bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDRE-35. PRE-CLINICAL ASSESSMENT OF PPRX-1701, A NANOPARTICLE FORMULATION OF 6-BROMO-ACETOXIME, FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Zdioruk Mykola , Finkelberg Tomer , Nowicki Michal , Wu Bin , Takeda Yuji , Chiocca Antonio , Lawler Sean 
Published: November 2021

Abstract
We previously showed that derivatives of the Chinese traditional medicine indirubin promote survival in murine glioblastoma models (Williams et al. Cancer Research 2011). However, poor drug solubility hampered further development of this approach. Here we introduce PPRX-1701, a 6’-bromoindirubin acetoxime (BiA) containing drug/polymer nanoparticle formulation which can be injected intravenously at relatively high concentrations. Mechanistically, BiA is thought to act as a broadly selective serine-threonine protein kinase inhibitor, with activity against Src family kinases, GSK-3 and JAK2. Our preliminary data show that intravenous administration of PPRX-1701 is well-tolerated and can reach intracranial murine glioblastoma as assessed by luminescent reporter assays. PPRX-1701 administration leads to improved survival in the GL261 glioblastoma mouse model (median survival 30 days (control), 47 days (treated), p &lt; 0.0001). Treatment with PPRX-1701 was associated with alterations in the tumor immune microenvironment, with reduced Tregs and pro-tumor macrophages, and increased CD8+ T cells. Further preliminary mechanistic studies have shown that PPRX-1701/BiA blocks the expression multiple immunosuppressive molecules in GBM downstream of interferon-g (IFNg) including PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1) - a key enzyme in the tryptophan–kynurenine–aryl hydrocarbon receptor (Trp–Kyn–AhR) immunosuppressive pathway. BiA promoted more effective T-cell mediated tumor cell killing using patient derived glioblastoma ex vivo co-culture models. This data supports further development of PPRX-1701 is a candidate immunotherapeutic agent for glioblastoma treatment. Ongoing pre-clinical studies are investigating combination with other relevant therapies.
DDRE-36. INVESTIGATING MEDULLOBLASTOMA HETEROGENEITY AND PREDICTING COMPOUND RESPONSE
Authors: Ruiz Luz , Ayad Nagi 
Published: November 2021

Abstract
Medulloblastoma is the most common malignant brain tumor found in children. It is a cerebellar tumor that affects motor and cognitive processes such as coordination and movement. The standard of care is surgical removal, radiation, and chemotherapy. These treatments can be very damaging to the developing child, in that they can impair vision and walking, among other body functions. Due to this, new treatments are necessary. Treatment plans for children with medulloblastoma need to be tailored to the specific subtype that they have. Genetic studies have revealed that there are four subtypes of pediatric medulloblastoma: Group 3, Group 4, SHH, and WNT. Beyond these bulk-resolution subtypes, we hypothesize intratumor heterogeneity as a barrier to new effective treatments. I have mined single-cell RNA sequencing data to investigate cellular heterogeneity and predict compound response. I analyzed Medulloblastoma patient tumor data along with data obtained from a 10X Genomics Chromium single-cell RNA sequencing experiment performed in the laboratory from a Tg (Neurod-Smoothened*A1) mouse. We hypothesize that distinct cell populations within medulloblastoma should show different predicted compounds that would target them. We have ranked compound predictions to investigate whether compounds may selectively target any of these populations using transcriptional response signatures derived from the LINCS L1000 perturbagen-response dataset. We also hypothesize that Medulloblastoma tumors have distinct subtypes of cells that are preferentially sensitive to BET bromodomain, casein kinase, and ATM/ATR inhibitors. Our analysis identified ten transcriptionally distinct cell types across these medulloblastoma tumors as well as compounds predicted to target them in each transcriptional subtype. Furthermore, we identified bromodomain and casein kinase inhibitors as a potential combination therapy due to their predicted synergy at targeting all cell populations within medulloblastoma. Our studies show the importance of considering cellular heterogeneity when identifying new treatments for medulloblastoma and other brain cancers.
DDRE-45. HIGH-THROUGHPUT SCREENING OF EPIGENETIC COMPOUNDS FOR THE TREATMENT OF CHORDOMA IDENTIFIES POTENTIAL NOVEL THERAPEUTICS
Authors: Wroblewski Tadeusz , Tatman Philip , Fringuello Anthony , Scherer Sam , Foreman William , Damek Denise , Youssef Samy , Lillehei Kevin , Ormond David , Graner Michael 
Published: November 2021

Abstract

BACKGROUND
Chordoma is a rare malignant tumor with few treatment options. While surgical resection is deemed the most effective treatment, the 5-year overall survival rate is 61% and 5-year recurrence free survival rate is approximately 50%. To date, no FDA approved pharmacotherapies exist for the treatment of chordoma, and adjuvant therapy remains highly debated. This necessitates the need for further research to provide clinicians with more options to treat this patient population.

