CAR-based therapeutic targets in pediatric high-grade glioma

High-grade glioma (HGG) patients have a dismal prognosis, due to a lack of effective treatments. In order to change the fate of HGG patients and decrease the current treatment-related side effects, therapy focus has shifted in the past years to immunotherapy, such as chimeric antigen receptor (CAR)-based treatments. Recent developments in CAR-based therapy show promising results in adult glioma patients, and the first clinical trials for pediatric patients with HGG are in progress. However, there are significant differences between pediatric HGG (pHGG) and their adult counterparts, including the composition of the tumor immune microenvironment (TIME), which strongly influences CAR treatment responsiveness. Therefore, we here provide a systematic overview of CAR-based therapeutic targets in pHGG entities, focusing on clinical trials and preclinical research, and comparing them to adult glioma. We conclude that target expression, TIME and CAR treatment-related toxicities vary across pHGG entities and differ from adult HGG, which suggests the need for more tailored immunotherapeutic CAR approaches in pHGG. Overall, we provide a target roadmap for future development of CAR-based therapeutic strategies for pediatric HGG patients, who are in desperate need for novel therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/24312703v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@a70590org.highwire.dtl.DTLVardef@15e6cc5org.highwire.dtl.DTLVardef@36fa36org.highwire.dtl.DTLVardef@1651f8c_HPS_FORMAT_FIGEXP M_FIG C_FIG The number of potential CAR-based therapeutic targets for glioblastoma and pHGG. CAR: Chimeric antigen receptor; pHGG: pediatric high-grade glioma; DHG: H3 G34-mutant diffuse hemispheric glioma; DMG: H3 K27-altered diffuse midline glioma; PFA: posterior fossa ependymoma type A. Image was created in Biorender.com.