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CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma

Author

Listed:
  • Guillem Pascual-Pasto

    (Children’s Hospital of Philadelphia)

  • Brendan McIntyre

    (Children’s Hospital of Philadelphia)

  • Margaret G. Hines

    (University of Pittsburgh School of Medicine)

  • Anna M. Giudice

    (Children’s Hospital of Philadelphia)

  • Laura Garcia-Gerique

    (The Wistar Institute
    University of Pennsylvania Perelman School of Medicine)

  • Jennifer Hoffmann

    (Children’s Hospital of Philadelphia)

  • Pamela Mishra

    (Children’s Hospital of Philadelphia
    Children’s Hospital of Philadelphia)

  • Stephanie Matlaga

    (Children’s Hospital of Philadelphia)

  • Simona Lombardi

    (Children’s Hospital of Philadelphia)

  • Rawan Shraim

    (Children’s Hospital of Philadelphia
    Children’s Hospital of Philadelphia)

  • Patrick M. Schürch

    (Children’s Hospital of Philadelphia)

  • Mark Yarmarkovich

    (Children’s Hospital of Philadelphia
    Grossman School of Medicine)

  • Ted J. Hofmann

    (Children’s Hospital of Philadelphia)

  • Fatemeh Alikarami

    (Children’s Hospital of Philadelphia)

  • Daniel Martinez

    (Children’s Hospital of Philadelphia)

  • Matthew Tsang

    (Children’s Hospital of Philadelphia)

  • Luis Gil-de-Gómez

    (Children’s Hospital of Philadelphia
    University of Cantabria School of Medicine)

  • Timothy T. Spear

    (Children’s Hospital of Philadelphia)

  • Kathrin M. Bernt

    (Children’s Hospital of Philadelphia
    Perelman School of Medicine at the University of Pennsylvania)

  • Adam J. Wolpaw

    (Children’s Hospital of Philadelphia
    Perelman School of Medicine at the University of Pennsylvania)

  • Dimiter S. Dimitrov

    (University of Pittsburgh School of Medicine)

  • Wei Li

    (University of Pittsburgh School of Medicine)

  • Kristopher R. Bosse

    (Children’s Hospital of Philadelphia
    Perelman School of Medicine at the University of Pennsylvania)

Abstract

Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells.

Suggested Citation

  • Guillem Pascual-Pasto & Brendan McIntyre & Margaret G. Hines & Anna M. Giudice & Laura Garcia-Gerique & Jennifer Hoffmann & Pamela Mishra & Stephanie Matlaga & Simona Lombardi & Rawan Shraim & Patrick, 2024. "CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51337-2
    DOI: 10.1038/s41467-024-51337-2
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    References listed on IDEAS

    as
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