Novel oncolytic adenovirus expressing enhanced cross-hybrid IgGA Fc PD-L1 inhibitor activates multiple immune effector populations leading to enhanced tumor killing in vitro, in vivo and with patient-derived tumor organoids

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dc.contributor.author Hamdan, Firas
dc.contributor.author Ylösmäki, Erkko
dc.contributor.author Chiaro, Jacopo
dc.contributor.author Giannoula, Yvonne
dc.contributor.author Long, Maeve
dc.contributor.author Fusciello, Manlio
dc.contributor.author Feola, Sara
dc.contributor.author Martins, Beatriz
dc.contributor.author Feodoroff, Michaela
dc.contributor.author Antignani, Gabriella
dc.contributor.author Russo, Salvatore
dc.contributor.author Kari, Otto
dc.contributor.author Lee, Moon
dc.contributor.author Järvinen, Petrus
dc.contributor.author Nisen, Harry
dc.contributor.author Kreutzman, Anna
dc.contributor.author Leusen, Jeanette
dc.contributor.author Mustjoki, Satu
dc.contributor.author McWilliams, Thomas G.
dc.contributor.author Grönholm, Mikaela
dc.contributor.author Cerullo, Vincenzo
dc.date.accessioned 2021-08-19T09:35:01Z
dc.date.available 2021-08-19T09:35:01Z
dc.date.issued 2021
dc.identifier.citation Hamdan , F , Ylösmäki , E , Chiaro , J , Giannoula , Y , Long , M , Fusciello , M , Feola , S , Martins , B , Feodoroff , M , Antignani , G , Russo , S , Kari , O , Lee , M , Järvinen , P , Nisen , H , Kreutzman , A , Leusen , J , Mustjoki , S , McWilliams , T G , Grönholm , M & Cerullo , V 2021 , ' Novel oncolytic adenovirus expressing enhanced cross-hybrid IgGA Fc PD-L1 inhibitor activates multiple immune effector populations leading to enhanced tumor killing in vitro, in vivo and with patient-derived tumor organoids ' , Journal for Immunotherapy of Cancer , vol. 9 , no. 8 , 003000 . https://doi.org/10.1136/jitc-2021-003000
dc.identifier.other PURE: 167714527
dc.identifier.other PURE UUID: 1bb6aa39-0ef5-42a2-9c09-9d7ed516068e
dc.identifier.other WOS: 000683445500002
dc.identifier.other ORCID: /0000-0002-9570-4152/work/98707629
dc.identifier.other ORCID: /0000-0002-1201-5010/work/98708194
dc.identifier.other ORCID: /0000-0002-3778-0237/work/98708972
dc.identifier.other ORCID: /0000-0002-0816-8241/work/98709141
dc.identifier.other ORCID: /0000-0002-6094-9838/work/107675184
dc.identifier.uri http://hdl.handle.net/10138/333309
dc.description.abstract Background Despite the success of immune checkpoint inhibitors against PD-L1 in the clinic, only a fraction of patients benefit from such therapy. A theoretical strategy to increase efficacy would be to arm such antibodies with Fc-mediated effector mechanisms. However, these effector mechanisms are inhibited or reduced due to toxicity issues since PD-L1 is not confined to the tumor and also expressed on healthy cells. To increase efficacy while minimizing toxicity, we designed an oncolytic adenovirus that secretes a cross-hybrid Fc-fusion peptide against PD-L1 able to elicit effector mechanisms of an IgG1 and also IgA1 consequently activating neutrophils, a population neglected by IgG1, in order to combine multiple effector mechanisms. Methods The cross-hybrid Fc-fusion peptide comprises of an Fc with the constant domains of an IgA1 and IgG1 which is connected to a PD-1 ectodomain via a GGGS linker and was cloned into an oncolytic adenovirus. We demonstrated that the oncolytic adenovirus was able to secrete the cross-hybrid Fc-fusion peptide able to bind to PD-L1 and activate multiple immune components enhancing tumor cytotoxicity in various cancer cell lines, in vivo and ex vivo renal-cell carcinoma patient-derived organoids. Results Using various techniques to measure cytotoxicity, the cross-hybrid Fc-fusion peptide expressed by the oncolytic adenovirus was shown to activate Fc-effector mechanisms of an IgA1 (neutrophil activation) as well as of an IgG1 (natural killer and complement activation). The activation of multiple effector mechanism simultaneously led to significantly increased tumor killing compared with FDA-approved PD-L1 checkpoint inhibitor (Atezolizumab), IgG1-PDL1 and IgA-PDL1 in various in vitro cell lines, in vivo models and ex vivo renal cell carcinoma organoids. Moreover, in vivo data demonstrated that Ad-Cab did not require CD8+ T cells, unlike conventional checkpoint inhibitors, since it was able to activate other effector populations. Conclusion Arming PD-L1 checkpoint inhibitors with Fc-effector mechanisms of both an IgA1 and an IgG1 can increase efficacy while maintaining safety by limiting expression to the tumor using oncolytic adenovirus. The increase in tumor killing is mostly attributed to the activation of multiple effector populations rather than activating a single effector population leading to significantly higher tumor killing. en
dc.format.extent 19
dc.language.iso eng
dc.relation.ispartof Journal for Immunotherapy of Cancer
dc.rights cc_by_nc
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject antibody formation
dc.subject immunotherapy
dc.subject oncolytic virotherapy
dc.subject GAMMA-RS
dc.subject T-CELLS
dc.subject ANTIBODY
dc.subject CANCER
dc.subject NEUTROPHILS
dc.subject RECEPTOR
dc.subject EFFICACY
dc.subject REPLICATION
dc.subject BLOCKADE
dc.subject THERAPY
dc.subject 317 Pharmacy
dc.subject 3122 Cancers
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title Novel oncolytic adenovirus expressing enhanced cross-hybrid IgGA Fc PD-L1 inhibitor activates multiple immune effector populations leading to enhanced tumor killing in vitro, in vivo and with patient-derived tumor organoids en
dc.type Article
dc.contributor.organization Division of Pharmaceutical Biosciences
dc.contributor.organization Drug Research Program
dc.contributor.organization ImmunoViroTherapy Lab
dc.contributor.organization Drug Delivery
dc.contributor.organization TRIMM - Translational Immunology Research Program
dc.contributor.organization STEMM - Stem Cells and Metabolism Research Program
dc.contributor.organization Department of Anatomy
dc.contributor.organization Medicum
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Research Services
dc.contributor.organization Drug Delivery Unit
dc.contributor.organization HUS Abdominal Center
dc.contributor.organization HUSLAB
dc.contributor.organization HUS Comprehensive Cancer Center
dc.contributor.organization Department of Clinical Chemistry and Hematology
dc.contributor.organization Digital Precision Cancer Medicine (iCAN)
dc.contributor.organization Research Programs Unit
dc.contributor.organization Faculty of Medicine
dc.contributor.organization Biosciences
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1136/jitc-2021-003000
dc.relation.issn 2051-1426
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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