CAR T cells: the missing piece needed to improve outcomes for children with cancer?

B cell acute lymphoblastic leukemia (B-ALL) is the most common cancer of childhood. Outcomes for B-ALL have steadily improved over the last five decades, most recently due to impressive activity of chimeric antigen receptor modified T (CAR-T) cells and bispecific antibodies targeting CD19. In contrast, progress against other pediatric cancers has largely stalled. Significant academic effort is underway to expand the reach of CAR T cell therapy in pediatric cancer beyond B-ALL to other hematologic malignancies, solid cancers and brain tumors. Promising clinical activity using CAR-modified T cells has already been demonstrated in neuroblastoma and diffuse midline glioma by targeting the GD2 ganglioside, in pediatric sarcomas by targeting Her2, in Hodgkin's disease by targeting CD30, in T cell lymphoblastic leukemia by targeting CD5 or CD7, and in CAR19 refractory B-ALL by targeting CD22. Comprehensive surfaceome profiling of pediatric tumors is revealing additional novel candidate CAR targets expressed on pediatric cancers, including oncofetal cell surface antigens such as GPC2 and GPC3, which are expressed broadly on pediatric solid and brain tumors, and major histocompatibility complex bound peptides from oncofetal intracellular proteins such as PHOX2B Next-generation CAR T cell therapeutics that incorporate suicide domains, regulatory circuits, logic gating and potency enhancements as well as combination immunotherapies are expected to further augment efficacy while maintaining safety. Current trials are administering CAR T cells in patients with refractory disease, but future studies are warranted to determine whether adjuvant use of CAR T cells could deliver cures with lower intensity standard therapy regimens and thereby reduce long-term toxicities in pediatric cancer survivors. Despite this scientific and clinical progress, the high cost of developing CAR T cells through the traditional biopharma pathway is limiting late-stage clinical development, necessitating the creation of new business models to commercialize CAR T cells for these small markets. CAR T cells hold great promise for improving outcomes for pediatric patients with cancer, but substantial additional research and clinical development is needed if this promise is to be realized for children afflicted with cancer.