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Germinal Immunogenetics predict treatment outcome for PD-1/PD-L1 checkpoint inhibitors

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A Correction to this article was published on 04 June 2020

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Summary

Background Checkpoint inhibitors bring marked benefits but only in a minority of patients and may also be associated with severe adverse events. Treatment outcome still cannot be faithfully predicted. The following study hypothesized that host genetics could be applied as predictive biomarkers for checkpoint inhibitor response and immune-related adverse events. We conducted a study based on germinal polymorphisms from genes coding for proteins involved in immune regulation. Methods Germinal DNA was obtained from advanced cancer patients treated with anti-PD-1/PD-L1 checkpoint inhibitors. DNA was genotyped using a custom panel of 166 single nucleotide polymorphisms covering 86 preselected immunogenetic-related genes. Computational analysis using a GTEX portal was made to determine potential expression Quantitative Trait Loci in tissues. Results Ninety-four consecutive patients were included. Objective response rate (complete or partial response) was significantly correlated to tumor microenvironment-related SNPs concerning CCL2, NOS3, IL1RN, IL12B, CXCR3 and IL6R genes. Toxicity were linked to target-related gene SNPs including UNG, IFNW1, CTLA4, PD-L1 and IFNL4 genes. The Area Under the ROC curve (AUC) was 0.81 (95% CI: 0.72–0.9) for response and 0.89 (95% CI: 0.76–1.00) for toxicity. In silico functionality exploring pointed rs4845618 (IL6R), rs10964859 (IFNW1) and rs3087243 (CTLA4) as potentially impacting gene expression. Conclusion These results strongly support a role for distinct immunogenetic-related gene SNPs able to predict efficacy and safety of anti-PD1/PD-L1 therapies. The results highlight the existence of patient-specific, germinal biomarkers able predict response to checkpoint inhibitor efficacy and, possibly, to predict treatment-related adverse events.

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  • 04 June 2020

    Corrections are needed to the original version of this article.

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Acknowledgements

The authors acknowledge support from University Côte d’Azur, Centre Antoine Lacassagne, Oncopharmacology Unit, France.

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Authors and Affiliations

  1. Centre Antoine Lacassagne, University Côte d’Azur, Oncopharmacology Unit, F-06189, Nice, France

    Sadal Refae, Nathalie Ebran & Gérard Milano

  2. Centre Antoine Lacassagne, Epidemiology and Biostatistics Department, University Côte d’Azur, F-06189, Nice, France

    Jocelyn Gal & Emmanuel Chamorey

  3. Centre Antoine Lacassagne, Medical Oncology Department, University Côte d’Azur, F-06189, Nice, France

    Josiane Otto, Delphine Borchiellini, Frederic Peyrade & Esma Saada-Bouzid

  4. Centre Antoine Lacassagne, CNRS, Inserm, Ircan, FHU-Oncoage, University Côte d’Azur, F-06189, Nice, France

    Patrick Brest

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  1. Sadal Refae
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All authors have been participated in the writing and involved in critical revision of this manuscript for important intellectual content. All authors approved this manuscript.

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Correspondence to Gérard Milano or Esma Saada-Bouzid.

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Gérard Milano is a member of an advisory board at BMS, MSD and Merck. Fréderic Peyrade is a member of an advisory board at MSD and Merck. Delphine Borchiellini is a member of an advisory board at MSD, Pfizer, Astra-Zeneca, Roche, BMS. The remaining authors declare no competing interests.

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Refae, S., Gal, J., Ebran, N. et al. Germinal Immunogenetics predict treatment outcome for PD-1/PD-L1 checkpoint inhibitors. Invest New Drugs 38, 160–171 (2020). https://doi.org/10.1007/s10637-019-00845-w

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