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PURPOSE To review data from DIPG Registry patients recorded to have received a second course of radiation therapy (rRT). METHODS The International DIPG Registry was searched for patients with DIPG who were treated with a known dose of rRT. Doses of rRT, timing from initial diagnosis and primary radiation therapy (pRT), radiographic response to rRT and survival from diagnosis (OS) were evaluated. RESULTS Sixty (11.2%) of 535 Registry patients underwent rRT; dose was provided for 44 patients. Median (range) data from those 44 revealed that rRT was given at 12 (2–65) months from initial diagnosis of DIPG and at 9.6 (1–61) months from completion of pRT at a dose of 26.7 (1.8–74) Gy. After completion of rRT, MRI showed response, progression, stable disease or was not available in 19, 8, 3 and 14 patients, respectively. Median PFS and OS were 11 and 18.1 months, respectively. 475 Registry patients did not undergo rRT; their ages, duration of symptoms, and primary treatment with or without chemotherapy were not significantly different from the rRT cohort. Median PFS and OS for the non-rRT patients were 6.9 and 10 months, respectively. rRT patients were more likely to have had radiographic evidence of tumor necrosis at diagnosis than non-rRT patients. CONCLUSIONS Administration of rRT to patients with DIPG has been inconsistent with respect to timing and dose. Toxicity, response and quality of life data are incomplete, but survival appears to be lengthened with rRT. Prospective clinical trials will elucidate benefits and risks of rRT.

BACKGROUND: Pre-clinical determination of disease-specific activity, effective dosing, safety, pharmacokinetics, and CNS delivery can optimize clinical trial designs. The proteasome inhibitor, marizomib, together with the HDAC inhibitor, panobinostat, is active and synergistic in pre-clinical DIPG studies, with target concentrations of 20 and 100 nM, respectively. The adult maximum tolerated dose (MTD) for marizomib is 0.8 mg/m(2). We evaluated the safety, tolerability and pharmacokinetics in a non-human primate model, predictive of pediatric patients. METHODS: Marizomib was administered (10-minute intravenous infusion) at three dose levels: 0.02 (n=4), 0.04 (n=5), and 0.06 mg/kg (n=1), equivalent to human doses (HED) of 0.4, 0.8, and 1.1 mg/m(2), respectively. Marizomib (dose 0.04 mg/kg) was subsequently administered (n=4) 1-hr post-panobinostat (dose 1 mg/kg, HED 20 mg/m(2), p.o.). Drug concentrations were determined by LC-MS/MS using validated assays and PK parameters calculated via noncompartmental methods. RESULTS: Marizomib +/- panobinostat was tolerable with the exception of one animal (single agent marizomib, dose 0.06 mg/kg, HED= 1.2 mg/m(2)) that expired 12–20 hr post administration; no clear etiology was found at necropsy. Remaining adverse events were Gr 1, 2 with the exception of lymphocytopenia, Gr 3 (n=2). Marizomib demonstrated rapid plasma clearance (1.22–10.25 L/min), short plasma half-life (4.45–8.24 min), non-linear increase in AUC(inf), and no significant difference across dose levels. Conversely, in CSF, there was a trend toward increasing exposure with increasing dose. T(1/2) was longer in CSF than blood (18–25 min vs. 4–7 min, respectively). Comparing marizomib PK before and after panobinostat, t(1/2) and clearance were similar (mean 7.80 vs. 9.49 min, and 6.04 vs. 4.24 L/min, respectively); CSF AUC(inf) increased, 65.69 vs. 121.68 min*nM, respectively. CONCLUSIONS: Marizomib penetrates into the CNS and CSF exposure was higher after panobinostat. This combination warrants clinical evaluation in DIPG; correlation of results with preclinical findings is planned.

The Children’s Brain Tumor Network (formerly known as Children’s Brain Tumor Consortium- CBTTC) is a global organization pioneering a model of open-science medical research to improve treatment and discover cures. Started in 2011, our objective was to utilize a regulatory, agreement, and governance architecture to remove existing research barriers that slowed down the pace of research and collaboration. Our network now includes 17 institutions working together to empower research. As of December 2019, over 3,600 subjects have been enrolled resulting in collection of over 45,000 specimens. Clinical data collection is longitudinal and includes medical history, diagnosis, treatment, pathology slides and reports, radiology imaging and reports, and outcome data. The tissue is collected flash-frozen, in freezing media, and fresh for the generation of pre-clinical models including cell lines. Blood is collected from the subject, with blood or saliva collected from the parents for germline comparison. Additionally, the Children’s Brain Tumor Network- Pediatric Brain Tumor Atlas has generated 952 WGS and RNAseq, 221 proteomics, with annotated clinical data. All of this data, both generated raw and processed data, has been made available broadly to the scientific community via cloud-based platforms, including the Gabriella Miller Kids First Data Resource Portal, Cavatica, and PedCbioportal. As of January 2020, we have 45 approved biospecimen requests and 80 genomic/molecular data requests. In summary, the Children’s Brain Tumor Network’s goal is to accelerate the pace of discovery by providing resources and expanding the network of scientists working towards a cure.

Diffuse intrinsic pontine glioma (DIPG) is a diffusely infiltrating high-grade glioma that has a peak incidence from ages 6-8 and only a 9-12 month median survival. Like adult gliomas, DIPG exhibits a significant expansion of myeloid cells, with microglia/macrophages accounting for ~30% of the tumor cell mass (Caretti & Monje, 2014). In adult glioma, these glioma-associated macrophages have been implicated as supporting angiogenesis and tumor cell invasion, proliferation, and survival (Glass & Synowitz, 2014). However, genomic and epigenomic characterizations of adult and pediatric high-grade gliomas revealed striking differences in the molecular nature of these tumors (Sturm et al., 2014), and traditional chemotherapeutic approaches to adult glioblastoma are not effective in DIPG, suggesting these are unique diseases with distinct pathophysiology. Our data demonstrates that tumor-associated macrophages from primary DIPG samples exhibit gene expression signatures that are associated with pro-tumorigenic functions, but are also significantly less inflammatory than tumor-associated macrophages isolated from adult glioblastoma samples. Moreover, the cytokine secretion profiles of patient-derived DIPG cell cultures are dramatically less inflammatory when compared to patient-derived adult high-grade glioma cell cultures, and are more similar to the profile of human neural precursor cell cultures. This suggests that DIPG is less immunogenic than adult GBM, which may allow the tumor cells to evade detection and infiltrate healthy tissue. We additionally show that DIPG cells express CD200, a ligand that inhibits myeloid cell activation. Knockdown of DIPG expression of CD200 increases primary microglial cell phagocytosis in direct co-culture experiments, and also inhibits DIPG progression in in vivo xenograft models. Thus, CD200 may represent a mechanism by which DIPG evades normal immune responses to tumor growth. By understanding the DIPG-microglial interaction in molecular detail, we will gain insight into the pathophysiology of DIPG that could direct future targeted therapies.