CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma
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.
Authors
- Luis Gil‐de‐Gómez (ORCID: https://orcid.org/0000-0002-7864-3976)
- Jennifer Hoffmann (ORCID: https://orcid.org/0000-0002-5202-0893)
- Kristopher R. Bosse (ORCID: https://orcid.org/0000-0002-1424-2858)
- Pamela Mishra
- Adam J. Wolpaw (ORCID: https://orcid.org/0000-0002-1373-7648)
- Fatemeh Alikarami (ORCID: https://orcid.org/0000-0002-3600-9192)
- Mark Yarmarkovich (ORCID: https://orcid.org/0000-0003-4638-2019)
- Timothy T. Spear (ORCID: https://orcid.org/0000-0001-7740-5119)
- Rawan Shraim (ORCID: https://orcid.org/0009-0005-5350-3386)
- Daniel Martínez (ORCID: https://orcid.org/0000-0002-4723-9989)
- Margaret G. Hines
- Matthew Tsang
- Brendan McIntyre (ORCID: https://orcid.org/0000-0002-6473-5140)
- Patrick M. Schürch (ORCID: https://orcid.org/0000-0003-3895-2149)
- Anna Maria Giudice (ORCID: https://orcid.org/0000-0002-3296-175X)
- Simona Lombardi (ORCID: https://orcid.org/0000-0002-4891-3920)
- Laura Garcia-Gerique (ORCID: https://orcid.org/0000-0002-5064-9233)
- Guillem Pascual‐Pasto (ORCID: https://orcid.org/0000-0001-8537-261X)
- Kathrin M. Bernt (ORCID: https://orcid.org/0000-0002-0691-356X)
- Dimiter S. Dimitrov (ORCID: https://orcid.org/0000-0002-2258-1024)
- Stephanie Matlaga (ORCID: https://orcid.org/0009-0005-7463-6022)
- Wei Li (ORCID: https://orcid.org/0000-0002-6960-7404)
- Ted J. Hofmann
Institutions
- The Wistar Institute (US)
- Universidad de Cantabria (ES)
- Children's Hospital of Philadelphia (US)
- University of Pittsburgh (US)
- Parker Institute for Cancer Immunotherapy (US)
- New York University (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1038/s41467-024-51337-2
- Citations
- 28
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 7.91
Funders
- American Association for Cancer Research
- Damon Runyon Cancer Research Foundation
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Solving Kids' Cancer
- Children's Hospital of Philadelphia
- University of Pennsylvania
- Stand Up To Cancer
- National Cancer Institute