我们展示了一种二元的溶瘤/助手依赖性腺病毒（CAdVEC），它既溶解肿瘤细胞，又能本地表达促炎症细胞因子IL-12和PD-L1阻断抗体，在人源鼠模型中具有强大的抗肿瘤活性。根据这些临床前研究，我们给四位患者单次肿瘤内注射超低剂量的CAdVEC治疗（NCT03740256），这代表一个溶瘤腺病毒剂量比以前的试验低了100倍以上。虽然CAdVEC没有引起重大的毒性反应，但它重新极化了肿瘤微环境，增加了CD8 T细胞的浸润。单次CAdVEC的治疗与局部和远隔的转移瘤的效果相关，并且与免疫检查点抗体的系统治疗结合，引发了持续的抗肿瘤反应，包括一个完全缓解和两个部分缓解。因此，无论是临床前还是临床研究，CAdVEC都非常安全，即使在极低剂量下也具有通过溶解肿瘤和免疫极化引发重大肿瘤控制的足够强的功效。

We show that a binary oncolytic/helper-dependent adenovirus (CAdVEC) that both lyses tumor cells and locally expresses the proinflammatory cytokine IL-12 and PD-L1 blocking antibody has potent antitumor activity in humanized mouse models. On the basis of these preclinical studies, we treated four patients with a single intratumoral injection of an ultralow dose of CAdVEC (NCT03740256), representing a dose of oncolytic adenovirus more than 100-fold lower than used in previous trials. While CAdVEC caused no significant toxicities, it repolarized the tumor microenvironment with increased infiltration of CD8 T cells. A single administration of CAdVEC was associated with both locoregional and abscopal effects on metastases and, in combination with systemic administration of immune checkpoint antibodies, induced sustained antitumor responses, including one complete and two partial responses. Hence, in both preclinical and clinical studies, CAdVEC is safe and even at extremely low doses is sufficiently potent to induce significant tumor control through oncolysis and immune repolarization.