Resistance mechanisms and translational bottlenecks in CAR-T cell therapy for pediatric acute lymphoblastic leukemia:...

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable remission rates exceeding 80% in relapsed/refractory pediatric B-cell acute lymphoblastic leukemia (B-ALL), yet 40-50% of patients eventually relapse within the first year. This therapeutic ceiling is not a single failure mode but the convergence of at least four interrelated layers: loss of CAR-T persistence, antigen escape driven by CD19 splicing variants and lineage switch, CAR-T cell-intrinsic exhaustion from chronic tonic signaling, and an immunosuppressive bone marrow microenvironment that actively extinguishes effector function. Our systematic analysis of 226 pediatric-eligible CAR-T trials shows that 95.6% are Phase I-II, 3.5% (8/226) are registered as Phase III/IV, and 58 of 102 completed trials (56.9%) had no outcome recorded in the source database. In this Perspective, we synthesize the molecular mechanisms of CAR-T resistance, contextualize them within the current clinical trial landscape, and critically evaluate emerging engineering strategies-from dual-targeting and armored CAR architectures to CRISPR-edited allogeneic products and in vivo mRNA delivery. We argue that progress depends on both smarter receptor design and structural reforms in trial design, outcome transparency and global collaboration.