A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma.

Abstract

Anti-programmed death (PD)-1 (aPD1) therapy is an effective treatment for metastatic melanoma (MM); however, over 50% of patients progress due to resistance. We tested a first-in-class immune-modulatory vaccine (IO102/IO103) against indoleamine 2,3-dioxygenase (IDO) and PD ligand 1 (PD-L1), targeting immunosuppressive cells and tumor cells expressing IDO and/or PD-L1 (IDO/PD-L1), combined with nivolumab. Thirty aPD1 therapy-naive patients with MM were treated in a phase 1/2 study ( https://clinicaltrials.gov/ , NCT03047928). The primary endpoint was feasibility and safety; the systemic toxicity profile was comparable to that of nivolumab monotherapy. Secondary endpoints were efficacy and immunogenicity; an objective response rate (ORR) of 80% (confidence interval (CI), 62.7-90.5%) was reached, with 43% (CI, 27.4-60.8%) complete responses. After a median follow-up of 22.9 months, the median progression-free survival (PFS) was 26 months (CI, 15.4-69 months). Median overall survival (OS) was not reached. Vaccine-specific responses assessed in vitro were detected in the blood of >93% of patients during vaccination. Vaccine-reactive T cells comprised CD4+ and CD8+ T cells with activity against IDO- and PD-L1-expressing cancer and immune cells. T cell influx of peripherally expanded T cells into tumor sites was observed in responding patients, and general enrichment of IDO- and PD-L1-specific clones after treatment was documented. These clinical efficacy and favorable safety data support further validation in a larger randomized trial to confirm the clinical potential of this immunomodulating approach.

• Authors: Julie Westerlin Kjeldsen, Cathrine Lund Lorentzen, Evelina Martinenaite, Eva Ellebaek, Marco Donia, Rikke Boedker Holmstroem, Tobias Wirenfeldt Klausen, Cecilie Oelvang Madsen, Shamaila Munir Ahmed, Stine Emilie Weis-Banke, Morten Orebo Holmström, Helle Westergren Hendel, Eva Ehrnrooth, Mai-Britt Zocca, Ayako Wakatsuki Pedersen, Mads Hald Andersen, Inge Marie Svane
• Journal: Nature medicine (Nat Med) Vol. 27 Issue 12 Pg. 2212-2223 (12 2021) ISSN: 1546-170X [Electronic] United States
• PMID: 34887574 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Adjuvants, Immunologic
• B7-H1 Antigen
• CD274 protein, human
• Cancer Vaccines
• Immune Checkpoint Inhibitors
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Nivolumab

Topics

• Adjuvants, Immunologic (administration & dosage)
• B7-H1 Antigen (immunology)
• Cancer Vaccines (administration & dosage)
• Humans
• Immune Checkpoint Inhibitors (therapeutic use)
• Indoleamine-Pyrrole 2,3,-Dioxygenase (immunology)
• Melanoma (pathology, therapy)
• Nivolumab (therapeutic use)
• Skin Neoplasms (pathology, therapy)