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

在儿童中，DNA复制修复缺陷（RRD），由错配修复突变引起， DNA聚合酶基因，是一个重要的癌症机制。RRD驱动一组致命的 癌症普遍以超突变、微卫星不稳定（MSI）in/dels和 对放化疗的抵抗力。生殖细胞/体质性错配修复缺陷的儿童 （CMMRD）在人类中具有最高的癌症负担，并且很少达到成年期。的 异常高数量的突变产生高度免疫原性的肽， 称为新抗原的正常细胞。CD 8 + T细胞活化在乳腺癌中重要性的临床证据 内源性新抗原免疫监视通过免疫检查点抑制剂证明 (ICI)免疫治疗效果。虽然ICI的成功引发了人们的猜测， ICI有助于初级癌症预防，但也有严重不良事件的显著发生率， 包括自身免疫相关的肺、肝、皮肤、神经、结肠、内分泌和淋巴瘤 毒性，其中一些是致命的。这些问题引起了人们对癌症的新兴趣 免疫预防疫苗，具有更温和和更少的不良事件，以促进癌症 新抗原免疫监视。最近，脂质纳米颗粒RNA（LNP-RNA）疫苗针对 COVID-19令人信服地证明了LNP-RNA疫苗接种更快，更灵活，更便宜 免疫原性比以往任何疫苗技术都要高。我们的总体目标是利用 CMMRD儿童分子诊断的范式转变进展是一种可识别的高 风险患者组，对CMMRD衍生RRD肿瘤突变的机制理解 结构，肿瘤基因组学的强大进展和疫苗技术的最新进展 在临床前发现、配制和验证新型LNP RNA疫苗， CMMRD儿科免疫预防。

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.