ABSTRACT

Introduction

The use of tumor-selectively replicating viruses is a rapidly expanding field that is showing considerable promise for cancer treatment. Retroviral replicating vectors (RRV) are unique among the various replication-competent viruses currently being investigated for potential clinical utility, because they permanently integrate into the cancer cell genome and are capable of long-term persistence within tumors. RRV can mediate efficient tumor-specific delivery of prodrug activator genes, and subsequent prodrug treatment leads to synchronized cell killing of infected cancer cells, as well as activation of antitumor immune responses.

Areas Covered

Here we review preclinical studies supporting bench-to-bedside translation of Toca 511, an optimized RRV for prodrug activator gene therapy, the results from Phase I through III clinical trials to date, and potential future directions for this therapy as well as other clinical candidate RRV.

Expert Opinion

Toca 511 has shown highly promising results in early-stage clinical trials. This vector progressed to a registrational Phase III trial, but the results announced in late 2019 appeared negative overall. However, the median prodrug dosing schedule was not optimal, and promising possible efficacy was observed in some prespecified subgroups. Further clinical investigation, as well as development of RRV with other transgene payloads, is merited.

中文翻译：

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用于癌症基因治疗的逆转录病毒复制载体 Toca 511 的临床开发

摘要

介绍

肿瘤选择性复制病毒的使用是一个快速扩展的领域，在癌症治疗方面显示出巨大的前景。逆转录病毒复制载体（RRV）在目前正在研究潜在临床用途的各种具有复制能力的病毒中是独一无二的，因为它们永久整合到癌细胞基因组中，并且能够在肿瘤内长期存留。RRV可以介导前药激活基因的有效肿瘤特异性递送，随后的前药治疗导致受感染癌细胞的同步细胞杀伤，以及抗肿瘤免疫反应的激活。

涵盖领域

在此，我们回顾了支持 Toca 511（一种用于前药激活剂基因治疗的优化 RRV）从实验室到临床转化的临床前研究、迄今为止 I 期至 III 期临床试验的结果，以及该疗法以及其他临床候选药物的潜在未来方向RRV。

专家意见

Toca 511 在早期临床试验中显示出非常有希望的结果。该载体已进入注册 III 期试验，但 2019 年底公布的结果总体呈阴性。然而，中位前药给药方案并不是最佳的，并且在一些预先指定的亚组中观察到了有希望的可能疗效。值得进一步的临床研究以及 RRV 与其他转基因有效负载的开发。