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Article
Julie Kjeldsen
National Center for Cancer Immune Therapy CCIT-DK
Corresponding Author
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Anti-PD-1 (aPD1) therapy is an effective treatment for metastatic melanoma (MM); however, >50% of the patients progress due to resistance. Improved combination therapies enhancing aPD1 efficacy without leading to increased toxicity are needed. In this non-randomized phase I/II study (ClinicalTrials.gov: NCT03047928), we treated 30 aPD1 naive MM patients with a novel immune-modulatory vaccine (IO102/IO103) activating indoleamine 2,3-dioxygenase (IDO) and programmed death ligand-1 (PD-L1) specific T-cells combined with nivolumab. The vaccine has a dual mechanism of action, targeting both immunosuppressive cells and tumour cells expressing IDO/PD-L1. The vaccine was administered every two weeks for the first 6 injections and every fourth week thereafter, for up to 15 vaccines. Nivolumab was administered every two weeks (3mg/kg) for a maximum of 2 years. The primary endpoint was safety and feasibility; the systemic toxicity profile was comparable to nivolumab monotherapy, except for local and transient reactions at the vaccination site. Secondary endpoints were clinical efficacy and immunogenicity. An ORR of 80% (CI: 62.7-90.5%) was reached, with the majority of 43% (CI: 27.4-60.8%) achieving a complete response. After a median follow-up of 22.9 months, the median PFS was 26 months (CI: 15.4-69). Vaccine-specific responses were detected in vitro in blood from >93% of the patients on vaccination, suggesting the induction of memory response up to 6 months after the last vaccine. Vaccine reactive T-cells comprised both CD4+ and CD8+ T-cells. Paired biopsies from five patients with matched longitudinal PBMCs showed T-cell influx at the tumour site of peripherally expanded T-cells in responding patients and general enrichment of IDO and PD-L1 clones after treatment. These unprecedented clinical efficacy data support further validation in a larger randomized trial, to confirm the clinical potential of this first-in-class immunomodulating vaccine.
Keywords
Combination Therapies, Immunosuppressive Cells, Tumor Cells, Systemic Toxicity Profile, Memory Response Induction, Paired Biopsies
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Yes there is potential Competing Interest. Mads Hald Andersen is named as an inventor on various patent applications relating to therapeutic uses of IDO and PD-L1 peptides. These patent applications are assigned to the company IO Biotech ApS, which is developing immune-modulating cancer treatments. Mads Hald Andersen is co-founder, shareholder and chief scientific officer of IO Biotech ApS. Inge Marie Svane is co-founders, shareholder, and advisor for the company IO Biotech ApS. Mai-Britt Zocca is CEO, founder and shareholder at IO Biotech ApS. Evelina Martinenaite, Ayako Wakatsuki Pedersen, and Eva Ehrnrooth are employees at IO Biotech ApS. Eva Ellebaek has received honorarium from BMS, Pierre Fabre, Roche, and Kyowa Kirin and travel support from MSD. Marco Donia has received honorarium from Genzyme, MSD, BMS, Roche, Novartis, and travel support from Novartis, MSD, BMS, Roche, and Pfizer. Inge Marie Svane has an advisory board relationship with or lectured for Roche, Novartis, MSD, Celgene, Incyte, TILT bio, Pfizer, BMS AstraZeneca, and has received limited grants for translational research from BMS, Roche, and Novartis. The remaining authors declare that they have no conflict of interest.
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This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Nature journals have partnered with Research Square to offer In Review, a journal-integrated preprint deposition service.
Article
Julie Kjeldsen
National Center for Cancer Immune Therapy CCIT-DK
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 01 Mar, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Anti-PD-1 (aPD1) therapy is an effective treatment for metastatic melanoma (MM); however, >50% of the patients progress due to resistance. Improved combination therapies enhancing aPD1 efficacy without leading to increased toxicity are needed. In this non-randomized phase I/II study (ClinicalTrials.gov: NCT03047928), we treated 30 aPD1 naive MM patients with a novel immune-modulatory vaccine (IO102/IO103) activating indoleamine 2,3-dioxygenase (IDO) and programmed death ligand-1 (PD-L1) specific T-cells combined with nivolumab. The vaccine has a dual mechanism of action, targeting both immunosuppressive cells and tumour cells expressing IDO/PD-L1. The vaccine was administered every two weeks for the first 6 injections and every fourth week thereafter, for up to 15 vaccines. Nivolumab was administered every two weeks (3mg/kg) for a maximum of 2 years. The primary endpoint was safety and feasibility; the systemic toxicity profile was comparable to nivolumab monotherapy, except for local and transient reactions at the vaccination site. Secondary endpoints were clinical efficacy and immunogenicity. An ORR of 80% (CI: 62.7-90.5%) was reached, with the majority of 43% (CI: 27.4-60.8%) achieving a complete response. After a median follow-up of 22.9 months, the median PFS was 26 months (CI: 15.4-69). Vaccine-specific responses were detected in vitro in blood from >93% of the patients on vaccination, suggesting the induction of memory response up to 6 months after the last vaccine. Vaccine reactive T-cells comprised both CD4+ and CD8+ T-cells. Paired biopsies from five patients with matched longitudinal PBMCs showed T-cell influx at the tumour site of peripherally expanded T-cells in responding patients and general enrichment of IDO and PD-L1 clones after treatment. These unprecedented clinical efficacy data support further validation in a larger randomized trial, to confirm the clinical potential of this first-in-class immunomodulating vaccine.
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