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

Julie Westerlin Kjeldsen,Ayako Wakatsuki Pedersen,Morten Orebo Holmström,Stine Emilie Weis-Banke,Evelina Martinenaite,Tobias Wirenfeldt Klausen,Helle Westergren Hendel,Eva Ellebaek,Inge Marie Svane,Cecilie Oelvang Madsen,Rikke Boedker Holmstroem,Mai-Britt Zocca,Marco Donia,Cathrine Lund Lorentzen,Mads Hald Andersen,Shamaila Munir Ahmed,Eva Ehrnrooth

doi:10.1038/s41591-021-01544-x

Julie Westerlin Kjeldsen, Ayako Wakatsuki Pedersen + Show 15 more

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https://doi.org/10.1038/s41591-021-01544-x

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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.

Highlights

Despite remarkable advances in the treatment of MM with immune checkpoint inhibitors (ICIs) targeting programmed death (PD)-1 and cytotoxic T lymphocyte antigen 4 (CTLA-4), around half of patients are resistant to ICI monotherapy[1]
We found no relation between clinical response and the enrichment of vaccine-specific clones, but an increase in IDO/ PD ligand 1 (PD-L1)-specific T cell clones was observed at different time points in the periphery in all five patients (Extended Data Fig. 3c)
Except for patient MM13 (PR), distance and clinical responses were associated: the two responders had reduced distance (80 μm). This observation indicates that responding patients have a higher intratumoral infiltration of CD8+ T cells, but that these cells can surround and attack PD-L1-expressing immune cells and tumor cells (Extended Data Fig. 10b). In this clinical trial, MM1636, 30 patients with metastatic melanoma were treated with a first-in-class immunomodulatory IDO/

Summary

Introduction

Despite remarkable advances in the treatment of MM with immune checkpoint inhibitors (ICIs) targeting PD-1 and cytotoxic T lymphocyte antigen 4 (CTLA-4), around half of patients are resistant to ICI monotherapy[1]. We hypothesize that the IDO/PD-L1 vaccine attracts T cells into the tumor, which induces type 1 helper T (TH1) cell inflammation and reverts the TME into an immune-permissive site, thereby turning the tumor ‘hot’. This would upregulate PD-L1 expression in cancer and immune cells, generating more susceptible targets to aPD1 therapy (Extended Data Fig. 1a). Nivolumab was given in parallel, biweekly (3 mg per kg) or every 4th week (6 mg per kg) for up to 2 years (Extended Data Fig. 1b)

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