Bioengineered cell therapies for pediatric solid tumors: unmet needs and a measurement-integrated approach.

Abstract

Pediatric solid tumors continue to pose a major therapeutic challenge, with survival gains lagging behind those achieved in pediatric hematologic malignancies. While traditional approaches have focused on dose escalation and intensification of systemic therapies to improve survival, this strategy is often limited by significant short- and long-term morbidity from intensive multimodal treatment. Because children have developing organs and decades of life ahead, therapeutic strategies must balance durable tumor control with preservation of neurodevelopment, organ function, and quality of life. Immunotherapy has generated significant interest as an alternative to dose escalation; however, clinical translation in pediatric solid tumors has been limited by antigen heterogeneity, tumor plasticity, immune-cold or immune-excluded phenotypes, and a profoundly immunosuppressive tumor microenvironment. Bioengineered cellular therapies, particularly chimeric antigen receptor (CAR) T cells and CAR-modified natural killer (CAR NK) cells, provide a modular platform to address these barriers through synthetic receptor design, multi-antigen targeting, controlled activation, and improved trafficking to anatomically restricted sites such as the brain. However, engineering advances alone are unlikely to achieve durable benefit without parallel integration of quantitative in vivo monitoring capable of reporting biodistribution, persistence, and functional engagement. Non-invasive imaging and measurement-enabled approaches can provide mechanistic insight into therapeutic performance, discriminate between delivery failure and functional dysfunction, and support rational iteration of construct design, dosing, and route of administration. In this perspective, we review the current status of CAR T and CAR NK therapies in pediatric solid malignancies, outline key biological and engineering challenges, and propose a pediatric-centered development framework that integrates controllable cell engineering with quantitative, non-invasive assessment of in vivo behavior. By embedding measurement into the therapeutic design loop and prioritizing long-term safety and developmental outcomes alongside efficacy, next-generation engineered cell therapies may evolve toward adaptable, precision-guided systems capable of improving both survival and quality of life for children.