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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http://hdl.handle.net/10138/333309

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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

Titel: 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
Författare: Hamdan, Firas; Ylösmäki, Erkko; Chiaro, Jacopo; Giannoula, Yvonne; Long, Maeve; Fusciello, Manlio; Feola, Sara; Martins, Beatriz; Feodoroff, Michaela; Antignani, Gabriella; Russo, Salvatore; Kari, Otto; Lee, Moon; Järvinen, Petrus; Nisen, Harry; Kreutzman, Anna; Leusen, Jeanette; Mustjoki, Satu; McWilliams, Thomas G.; Grönholm, Mikaela; Cerullo, Vincenzo
Upphovmannens organisation: Division of Pharmaceutical Biosciences
Drug Research Program
ImmunoViroTherapy Lab
Drug Delivery
TRIMM - Translational Immunology Research Program
STEMM - Stem Cells and Metabolism Research Program
Department of Anatomy
Medicum
Institute for Molecular Medicine Finland
Research Services
Drug Delivery Unit
HUS Abdominal Center
HUSLAB
HUS Comprehensive Cancer Center
Department of Clinical Chemistry and Hematology
Digital Precision Cancer Medicine (iCAN)
Research Programs Unit
Faculty of Medicine
Biosciences
Datum: 2021
Språk: eng
Sidantal: 19
Tillhör serie: Journal for Immunotherapy of Cancer
ISSN: 2051-1426
DOI: https://doi.org/10.1136/jitc-2021-003000
Permanenta länken (URI): http://hdl.handle.net/10138/333309
Abstrakt: 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.
Subject: antibody formation
immunotherapy
oncolytic virotherapy
GAMMA-RS
T-CELLS
ANTIBODY
CANCER
NEUTROPHILS
RECEPTOR
EFFICACY
REPLICATION
BLOCKADE
THERAPY
317 Pharmacy
3122 Cancers
1182 Biochemistry, cell and molecular biology
Referentgranskad: Ja
Licens: cc_by_nc
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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