IL-12R x IL-15Rα x PDL1

Safety Run-in Cohort (cohort 1):
10 patients will be treated with IT injection of VG161 in the cohort 1 at dose level of 1.0x10E8 PFU x 3 days.
Monotherapy Cohorts (Cohort 2 and 3) Cohort 2 (HCC) This part is a single-agent, single one-dose level and single-arm design. Approximately 39 subjects will be enrolled in the study to receive VG161. In the first stage, 21 subjects will be enrolled. If there is only 1 or fewer subjects has been observed with objective response and no more than 12 (<13) subjects have PFS longer than 3 months, the trial will be stopped. Otherwise, this study will continue to enter the second stage, and 18 additional subjects will be added, and the total number of trial subjects will reach 39.
Cohort 3 (ICC) This part is a single-agent, single one-dose level and single-arm design. The trial will be carried out in two periods. In the first period, a total of 20 subjects will be enrolled. If there is only 1 or fewer response case in the 20 subjects, the trial will be stopped to investigate the efficacy of the IP, otherwise, subjects will continue to enter the second period, and 13 additional subjects will be added, and the total number of trial cases will reach 33.
Cohort 4 (ICC and HCC) Combination with Nivolumab Combination cohort and subjects will receive VG161 at the same schedule as the monotherapy cohorts and 240 mg of intravenous Nivolumab on days 8 and 15 of each treatment cycle. The Nivolumab dose can be changed to 480 mg every 4 weeks after cycle one based on investigator's discretion.

Ib期主要目的：评价VG161连续多次肿瘤内注射给药联合卡瑞利珠单抗治疗晚期原发性肝细胞癌患者的安全性和耐受性，探索联合治疗最适合的II期推荐剂量（RP2D）。次要目的： 1）初步评价VG161联合卡瑞利珠单抗治疗晚期原发性肝细胞癌患者的抗肿瘤活性；2）监测药效学相关的免疫学指标变化； 3）评价I型单纯疱疹病毒抗体滴度水平对VG161安全性、有效性的影响。IIa期主要目的：评价VG161连续多次肿瘤内注射给药联合卡瑞利珠单抗治疗晚期原发性肝细胞癌患者的有效性，主要观察指标是客观缓解率（ORR）。次要目的：1）评价联合治疗有效性的次要观察指标，包括疾病控制率（DCR）、无进展生存期（PFS）、总生存期（OS）、缓解持续时间（DOR）；2）监测药效学相关的免疫学指标变化；3）进一步评价 VG161联合卡瑞利珠单抗治疗的安全性。4）评价I型单纯疱疹病毒抗体滴度水平对VG161安全性、有效性的影响