METHODS
In this study, we conducted a high-throughput 139-compound epigenetic inhibitor screen against 12 chordoma patient-derived cell lines; 4 were resected at our institution and 8 were graciously donated by the Chordoma Foundation.

RESULTS
8 tumors were located in the sacrum, 3 were located in the mobile spine, and 1 tumor was located in the clivus. 5 tumors were primary, 5 were recurrent, and 2 were metastatic. 6 tumors came from female patients and 6 tumors came from male patients. The top three most effect compounds across the cohort were the G9a inhibitor UNC0631 (cell viability = 64.5% +/-25.1SD; p=1.53x10-9), the KDM inhibitor JIB-04 (cell viability = 68.4% +/-27.2SD; p=9.81x10-8), and the G9a inhibitor BIX01294 (cell viability = 68.6% +/-27.9SD; p=1.27x10-7). No single compound significantly reduced viability in every tumor in the cohort, although the HDAC inhibitor HC Toxin significantly reduced viability in 9 tumors (cell viability = 69.7% +/-16.6SD; p=2.6x10-12). The most effective compound for sacral tumors was UNC0631 (viability = 68.6% +/-22.1SD; p=4x10-7), UNC0631 was also the most effective for spinal tumors (viability = 54.4% +/-32.1SD; p=2.72x10-3), and notably, no significant compounds were identified for the single clival tumor.

CONCLUSIONS
Based on our drug screen results, epigenetic inhibition, particularly methyltransferase inhibition, may be a promising therapeutic avenue for the treatment of chordomas.
EPID-15. AGE AND DOSIMETRIC IMPACTS ON RADIOTHERAPY ASSOCIATED GROWTH IMPAIRMENT FOR PATIENTS WITH INTRACRANIAL GERM CELL TUMORS (GCTs)
Authors: Deng Guanhua , Zhou Zhaoming , Li Juan , Lai Mingyao , Hu Qingjun , Zhou Cheng , Cai Linbo 
Published: November 2021

Abstract

PURPOSE
Intracranial germ cell tumors (GCTs) are rare pediatric central nervous system (CNS) tumors. Growth impairment induced by radiation treatments was rarely evaluated. We aimed to study the impacts of radiotherapy on height development and identify the dosimetric constraints.

MATERIALS AND METHODS
A total of 148 pediatric patients diagnosed with GCTs were retrospectively analyzed. Sex, age at irradiation, physical doses and biologically effective dose (BED), height, and endocrine status were obtained from patient records. The cumulative change in height was assessed using age-matched normalized height (ANH). Variables were assessed for correlations and statistical significance.

RESULTS
Cumulative physical doses and BEDs for the whole brain and pituitary were derived via DVHs and BEDVHs. In contrast to patients &gt;11.5 yr, linear correlations between ANH and cumulative physical doses as well as BEDs to the whole brain and pituitary were identified in patients≤11.5 yr. Dosimetric constrains to the pituitary was 36 Gy for physical dose (AUC=0.70 [95% CI, 0.54-0.86], P&lt; 0.05) and 63 Gy2 BED (AUC=0.69 [95% CI, 0.53-0.86], P&lt; 0.05). Intriguingly, no significant differences in ANH were found among different CSI dose groups in patients ≤11.5 yr. (all P&gt;0.05). Impaired hormone secretions in terms of GH and TSH were identified following cranial irradiation (both P&lt; 0.001), particularly for those with tumors at the suprasellar region (GH: P&lt; 0.01, TSH: P&lt; 0.001).

CONCLUSION
Our study revealed the impacts of age, dosimetrics and tumor locations for growth impairment. This study will contribute to the optimization of radiation treatment planning and facilitate more individualized therapeutic strategies in pediatric patient with GCTs.
EPID-16. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR IN PEDIATRIC PATIENTS: A QUANTITATIVE EXPLORATION
Authors: Lu Victor , Di Long , Daniels David , Maher Ossama , Niazi Toba 
Published: November 2021

Abstract

BACKGROUND
Diffuse leptomeningeal glioneuronal tumor (DLGNT), also known as oligodendrogliomatosis, is a rare neuro-oncologic condition along the neuraxis that remains poorly understood in children. We sought to describe our institutional experience and quantitively summarize the clinical survival and prognostic features of DLGNT in the pediatric population across the contemporary literature.

