Towards a preventive cancer vaccine for children with constitutional mismatch repair deficiency

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In children, DNA replication repair deficiency (RRD), caused by mutations in the mismatch repair of DNA polymerase genes, is an important cancer mechanism. RRD drives a deadly group of cancers universally characterized by hypermutation, microsatellite instable (MSI) in/dels and resistance to chemoradiation. Children with germline/constitutional mismatch repair deficiency (CMMRD) have the highest burden of cancers in humans and rarely reach adulthood. The exceptionally high number of mutations creates highly immunogenic peptides never expressed in normal cells called neoantigens. Clinical evidence for the importance of CD8+ T cell activation in endogenous neoantigen immune surveillance is demonstrated by immune checkpoint inhibitor (ICI) immunotherapy efficacy. While the success of ICI has led to speculation that they may also be helpful for primary cancer prevention, ICI also has significant rates of severe adverse events, including autoimmunity-related lung, hepatic, skin, neuro, colon, endocrine, and lymphoma toxicities, some of which are fatal. These problems have led to new interest in cancer immunoprevention vaccines, which have milder and fewer adverse events, to boost cancer neoantigen immune surveillance. Recently, lipid nanoparticle RNA (LNP-RNA) vaccines against COVID-19 demonstrated convincingly that LNP-RNA vaccination is faster, more flexible, cheaper and more immunogenic than any previous vaccine technology. Our overall goal is to leverage paradigm-shifting advances in molecular diagnosis of CMMRD children as an identifiable high- risk patient group, a mechanistic understanding of CMMRD derived RRD tumor mutation architecture, powerful advances in tumor genomics and recent advances in vaccine technology to pre-clinically discover, formulate, and validate novel LNP RNA vaccines for effective and safe CMMRD pediatric immunoprevention.