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

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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.

OriginalsprogEngelsk
TidsskriftNature Medicine
Vol/bind27
Udgave nummer12
Sider (fra-til)2212-2223
Antal sider12
ISSN1078-8956
DOI
StatusUdgivet - dec. 2021

Bibliografisk note

Funding Information:
We thank all patients and their relatives for being a part of the trial. We thank Ö. Met, M. Jonassen, S. Ullitz Færch, B. Saxild, S. Wendt and C. Grønhøj for technical support. We thank M. Cumberbatch for input with translational analysis. We thank the nurses at clinic 5 and the head of the Oncology Department at Herlev and Gentofte Hospital, L. Sengeløv. The study was funded through a research funding agreement between IO Biotech and the CCIT-DK, Herlev Hospital and the Oncology Department at Herlev Hospital.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

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