METHODS
We report four institutional cases of pediatric DLGNT diagnosed between 2000-2020 based on retrospective review of our records, and performed a comprehensive literature search for published cases from 2000 onwards to create an integrated cohort for analysis. Kaplan-Meier estimations, Fisher’s exact test, and logistic regression were utilized to interrogate the data.

RESULTS
Our overall integrated cohort consisted of 54 pediatric DLGNT patients, with 19 (35%) female and 35 (65%) male patients diagnosed at an average age of 6.4 years (range, 1.3-17 years) by means of surgical biopsy. Chemotherapy was used in 45 cases (83%), and mean follow-up time of 54 months (range, 3-204). Across the entire cohort, overall survival 1 month after diagnosis was 96% (95% CI 86-99%), and by 10 years was 69% (95% CI 49-82%). On multivariate analysis of complete data, chemotherapy treatment (HR=0.23, P=0.04) was statistically predictive of longer overall survival. When including limited data, longer duration of symptoms by presentation (HR=1.03, P=0.03) was statistically predictive of shorter overall survival.

CONCLUSIONS
This is the first quantitative study of pediatric DLGNT clinical course. More than 2-out-of-3 pediatric DLGNT patients survive beyond one decade. Chemotherapy is statistically associated with longer survival in DLGNT pediatric patients and should form the core of any treatment regimen in this setting. Early detection by means of judicious imaging and surgical biopsy for tissue diagnosis can lead to earlier treatment and likely superior outcomes.
EPID-18. USING GERMLINE VARIANTS FOR DIFFERENTIAL DIAGNOSIS OF INDETERMINATE BRAIN LESIONS: EVALUATING THE EFFECT OF TUMOR TYPE AND RACE ON SENSITIVITY AND SPECIFICITY OF GLIOMA polygenic risk models
Authors: Eckel-passow Jeanette , Paul Decker , Kosel Matthew , Kollmeyer Thomas , Drucker Kristen , Conte Gian Marco , Erickson Bradley , Slager Susan , Lachance Daniel , Jenkins Robert , Tobin Oliver 
Published: November 2021

Abstract
Abnormalities on brain MRI may be identified in ~15% of individuals aged 50-66. It can be difficult to discriminate glioma, CNS lymphoma, Inflammatory Demyelinating Disease (CNSIDD) and solitary metastasis, and misdiagnosis may expose patients to unnecessary anxiety, surgery, or radiotherapy. CNS lymphoma requires only biopsy, solitary metastasis may be resected and radiated or radiated empirically, and high-grade glioma requires maximal safe resection followed by chemoradiation. CNSIDD should only be biopsied when diagnostic uncertainty requires it, and resection and radiotherapy are unnecessary, introducing unwarranted morbidity. Polygenic risk models can identify patients at the highest risk of developing glioma; we hypothesized that these polygenic models could help with differential diagnosis of indeterminate brain lesions. We also hypothesized that race would be an important contributing factor in the models. In the initial discovery and validation European (EUR) cohorts the mean probability of glioma for IDHmut non-codeleted glioma was 0.55 and 0.52, respectively, and in healthy controls was 0.19 and 0.21, respectively. To further evaluate sensitivity, we analyzed additional genotype data from 867 gliomas (764 EUR, 54 AFR, 24 AMR, 15 EAS, 10 SAS) from The Cancer Genome Atlas (TCGA). Across 764 EUR IDHmut non-codeleted glioma, the mean probability 0.53, whereas across 54 AFR and 24 AMR the mean was 0.22 and 0.32, respectively. To evaluate specificity, we analyzed 3200 TCGA patients with primary tumor types that commonly metastasize to the brain (2676 EUR, 365 AFR, 46 AMR, 95 EAS, 18 SAS), and 236 AFR healthy controls. For patients with non-CNS primary tumors, the mean probability ranged from 0.09-0.18 for EUR and 0.04-0.07 for AFR. For AFR healthy controls, the mean was 0.05. Overall, race is a significant factor for polygenic risk models. Further work entails evaluating polygenic risk models in IDHwt glioma, CNS lymphoma and CNSIDD cohorts as well as in additional races.
IMMU-05. CCR2+ MYELOID-DERIVED SUPPRESSOR CELLS FROM MURINE GLIOMAS ARE SOURCED FROM THE BONE MARROW, SUPPRESS T CELL ACTIVATION, AND MIGRATE TO CCL2
Authors: Takacs Gregory , Kreiger Christian , Luo Defang , Flores-Toro Joseph , Deleyrolle Loic , Rahman Maryam , Mitchell Duane , Harrison Jeffrey 
Published: November 2021

