Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
Targeted Therapy Group, Institute of Cancer Research, London, United Kingdom.
Clin Cancer Res. 2019 Oct 1;25(19):5818-5831. doi: 10.1158/1078-0432.CCR-18-4022. Epub 2019 Jul 4.
The CANON [VATAK in -muscle-invasive bladder cancer (NMIBC)] study evaluated a novel ICAM-1-targeted immunotherapeutic-coxsackievirus A21 as a novel oncolytic agent against bladder cancer.
Fifteen patients enrolled in this "window of opportunity" phase I study, exposing primary bladder cancers to CAVATAK prior to surgery. The first 9 patients received intravesical administration of monotherapy CAVATAK; in the second stage, 6 patients received CAVATAK with a subtherapeutic dose of mitomycin C, known to enhance expression of ICAM-1 on bladder cancer cells. The primary endpoint was to determine patient safety and maximum tolerated dose (MTD). Secondary endpoints were evidence of viral replication, induction of inflammatory cytokines, antitumor activity, and viral-induced changes in resected tissue.
Clinical activity of CAVATAK was demonstrated by induction of tumor inflammation and hemorrhage following either single or multiple administrations of CAVATAK in multiple patients, and a complete resolution of tumor in 1 patient. Whether used alone or in combination with mitomycin C, CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by upregulating IFN-inducible genes, including both immune checkpoint inhibitory genes (PD-L1 and LAG3) and Th1-associated chemokines, as well as the induction of the innate activator RIG-I, compared with bladder cancer tissue from untreated patients. No significant toxicities were reported in any patient, from either virus or combination therapy.
The acceptable safety profile of CAVATAK, proof of viral targeting, replication, and tumor cell death together with the virus-mediated increases in "immunological heat" within the tumor microenvironment all indicate that CAVATAK may be potentially considered as a novel therapeutic for NMIBC.
CANON [VATAK 在肌层浸润性膀胱癌（NMIBC）] 研究评估了一种新型的 ICAM-1 靶向免疫治疗 - 柯萨奇病毒 A21 作为一种新型溶瘤剂治疗膀胱癌。
15 名患者参加了这项“机会之窗”I 期研究，在手术前将原发性膀胱癌暴露于 CAVATAK 下。前 9 名患者接受了单药 CAVATAK 膀胱内给药；在第二阶段，6 名患者接受了 CA-VATAK 联合亚治疗剂量丝裂霉素 C，已知丝裂霉素 C 可增强膀胱癌细胞上 ICAM-1 的表达。主要终点是确定患者的安全性和最大耐受剂量（MTD）。次要终点是病毒复制的证据、炎症细胞因子的诱导、抗肿瘤活性和病毒引起的切除组织变化。
CAVATAK 的临床活性表现为在多个患者中单次或多次给予 CAVATAK 后诱导肿瘤炎症和出血，并且 1 例患者的肿瘤完全消退。CAVATAK 无论是单独使用还是与丝裂霉素 C 联合使用，都通过上调 IFN 诱导基因，包括免疫检查点抑制基因（PD-L1 和 LAG3）和 Th1 相关趋化因子，以及诱导先天激活剂 RIG-I，引起 NMIBC 组织活检中的明显炎症变化，与未经治疗的患者的膀胱癌组织相比。没有报道任何患者因病毒或联合治疗而出现明显毒性。
CAVATAK 的可接受安全性特征、病毒靶向、复制和肿瘤细胞死亡的证据，以及肿瘤微环境中病毒介导的“免疫热”增加，都表明 CAVATAK 可能被认为是 NMIBC 的一种新型治疗方法。
