文章：

基于自我复制RNA的癌症疫苗的临床试验

Clinical trials of self-replicating RNA-based cancer vaccines 

原文发布日期：2023-02-10 

英文摘要：

Therapeutic cancer vaccines, designed to activate immune effectors against tumor antigens, utilize a number of different platforms for antigen delivery. Among these are messenger RNAs (mRNA), successfully deployed in some prophylactic SARS-CoV2 vaccines. To enhance the immunogenicity of mRNA-delivered epitopes, self-replicating RNAs (srRNA) that markedly increase epitope expression have been developed. These vectors are derived from positive-strand RNA viruses in which the structural protein genes have been replaced with heterologous genes of interest, and the structural proteins are provided in trans to create single cycle viral replicon particles (VRPs). Clinical stage srRNA vectors have been derived from alphaviruses, including Venezuelan Equine Encephalitis (VEE), Sindbis, and Semliki Forest virus (SFV) and have encoded the tumor antigens carcinoembryonic antigen (CEA), human epidermal growth factor receptor 2 (HER2), prostate specific membrane antigen (PSMA), and human papilloma virus (HPV) antigens E6 and E7. Adverse events have mainly been grade 1 toxicities and minimal injection site reactions. We review here the clinical experience with these vaccines and our recent safety data from a study combining a VRP encoding HER2 plus an anti-PD1 monoclonal antibody (pembrolizumab). This experience with VRP-based srRNA supports recent development of fully synthetic srRNA technologies, where the viral structural proteins are replaced with protective lipid nanoparticles (LNP), cationic nanoemulsions or polymers. 

摘要翻译： 

治疗性癌症疫苗旨在激活免疫效应细胞对抗肿瘤抗原，采用了多种不同的抗原递送平台。其中包括信使RNA（mRNA）技术——该技术已成功应用于部分预防性SARS-CoV2疫苗。为增强mRNA递送表位的免疫原性，现已开发出能显著提高表位表达的自复制RNA（srRNA）技术。这些载体源自正链RNA病毒，其结构蛋白基因被替换为异源目的基因，并通过反式提供结构蛋白形成单周期病毒复制子颗粒（VRPs）。处于临床研发阶段的srRNA载体源自甲病毒属，包括委内瑞拉马脑炎病毒（VEE）、辛德毕斯病毒和塞姆利基森林病毒（SFV），已编码的肿瘤抗原包括癌胚抗原（CEA）、人类表皮生长因子受体2（HER2）、前列腺特异性膜抗原（PSMA）以及人类乳头瘤病毒（HPV）抗原E6和E7。不良反应主要为1级毒性反应和轻微的注射部位反应。本文综述了这些疫苗的临床实践经验，以及我们最近将编码HER2的VRP与抗PD1单克隆抗体（帕博利珠单抗）联合研究的安全性数据。基于VRP的srRNA实践经验支持了最新全合成srRNA技术的发展——即用保护性脂质纳米颗粒（LNP）、阳离子纳米乳剂或聚合物替代病毒结构蛋白。

原文链接：

Clinical trials of self-replicating RNA-based cancer vaccines