Immunotherapy for Pediatric Brain and Spine Tumors: Current State and Future Directions

Abstract

Background Brain tumors are the most common solid tumors and the leading cause of cancer-related deaths in children. Incidence in the US has been on the rise for the last 2 decades. While therapeutic advances in diagnosis and treatment have improved survival and quality of life in many children, prognosis remains poor and current treatments have significant long-term sequelae. Summary There is a substantial need for the development of new therapeutic approaches, and since the introduction of immunotherapy by immune checkpoint inhibitors there has been an exponential increase in clinical trials to adopt these and other immunotherapy approaches in children with brain tumors. In this review, we summarize the current immunotherapy landscape for various pediatric brain tumor types including choroid plexus tumors, embryonal tumors (medulloblastoma, AT/RT, PNETs), ependymoma, germ cell tumors, gliomas, glioneuronal and neuronal tumors, and mesenchymal tumors. We discuss the latest clinical trials and noteworthy preclinical studies to treat these pediatric brain tumors using immune checkpoint inhibitors, cellular therapies (CAR-T, NK, T cell), oncolytic virotherapy, radioimmunotherapy, tumor vaccines, immunomodulators, and other targeted therapies. Key Messages The current landscape for immunotherapy in pediatric brain tumors is still emerging, but results in certain tumors have been promising. In the age of targeted therapy, genetic tumor profiling, and many ongoing clinical trials, immunotherapy will likely become an increasingly effective tool in the neuro-oncologist armamentarium.

Non-cellular immunotherapies in pediatric central nervous system tumors

“…While most of the research on the CNS TME is in adult gliomas ( 37 – 39 ), more information is becoming available regarding the pediatric CNS TME, and how it relates to the pediatric microvasculature and BBB permeability ( 26 ). In general, pediatric CNS tumors are considered “cold”, due to the presumed lack of genetic mutations (generation of neoantigens) ( 21 , 40 ). Additionally, pediatric tumors tend to have loss of expression of major histocompatibility complex I (MHC I), which decreases the ability of T-lymphocytes to recognize and become activated ( 41 ).…”

“…( 50 ), similar differences in expression patterns were noted across different subtypes of medulloblastoma including wingless (WNT), sonic hedgehog (SHH), and group 3. The heterogeneity of the TME, BBB, and BBTB when compared to pediatric versus adult tumors, and the variability across different pediatric tumor types, could help to explain why some CNS tumors respond better than others to various types of immune therapies, both in the pediatric arena and when compared to adult tumors ( 40 – 46 ).…”

“…These TILs have decreased effector function, increased expression of inhibitory receptors, and decreased production of immunostimulatory cytokines (42), further decreasing the recruitment of additional immune response. Notably, there is some variation in the TME of different types of pediatric CNS lesions (21,(39)(40)(41)(42)(43)(44)(45)(46). Griesinger, et al (47) used flow cytometry to analyze the phenotype and frequency of immune cells that infiltrate tumors in the most common pediatric brain tumor types (pilocytic astrocytoma, ependymoma, glioblastoma, and medulloblastoma).…”

Decoding Prognostic Markers: Bioinformatics Insights into PIH1D1 and p53 in Children’s Brain Cancer

“…The cerebral hemispheres of the brain contain the other 40% of paediatric brain tumours. These include oligodendrogliomas, meningiomas, supratentorial primitive neuroectodermal tumours (PNET), astrocytomas, gangliogliomas, craniopharyngiomas, germ cell tumours, and dysembryoplastic neuroepithelial tumours (DNET)(Estevez-Ordonez et al, 2022, n.d.).…”