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Pediatric cancers often mimic fetal tissues and express proteins normally silenced postnatally that could serve as immune targets. We developed T cells expressing chimeric antigen receptors (CARs) targeting glypican-2 (GPC2), a fetal antigen expressed on neuroblastoma (NB) and several other solid tumors. CARs engineered using standard designs control NBs with transgenic GPC2 overexpression, but not those expressing clinically relevant GPC2 site density (∼5,000 molecules/cell, range 1–6 × 103). Iterative engineering of transmembrane (TM) and co-stimulatory domains plus overexpression of c-Jun lowered the GPC2-CAR antigen density threshold, enabling potent and durable eradication of NBs expressing clinically relevant GPC2 antigen density, without toxicity. These studies highlight the critical interplay between CAR design and antigen density threshold, demonstrate potent efficacy and safety of a lead GPC2-CAR candidate suitable for clinical testing, and credential oncofetal antigens as a promising class of targets for CAR T cell therapy of solid tumors. [Display omitted] • GPC2-CARs with standard 41BB designs require >3 × 104 molecules for full activation • Metastatic neuroblastomas express ∼5 × 103 GPC2 molecules/cell • CAR antigen density threshold is highly tunable using modular engineering and c-Jun overexpression • Tuned GPC2 CAR T cells mediate potent neuroblastoma regression without toxicity Heitzeneder et al. develop potent chimeric antigen receptor (CAR) T cells targeting glypican-2 (GPC2), an oncofetal antigen expressed in neuroblastoma. Accurate quantification of antigen density on clinical samples demonstrated that potency of traditionally designed GPC2-CARs was limited due to inadequate antigen sensitivity. Iterative engineering of CARs overcomes this limit, achieving profound anti-tumor efficacy without compromising safety. [ABSTRACT FROM AUTHOR]