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

在儿童中，由错配修复突变引起的DNA复制修复缺陷(RRD) 在DNA聚合酶基因中，是一种重要的致癌机制。RRD驾驶着一群致命的 肿瘤普遍表现为高突变、微卫星不稳定(MSI)和 对放化疗的抗药性。患有生殖系/体质错配修复缺陷的儿童 (CMMRD)是人类癌症负担最高的，很少成年。这个 异常大量的突变产生了从未在体内表达的高免疫原性多肽 正常细胞称为新抗原。CD8+T细胞活化在慢性阻塞性肺疾病中重要性的临床证据 免疫检查点抑制物对内源性新抗原的免疫监视作用 (ICI)免疫治疗疗效。虽然ICI的成功引发了人们的猜测，即他们可能还会 有助于癌症的一级预防，ICI也有显著的严重不良事件发生率， 包括与自身免疫相关的肺、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反应，以促进癌症 新抗原免疫监测。近年来，脂类纳米RNA(LNP-RNA)疫苗针对 新冠肺炎令人信服地表明，核糖核酸疫苗接种更快、更灵活、更便宜 而且比任何以前的疫苗技术都更具免疫原性。我们的总体目标是利用 CMMRD儿童作为一种可识别的高血压病的分子诊断的范式转换进展 高危患者组对CMMRD所致RRD肿瘤突变的机制认识 架构、肿瘤基因组学的强大进展和疫苗技术的最新进展 临床前发现、配制和验证有效和安全的新型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.