Toca 511是一种编码酵母胞嘧啶脱氨酶（yCD）基因的肿瘤选择性逆转录病毒复制载体，通过yCD将肿瘤内前药5-氟胞嘧啶（5-FC）转化为活性药物5-氟尿嘧啶来发挥直接抗肿瘤作用，并已证明具有治疗功效各种癌症的临床前和临床试验。 Toca 511/5-FC 治疗还可能诱导抗肿瘤免疫。在这里，我们首先在免疫功能正常的小鼠胰腺癌模型中检查了 Toca 511/5-FC 治疗激活的抗肿瘤免疫反应。然后我们评估了与抗程序性细胞死亡蛋白 1 抗体联合使用所达到的治疗效果。在双侧皮下肿瘤模型中，与对照组相比，未转导 Toca 511 的对侧肿瘤中观察到 CD8 T 细胞介导的细胞毒性增强，T 细胞浸润增加。此外，治疗期间 CD8 T 细胞上 T 细胞共抑制受体的表达水平增加。在双侧皮下肿瘤模型中，联合治疗显示出比任一单一治疗显着更强的肿瘤生长抑制作用。在原位肿瘤和腹膜播散模型中，联合治疗导致转导的原位肿瘤和未转导的腹膜播散完全消退。因此，Toca 511/5-FC 治疗诱导了全身抗肿瘤免疫反应，联合疗法可能成为治疗转移性胰腺癌的一种有前途的临床策略。© 2024。作者，获得 Springer Nature America, Inc 的独家许可。

Toca 511, a tumor-selective retroviral replicating vector encoding the yeast cytosine deaminase (yCD) gene, exerts direct antitumor effects through intratumoral prodrug 5-fluorocytosine (5-FC) conversion to active drug 5-fluorouracil by yCD, and has demonstrated therapeutic efficacy in preclinical and clinical trials of various cancers. Toca 511/5-FC treatment may also induce antitumor immunity. Here, we first examined antitumor immune responses activated by Toca 511/5-FC treatment in an immunocompetent murine pancreatic cancer model. We then evaluated the therapeutic effects achieved in combination with anti-programmed cell death protein 1 antibody. In the bilateral subcutaneous tumor model, as compared with the control group, enhanced CD8+ T-cell-mediated cytotoxicity and increased T-cell infiltration in Toca 511-untransduced contralateral tumors were observed. Furthermore, the expression levels of T-cell co-inhibitory receptors on CD8+ T-cells increased during treatment. In the bilateral subcutaneous tumor model, combination therapy showed significantly stronger tumor growth inhibition than that achieved with either monotherapy. In an orthotopic tumor and peritoneal dissemination model, the combination therapy resulted in complete regression in both transduced orthotopic tumors and untransduced peritoneal dissemination. Thus, Toca 511/5-FC treatment induced a systemic antitumor immune response, and the combination therapy could be a promising clinical strategy for treating metastatic pancreatic cancer.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.