH #10 - Developing a robust, tumour-specific target discovery platform for next-generation immunotherapies

ABSTRACT: 

Development of successful immunotherapies, especially for solid tumours, is hampered by the paucity of specific and highly recurrent cancer targets. To date, cancer targets are traditionally derived from the coding genome, which encompasses roughly 4% of human DNA, leaving 96% of the genome (Dark Genome) vastly unexplored. Within that unexplored fraction lie unannotated regions and transposable elements (TEs), with poorly defined functionality. We recently discovered that due to epigenetic alterations, these transposable elements are included within coding-genome-derived proteins through non-canonical splicing generating novel proteins that we call Epigenetic Antigens (E-antigens)


Here, we review the development of Mnemo’s discovery engine that can readily identify highly recurrent and tumour-specific antigens by mining the Dark Genome. E-Antigens occur in two forms: peptides presented in the context of Major Histocompatibility Complex molecules (pMHC), and novel tumour-specific isoforms of transmembrane proteins (TM). Dark Genome-derived peptides are immunogenic in vitro and specific CD8+ T cells are identified in primary tumours and draining lymph nodes. Moreover, using in vitro and in vivo models, we demonstrate that E-Antigens are druggable and targetable by multiple immunotherapy modalities, such as chimeric antigen receptors (CARs), T-cell receptors (TCRs) and T-cell engagers (TCEs), representing an actionable target reservoir for cancer vaccines. In summary, at Mnemo, we have developed an end-to-end discovery and validation pipeline, and we have demonstrated that E-Antigens are setting a new paradigm for antigen-based immunotherapies. 




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