@article{10902/34532,
year = {2024},
url = {https://hdl.handle.net/10902/34532},
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.},
organization = {Acknowledgements: Kristopher R. Bosse is a Damon Runyon Physician-Scientist supported (in part) by the Damon Runyon Cancer Research Foundation (PST-07-16). This work was supported in part by a St. Baldrick’s-Stand Up to Cancer Dream Team Translational Research Grant (SU2C-AACR-DT-27-17). Stand Up to Cancer is a division of the Entertainment Industry Foundation. Research Grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. This work was also supported by the Alex’s Lemonade Stand Foundation (G.P.-P, A.J.W. and K.R.B.), by NCI K08 CA230223 (K.R.B.) and CA266914 (A.J.W.), NCI R37 CA282041 (K.R.B.), NCI U54 CA232568 (K.R.B.), a Children’s Hospital of Philadelphia Cell and Gene Therapy Collaborative Seed Grant (K.R.B.), the EVAN Foundation (K.R.B.), Solving Kids’ Cancer (K.R.B.), Fishin’ For The Cure (K.R.B.), Pierce Phillips Charity (K.R.B.), Catherine Elizabeth Blair Memorial Foundation (K.R.B.) and the Ronan Thompson Foundation (K.R.B.). We thank the DNA sequencing and Human Immunology core facilities at the University of Pennsylvania for their work on plasmid verification and human immune cell isolation, respectively. We also would like to thank the Pathology and Small Animal Imaging facility cores at the Children’s Hospital of Philadelphia. We would like to acknowledge the Center for Childhood Cancer Research (CCCR) Biorepository and Registry for providing the bone marrow specimens from neuroblastoma patients and Drs. Amy Erbe and Paul Sondel for providing the GD2 synthase vector.},
publisher = {Nature Publishing Group},
publisher = {Nature Communications, 2024, 15, 7141},
title = {CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma},
author = {Pascual-Pasto, Guillem and McIntyre, Brendan and Hines, Margaret G. and Giudice, Anna M. and García-Gerique, Laura and Hoffmann, Jennifer and Mishra, Pamela and Matlaga, Stephanie and Lombardi, Simona and Alikarami, Fatemeh and Martínez, Daniel and Tsang, Matthew and Gil de Gómez Sesma, Luis and Spar, Timothy and Bernt, Kathrin and Wolpaw, Adam J. and Dimitrov, Dimiter S. and Li, Wei and Bosse, Kristopher R.},
}