Table 2.

Clinical trials of a combination of PD-1/PD-L1 blockade with type I interferon in cancer therapy.

Summary	Clinical stage	Reference
The combined safe dose was determined to be 3x106 units. The rate of complete tumour response was ~22% (95% CI), higher than nivolumab alone (~9%). Overall, IFNβ does not increase the rate of immune-related adverse events and may even enhance nivolumab’s anti-melanoma effects.	Phase I, IFNβ plus nivolumab in metastatic melanoma (9 patients).	(6)
The combinatorial treatment was well-tolerated and showed promising efficacy in the treatment of melanoma. Additionally, the treatment was found to have a positive impact on the T-cell repertoire enhancing the immune response against melanoma cells.	Phase I, a combination treatment of neoadjuvant ipilimumab (3 mg/kg or 10 mg/kg) and high dose IFNα-2b in patients with advanced melanoma (30 patients).	(22)
The standard dose (2 mg/kg) of pembrolizumab plus pegylated IFNα-2b (1 μg/kg/week) was identified as the maximum tolerated dose. However, a poor tolerability profile and minimal antitumor activity were observed.	Phase Ib, combining pembrolizumab with either pegylated IFMα-2b for the treatment of advanced melanoma or renal cell carcinoma (17 patients)	(23)
The combinational treatment pembrolizumab (2 mg/kg) and pegylated-IFN (3 μg/kg) per week showed to be an active and safe option for patients with the objective response rate (ORR) ~23%.	Phase Ib/II, a combination of pembrolizumab and pegylated-IFNα-2b in metastatic melanoma (PD-1-naïve melanoma) (26 patients)	(24)
The combinatorial treatment was largely well-tolerated, with side effects being mild or moderate. The overall response rate was 61%, with 14 patients having a complete or partial response. The pathologic response rate was 78%, indicating significant tumour shrinkage with a median disease-free survival (~22 months) and a 2-year overall survival rate (74%). Overall, the treatment was considered efficient with hypophosphatemia and fatigue as side effects.	Phase Ib/II, neoadjuvant pembrolizumab (200 mg intravenously every 3 weeks) and high-dose IFNα-2b (intravenously 20 MU/m2/day, 5 days/week for 4 weeks, followed subcutaneously 10 MU/m2/day, 3 days/week for 2 weeks) were given to resectable stage III melanoma in two cycles before surgery (30 patients).	(25)
Prior pegylated IFNα-2b therapy improved the efficacy of subsequent adjuvant pembrolizumab and increased recurrence-free survival (median 8.5 vs. 4.5 months).	Clinical retrospective analysis for melanoma (25 patients)	(26)