Towards Immunotherapy for Pediatric Brain Tumors

Abstract

Pediatric brain tumors are the leading cause of childhood cancer-related death. Immunotherapy is a powerful new approach for treating some refractory cancers; applying this 'fourth pillar' of cancer treatment to pediatric brain tumors is an exciting but challenging prospect. This review offers new perspectives on moving towards successful immunotherapy for pediatric brain tumors, focusing on pediatric high-grade glioma (HGG), a subgroup with universally poor outcomes. We cover chimeric antigen receptor T cell (CAR-T) therapy, vaccine therapy, and checkpoint inhibition in this context, and focus on the need for intimately understanding the growing brain and its immune system. We highlight the challenges associated with the application of immunotherapy in pediatric neuro-oncology, as well as the tissue-specific challenges to be overcome, to achieve improved outcomes. Immunotherapy: A New Approach for Pediatric Brain Tumors Recent advances in cancer immunotherapy have improved outcomes for several human cancers, and in some cases have produced dramatic responses in patients refractory to all other conventional modes of treatment [1-3]. Although the concept of strengthening, redirecting, or generating an immune response against malignancy is by no means new, cancer immunotherapy has only recently received worldwide attention. Immunotherapy has demonstrated remarkable success in improving overall survival in Phase II-III trials in tumor subtypes such as melanoma and leukemia [1,4]. This novel approach has been a welcome addition to the oncologist's conventional armamentarium of surgery, chemotherapy, and radiation, especially in the relapsed and/or refractory disease setting. This rapid advancement in the immuno-oncology field occurs in a timely manner for childhood brain tumors, which urgently require a new approach. Tumors of the central nervous system (CNS) are the most common solid tumor of childhood, and represent the leading cause of childhood cancer-related death [5]. Although survival rates for childhood cancers overall have markedly improved over recent decades, outcomes in pediatric CNS tumors have lagged behind the dramatic gains achieved in hematological cancers. The overall survival rate in childhood acute lymphoblastic leukemia now exceeds 90% at 5 years [6]. In stark contrast, children with pediatric high-grade glioma (HGG; see Glossary), including diffuse midline glioma (DMG), and glioblastoma multiforme (GBM), have a dismal 5 year overall survival of b20% [6]. This occurs despite recent increased knowledge of the genomics of pediatric HGG and how this diverges markedly from adult brain tumors [7], and multiple trials of differing combinations of radiation, chemotherapeutic agents, and novel adjuvants. Furthermore, given that current conventional treatments involve irradiation of the brain, the few survivors of pediatric brain tumors are often left with devastating morbidities, including endocrine disease, psychiatric, cognitive and developmental disorders, and neurological disease, as well as a high i...

Therapeutic efficacy of an immune stimulatory gene therapy strategy in a mouse model of high grade brainstem glioma

“…There has been significant progress in the field of cancer immunotherapy leading to improvements in overall survival in many types of solid tumors (11)(12)(13)39,40). Advances in immunotherapies include the development of immune therapies targeting immune checkpoints, vaccine approaches against tumor antigens or dendritic cell vaccines designed to stimulate the adaptive immune response, adoptive cell therapy, oncolytic viral therapy, and immune stimulatory gene therapy (40)(41)(42). This has led to a growing number of clinical trials testing immunotherapies in DIPG (42).…”

<p>Immunotherapy for Medulloblastoma: Current Perspectives</p>

“…The fusion protein is incubated for many days with antigen-presenting cells taken from the patient, then re-infused into the patient. 56 Sipuleucel-T has increased overall survival by 4 months in hormone-resistant prostate cancer. 57 In contrast, DNA-and RNA-based cancer vaccines bypass the human leukocyte antigen (HLA) haplotype restriction; this system allows a person's own cellular processes to generate proteins via transcription/translation for more personalized processing.…”

“…In one study, C3H mice with intracerebral melanoma expressing EGFRvIII and treated with the vaccine had a 600% increase in median survival compared to controls. 56,69 However, a phase III trial of 165 glioblastoma patients with EGFRvIII was stopped due to lack of efficacy. 36 EGFRvIII, while specific in a variety of tumors, can downregulate and escape immune system surveillance.…”

“…10,[105][106][107][108][109][110] As another form of adoptive cell therapy, CAR T therapy involves use of a patient's own reengineered T cells and was first reported in the 1980s. 56,111 The technology has been translated clinically only recently. CAR T therapy consists of hybrid receptors, which fuse T lymphocytes and other cells with an antibody-binding domain.…”

Molecular Heterogeneity and Cellular Diversity: Implications for Precision Treatment in Medulloblastoma

“…Therefore, these TME characteristics provide promising potential of immunotherapy for treating MB. Several clinical trials have been conducting by using immune checkpoint blockade and chimeric antigen receptor T (CAR-T) cell therapies as well as therapeutic vaccines [71]. Nonetheless, it would be essential to integrate molecular and immune classification of MB for guiding future precision immunotherapy.…”