Phase I study of nivolumab combined with IFN-β for patients with advanced melanoma

Abstract

The efficacy of nivolumab is greater than that of other anti-melanoma drugs, so nivolumab-based combined therapies that enhance anti-tumor immune responses in patients with metastatic melanoma are of great interest to dermato-oncologists. As we have previously reported, IFN-β enhances the anti-tumor immune response of anti-PD-1 antibodies against B16F10 melanoma in vivo. To explore the potential of this property of IFN-β as part of a combination therapy for the treatment of metastatic melanoma patients, we performed a phase 1 trial, using a traditional rule-based 3 + 3 design, on patients with advanced melanoma. The nivolumab dose was fixed at 2 mg/kg, every 3 weeks. IFN-β was administered to three groups at doses of 1 million, 2 million, and 3 million units, respectively. Dose-limiting toxicities were defined as any grade 3-5 adverse events occurring between day 0 and day 42 that might possibly be related to nivolumab and IFN-β. Of the nine patients who received this combined therapy, none experienced dose-limiting toxicities, and all completed the treatment phase of the study. Patient follow-up continued for 6 months following the final treatment. There were two complete responses (22%) and one partial response (11%), all of which occurred in patients who had received monthly IFN-β immediately prior to the study. In this study, we determined the safe dose of IFN-β, when combined with nivolumab, to be 3 million units. To determine the efficacy of this combination therapy, further phase II trials are required.

Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance

“…Nevertheless, our data suggest that the next-generation PD-L1 antibody armed with IFNα can overcome tumor resistance to checkpoint blockade therapy in advanced tumors. The combination therapy of type I IFN with PD-1 blockade Ab for patients with advanced melanoma tested in phase I study have demonstrated the safety, and several other clinical trials are ongoing 34 . Our strategy of constructing IFNα-anti-PD-L1 may be important for improving current immunotherapies.…”

Immunomodulatory Effect of Imiquimod Through CCL22 Produced by Tumor-associated Macrophages in B16F10 Melanomas

“…Notably, TAMs are a heterogeneous population of cells that could be polarized to M1-like macrophages in the tumor microenvironment (21). Therefore, TAMs could be a promising immunotherapy target in the treatment of melanoma (13,28).…”

Synergistic effects of interferon‐beta and nivolumab in oral mucosal melanoma

“…Nivolumab can mediate tumor regression by binding to and blocking the activation of PD‐1, and these responses are durable and persisted after drug discontinuation . It has been reported that IFN‐β enhances the antitumor immune response of anti‐PD‐1 antibodies against melanoma cells in vivo and a phase I study of nivolumab combined with IFN‐β for patients with advanced melanoma has been performed . In our case, DAV‐feron therapy provided antitumor effects on an invasive tumor on the upper gingiva, but not black macular lesions on the hard palate.…”