Abstract
Despite decades of research, pediatric central nervous system (CNS) tumors remain the most debilitating, difficult to treat, and deadliest cancers. Current therapies, including radiation, chemotherapy, and/or surgery, are unable to cure these diseases and are associated with serious adverse effects and long-term impairments. Immunotherapy using chimeric antigen receptor (CAR) T cells has the potential to elucidate therapeutic antitumor immune responses that improve survival without the devastating adverse effects associated with other therapies. Yet, despite the outstanding performance of CAR T cells against hematologic malignancies, they have shown little success targeting brain tumors. This lack of efficacy is due to a scarcity of targetable antigens, interactions with the immune microenvironment, and physical and biological barriers limiting the homing and trafficking of CAR T cells to brain tumors. In this review, we summarize experiences with CAR T–cell therapy for pediatric CNS tumors in preclinical and clinical settings and focus on the current roadblocks and novel strategies to potentially overcome those therapeutic challenges.
Highlights
Central nervous system (CNS) tumors are second only to leukemias, in terms of being the most common pediatric malignancies, and gliomas account for a quarter of all childhood cancers in the U.S [1]
Human epidermal growth factor receptor 2 (HER2) is robustly expressed in gastric, ovarian, prostate, and CNS tumors [44]
HER2 is highly expressed in adult HGG (~42%) and pediatric medulloblastomas (~40%), along with less robust expression in pediatric high-grade diffuse gliomas (pHGGs) (~37%) [22, 46]
Summary
Central nervous system (CNS) tumors are second only to leukemias, in terms of being the most common pediatric malignancies, and gliomas account for a quarter of all childhood cancers in the U.S [1]. We review the lessons learned from preclinical and clinical testing of CAR T cells, with a specific reflection on the unique features of pHGGs that need to be addressed in future efforts to develop effective and safe CAR T– cell immunotherapies for PBTs. Pediatric gliomas include heterogenous groups of brain malignancies that are histologically similar to adult tumors but with distinct molecular and genetic alterations that dictate clinical behavior and therapeutic considerations [10]. Results from patients with DMGs treated with GD2 CAR T cells suggest promising clinical responses along with tolerable safety profiles (including incidences of manageable cytokine release syndrome and neurotoxicity) [28] Data from these clinical studies will define the strategies for GD2-directed CAR T–cell therapy and provide general insights on CAR T–cell therapy efficacy and safety in pHGGs. B7 Homolog 3 B7 homolog 3 (B7-H3), known as cluster of differentiation 276 (CD276), is a member of the B7 and CD28 immune checkpoint family [32].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
