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

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 M. Schürch, Mark Yarmarkovich, Ted J. Hofmann, Fatemeh Alikarami, Daniel Martinez, Matthew Tsang, Luis Gil- de-Gómez, Timothy T. Spear, Kathrin M. Bernt, Adam J. Wolpaw, Dimiter S. Dimitrov, Wei Li and Kristopher R. Bosse ()
Additional contact information
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
Jennifer Hoffmann: Children’s Hospital of Philadelphia
Pamela Mishra: 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
Patrick M. Schürch: Children’s Hospital of Philadelphia
Mark Yarmarkovich: Children’s Hospital of Philadelphia
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
Timothy T. Spear: Children’s Hospital of Philadelphia
Kathrin M. Bernt: Children’s Hospital of Philadelphia
Adam J. Wolpaw: Children’s Hospital of Philadelphia
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

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51337-2

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