Chimeric antigen receptor (CAR) therapies in retinoblastoma: A comprehensive review

Abstract

Retinoblastoma (RB) is the most common malignant intraocular tumor in children and remains a major concern in pediatric ophthalmology, particularly in advanced, metastatic, or treatment-resistant cases. Although current treatment approaches have greatly improved survival in high-income countries, important limitations remain. Safer and more effective therapies are still needed. Chimeric antigen receptor (CAR)-based immunotherapy has emerged as a novel treatment strategy and may offer new possibilities for RB management. In this review, we summarize current evidence on CAR therapies in RB, including CAR-T cells, CAR-natural killer (NK) cells, CAR-macrophages (CAR-M), CAR-induced microglia (iMG), and CAR-natural killer T (NKT) cells, and we compare these platforms in the context of the immune-privileged ocular environment. We also discuss important therapeutic targets, including GD2, B7-H3, glypican-2 (GPC2), and EpCAM, as well as PD-1/PD-L1 blockade as a combination strategy rather than a direct CAR target. Experimental studies have demonstrated encouraging antitumor activity, while local delivery strategies and cytokine-support approaches may improve treatment persistence and reduce systemic toxicity. However, most of this evidence comes from in vitro assays and immunodeficient xenograft models that do not reproduce the human ocular immune microenvironment, tumor heterogeneity, or the blood-retinal barrier. Clinical experience remains limited to early-phase pediatric trials, and translation will depend on addressing cell manufacturing in young children, ocular delivery, and long-term ocular safety monitoring. In addition, ongoing progress in gene editing, multi-target design, non-viral engineering methods, and large-scale manufacturing is expected to further advance this field. Overall, CAR-based therapies represent a promising and rapidly developing area that could improve globe preservation and survival in patients with difficult-to-treat RB.