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...

Background: Invasive fungal infections (IFI) are an important complication of acute lymphoblastic leukaemia (ALL) treatment. Our study describes the prevalence and outcomes of IFI in children with ALL. Methods: IFI episodes in children with primary or relapsed ALL, identified for The Epidemiology and Risk Factors for Invasive Fungal Infections in Immunocompromised Children study, were analysed. IFI were classified according to European Organization for Research and Treatment of Abbreviations: ALL, acute lymphoblastic leukaemia; CCG, Children'

Abtract Background This study describes imaging features of diffuse intrinsic pontine glioma (DIPG) and correlates with overall survival (OS) and histone mutation status in the International DIPG Registry (IDIPGR). Methods Four hundred cases submitted to the IDIPGR with a local diagnosis of DIPG and baseline MRI were evaluated by consensus review of 2 neuroradiologists; 43 cases were excluded (inadequate imaging or alternative diagnoses). Agreement between reviewers, association with histone status, and univariable and multivariable analyses relative to OS were assessed. Results On univariable analysis imaging features significantly associated with worse OS included: extrapontine extension, larger size, enhancement, necrosis, diffusion restriction, and distant disease. On central review, 9.5% of patients were considered not to have DIPG. There was moderate mean agreement of MRI features between reviewers. On multivariable analysis, chemotherapy, age, and distant disease were predictors of OS. There was no difference in OS between wild-type and H3 mutated cases. The only imaging feature associated with histone status was the presence of ill-defined signal infiltrating pontine fibers. Conclusions Baseline imaging features are assessed in the IDIPGR. There was a 9.5% discordance in DIPG diagnosis between local and central review, demonstrating need for central imaging confirmation for prospective trials. Although several imaging features were significantly associated with OS (univariable), only age and distant disease were significant on multivariable analyses. There was limited association of imaging features with histone mutation status, although numbers are small and evaluation exploratory.

Background DIPG generally occurs in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). Methods Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). Results Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years [range 10-26.8]. Median OS was 13 [2–82] months. The 1-, 3- and 5- years OS was 61.9%, 3.7%, and 1.5%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P<0.01) and present with longer symptom duration (P<0.01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and one was a LTS. The presence or absence of H3 alterations did not affect survival. Conclusion Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.

Chimeric Antigen Receptor (CAR) T cell therapy is a promising form of adoptive cell therapy that re-engineers patient-derived T cells to express a hybrid receptor specific to a tumour-specific antigen of choice. Many well-characterised tumour antigens are intracellular and therefore not accessible to antibodies at the cell surface. Therefore, the ability to target peptide-MHC tumour targets with antibodies is key for wider applicability of CAR T cell therapy in cancer. One way to evaluate the effectiveness and efficiency of ligating tumour target cells is studying the immune synapse. Here we generated a second-generation CAR to targeting the HLA-A*02:01 restricted H3.3K27M epitope, identified as a possible therapeutic target in ~75% of diffuse midline gliomas, used as a model antigen to study the immune synapse. The pMHCI-specific CAR demonstrated specificity, potent activation, cytokine secretion and cytotoxic function. Furthermore, we characterised killing kinetics using live cell imaging as well as CAR synapse confocal imaging. Here we provide evidence of robust CAR targeting of a model peptide-MHC antigen and that, in contrast to protein-specific CARs, these CARs form a TCR-like immune synapse which facilitates TCR-like killing kinetics.

Background Children ≤36 months with Diffuse Intrinsic Pontine Glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes. Methods Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed. Results Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥ 5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3-, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (p=0.018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation. Conclusions Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis.

This study has identified potential utility for FDG-PET/CT in immunocompromised children with prolonged or recurrent fever. Further prospective studies are needed to compare FDG-PET/CT versus conventional imaging, to identify the optimal timing of FDG-PET/CT and to study the role of subsequent scans to monitor response to therapy.

Background Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMG) of the thalamus and spinal cord are rare but devastating high-grade glial tumors of childhood with no curative treatment. Despite aggressive treatment attempts the prognosis has remained poor. Chimeric antigen receptor (CAR) T cell therapy has been identified as a promising new approach in the treatment of DMG tumors; however, additional targets are urgently required given known tumor heterogeneity and the prospect of antigen escape of this cancer. Methods Using cell surface mass spectrometry, we detected high HER2 cell surface protein across a panel of patient-derived DIPG cells, thereby identifying an existing CAR T cell therapy for use in DIPG. Primary human T cells were transduced to express a second-generation HER2 CAR and interrogated for efficacy against patient-derived DIPG cells. Results HER2 CAR T cells demonstrated potent and antigen-specific cytotoxicity and cytokine secretion when co-cultured with patient-derived DIPG cells. Furthermore, HER2 CAR T cells provided a significant regression in intracranial DIPG xenograft tumors. Conclusions HER2 CAR T cells are already in clinic development and are well tolerated in pediatric patients. Here we provide strong preclinical evidence for the inclusion of DIPG patients in future pediatric CNS tumor HER2 CAR T cell clinical trials.