Clonal mutations represent the initiating molecular defects related to cellular transition of a normal phenotype to a malignant phenotype. Molecular genomic assessment utilizing next generation and whole exome sequencing is now being increasingly applied to biomarker determination to refine the use of targeted immune therapies. Case examples followed by retrospective study assessment have convincingly demonstrated clonal neoantigens provide a relevant predictor of response to checkpoint inhibition. A meta-analysis, by Litchfield et al., of over 1000 cancer patients from 12 landmark trials demonstrated no clinical benefit to checkpoint inhibitor (CPI) therapy in correlation to high subclonal tumor mutational burden (TMB), whereas high clonal TMB was found to be significantly correlated with better overall survival (p= 0.000000029). We discuss the mechanism of clonal vs. subclonal neoantigen targeting relationship to homologous recombination proficient (HRP) profile, evidence of preclinical and clinical benefit related to clonal neoantigens, and review a novel developing therapy called Vigil®, designed to expand the clonal neoantigen targeting effector cell populations. Vigil®is an autologous cellular immunotherapy which is designed to carry the full set of personal clonal neoantigens. Phase 2b results demonstrate a durable recurrence-free survival (RFS) and overall survival (OS) advantage for Vigil®in a subset ovarian cancer population with an HRP cancer profile.
克隆突变代表了与细胞从正常表型向恶性表型转变相关的起始分子缺陷。目前，利用新一代测序和全外显子测序的分子基因组学评估正日益应用于生物标志物的测定，以优化靶向免疫疗法的使用。通过病例分析及后续回顾性研究评估，已令人信服地证明克隆新抗原可作为检查点抑制剂治疗反应的相关预测因子。Litchfield等人对来自12项里程碑式试验的1000多名癌症患者进行的荟萃分析表明，高亚克隆肿瘤突变负荷（TMB）与检查点抑制剂（CPI）治疗的临床获益无关，而高克隆TMB则被发现与更好的总生存期显著相关（p=0.000000029）。我们讨论了克隆性与亚克隆性新抗原靶向与同源重组功能正常（HRP）特征之间的作用机制，列举了克隆新抗原相关临床前及临床获益的证据，并综述了一种名为Vigil®的新型开发疗法，该疗法旨在扩增靶向克隆新抗原的效应细胞群。Vigil®是一种自体细胞免疫疗法，其设计旨在携带完整的个体克隆新抗原。2b期研究结果显示，在具有HRP癌症特征的特定卵巢癌人群中，Vigil®疗法能带来持久的无复发生存期（RFS）和总生存期（OS）获益。
Clonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy Response
肿瘤(癌症)患者之家