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
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
(2021) Journal for ImmunoTherapy of Cancer, volume 9, issue 8
(Article)
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
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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.
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Keywords: antibody formation, immunotherapy, oncolytic virotherapy, Molecular Medicine, Oncology, Cancer Research, Immunology and Allergy, Pharmacology, Immunology, Journal Article
ISSN: 2051-1426
Publisher: BioMed Central Ltd.
Note: Funding Information: Funding FH thanks the Research Foundation of the University of Helsinki for funding his doctoral studies at the Faculty of Pharmacy, Helsinki University. VC acknowledges the European Research Council under the Horizon 2020 framework (https://erc.europa.eu), ERC-consolidator Grant (Agreement no. 681219), Jane and Aatos Erkko Foundation (Project no. 4705796), HiLIFE Fellow (Project no. 797011004), Cancer Finnish Foundation (Project no. 4706116), Magnus Ehrnrooth Foundation (Project no. 4706235), Academy of Finland and Digital Precision Cancer Medicine Flagship iCAN. SM received funding from the Cancer Foundation Finland, the Sigrid Juselius Foundation, the Relander Foundation, state funding for university-level research in Finland and HiLife fellow funds from the University of Helsinki. Publisher Copyright: © 2021 EDP Sciences. All rights reserved.
(Peer reviewed)