Department of Medicine, Division of Medical Oncology, Duke University School of Medicine, Durham, NC, USA.
Center for Applied Therapeutics, Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
Cancer Gene Ther. 2023 Jun;30(6):803-811. doi: 10.1038/s41417-023-00587-1. Epub 2023 Feb 10.
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.
治疗性癌症疫苗旨在激活针对肿瘤抗原的免疫效应物，利用多种不同的平台进行抗原传递。其中包括信使 RNA（mRNA），已成功应用于一些预防 SARS-CoV2 的疫苗中。为了提高 mRNA 传递表位的免疫原性，已经开发了能够显著增加表位表达的自我复制 RNA（srRNA）。这些载体源自正链 RNA 病毒，其中结构蛋白基因已被感兴趣的异源基因取代，并且结构蛋白以转染方式提供以产生单周期病毒复制子颗粒（VRP）。临床阶段的 srRNA 载体源自甲病毒，包括委内瑞拉马脑炎（VEE）、辛德比斯和塞姆利基森林病毒（SFV），并编码肿瘤抗原癌胚抗原（CEA）、人表皮生长因子受体 2（HER2）、前列腺特异性膜抗原（PSMA）和人乳头瘤病毒（HPV）抗原 E6 和 E7。不良事件主要为 1 级毒性和最小的注射部位反应。我们在这里回顾了这些疫苗的临床经验，以及我们最近一项联合 VRP 编码 HER2 和抗 PD1 单克隆抗体（pembrolizumab）的研究的安全性数据。基于 VRP 的 srRNA 的这一经验支持了完全合成 srRNA 技术的最新发展，其中病毒结构蛋白被保护性脂质纳米颗粒（LNP）、阳离子纳米乳液或聚合物取代。
