Year: 2024
Type: article
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. GPC2 and GD2 have been described as immunotherapeutic targets in neuroblastoma. Here the authors engineer T cells to simultaneously express a GPC2-directed CAR and a bispecific innate immune cell engager targeting GD2 and CD16a, showing antitumor activity in neuroblastoma preclinical models.
Source: Nature Communications
Authors: 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, Kristopher R. Bosse
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: U.S. Department of Health and Human Services, 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, National Institutes of Health, Stand Up To Cancer, National Cancer Institute
Awards: G181383032, G2118268411, G2157051813, Engaging and Enhancing Neuroblastoma Immune Targeting, G2635147154, G2775813377, G2806048016, G3213234327, cGAS-STING and therapeutic immune responses in neuroblastoma, G4882979701, G5017209498, G5250792273, Targeting the GPC2 oncoprotein with immune-based therapies in neuroblastoma, G7407334923, G7675210593, GPC2 CARs in neuroblastoma: Mechanisms of resistance and efficacy of next-generation constructs
OpenAlex ID: W4401728901