Aduro Biotech, Inc., Berkeley, California, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
Infect Immun. 2019 Jul 23;87(8). doi: 10.1128/IAI.00144-19. Print 2019 Aug.
Live-attenuated has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. However, additional safety measures will enable application across malignant and infectious diseases. Here, we describe a new vaccine platform, termed Lm-RIID ( recombinase-induced intracellular death), that induces the deletion of genes required for bacterial viability yet maintains potent T cell responses to encoded antigens. Lm-RIID grows normally in broth but commits suicide inside host cells by inducing Cre recombinase and deleting essential genes flanked by sites, resulting in a self-limiting infection even in immunocompromised mice. Lm-RIID vaccination of mice induces potent CD8 T cells and protects against virulent challenges, similar to live vaccines. When combined with α-PD-1, Lm-RIID is as effective as live-attenuated in a therapeutic tumor model. This impressive efficacy, together with the increased clearance rate, makes Lm-RIID ideal for prophylactic immunization against diseases that require T cells for protection.
减毒活疫苗在临床前和临床环境中显示出作为免疫疗法平台的令人鼓舞的潜力。然而，额外的安全措施将使其能够应用于恶性和传染病。在这里，我们描述了一种新的疫苗平台，称为 Lm-RIID（重组酶诱导的细胞内死亡），它诱导细菌存活所需基因的缺失，同时保持对编码抗原的有效 T 细胞反应。Lm-RIID 在肉汤中正常生长，但通过诱导 Cre 重组酶并删除两侧带有 位点的必需基因，在宿主细胞内自杀，导致即使在免疫功能低下的小鼠中也会发生自我限制的感染。Lm-RIID 疫苗接种可诱导强烈的 CD8 T 细胞反应，并可预防毒力挑战，类似于活疫苗。当与 α-PD-1 联合使用时，Lm-RIID 在治疗性肿瘤模型中与减毒活疫苗一样有效。这种令人印象深刻的疗效，加上清除率的提高，使得 Lm-RIID 成为预防需要 T 细胞保护的疾病的理想选择。