Abstract

INTRODUCTION
Mounting evidence suggests infiltrating immune-suppressive cells contribute to immune checkpoint inhibitor resistance and poor survival in Glioblastoma (GBM) patients. We have previously shown glioma-associated monocytic-myeloid derived suppressor cells (M-MDSCs) express chemokine receptors CCR2 and CX3CR1. Genetic and pharmacologic targeting of CCR2 promoted sequestration of M-MDSCs in the bone marrow and, in combination with PD-1 blockade, slowed progression of KR158 and 005GSC murine gliomas. This combination treatment also enhanced infiltration of IFNg-producing T cells that were less exhausted. Although CCR2+/CX3CR1+ cells display surface markers indicative of bone marrow-derived M-MDSCs, additional studies are needed to formally establish the source of these cells and to determine if they exhibit an immune-suppressive phenotype as well as migrate to the CCR2 ligands, CCL2 and/or CCL7.

OBJECTIVE
Evaluate the source, migration, and immune suppressive function of CCR2+/CX3CR1+ myeloid cells from glioma bearing mice.

METHODS
To identify the source of CCR2+/CX3CR1+ myeloid cells, chimeric wild type mice harboring bone marrow cells from transgenic CCR2WT/RFP/CX3CR1WT/GFP mice were generated. CCR2+/CX3CR1+ cells were enriched from bone marrow obtained from either wild-type or CCR2WT/RFP/CX3CR1WT/GFP naïve and glioma-bearing mice in order to evaluate their immune suppressive phenotype and ability to migrate to CCL2 and CCL7.

RESULTS
CCR2+/CX3CR1+ cells are present in glioma isolates from chimeric mice, indicative of a bone marrow-derived cell population, and are detectable within the tumor microenvironment as early as 3 days post orthotopic implantation of KR158 cells; these cells accumulate as tumors increase in size (r=0.7605, p=0.007). CCR2+/CX3CR1+ M-MDSCs isolated from the bone marrow of tumor bearing mice suppress CD8+ T cell production of IFNg and migrate to CCL2 more efficiently than CCL7.

CONCLUSION
CCR2+/CX3CR1+ cells from glioma bearing mice are derived from the bone marrow and represent an immune suppressive population that migrates to CCL2.
IMMU-29. B-CELL-BASED VACCINE PRODUCES GLIOBLASTOMA-REACTIVE ANTIBODIES THAT CONTRIBUTE TO TUMOR CLEARANCE
Authors: Castro Brandyn , Dapash Mark , Hou David , Rashidi Aida , Kanojia Deepak , Zhang Peng , Lopez-Rosas Aurora , Han Yu , Balyasnikova Irina , Stupp Roger , Miska Jason , Lesniak Maciej , Chang Catalina 
Published: November 2021

Abstract
Glioblastomas (GBM) are characterized by a strong immunosuppressive environment, contributing to their poor prognosis and limited therapeutic response to immunotherapies. B-cells represent a unique opportunity to promote immunotherapy due to their potential to kill tumors by both cellular and humoral immunity. To generate our B-cell-based vaccine (BVax) platform, we activated 41BBL+ B cells from tumor bearing mice or GBM patient blood with BAFF, CD40, and IFNg. We have previously demonstrated that BVax potentiates radiation therapy, temozolomide and checkpoint blockade in murine models of GBM via enhancement of CD8+ T-cell based immunity. The aim of this current study is to evaluate the humoral effector functions of BVax. We examined the antibody (Ab) repertoire in vivo from serum of tumor-bearing B-cell knockout mice treated with BVax or by ex vivo stimulation of patient-derived BVax. Upon systemic administration, BVax infiltrates the tumor where it differentiates into plasmablasts. Murine BVax- and BNaive-derived serum immunoglobulin generated in vivo showed that the majority of murine BVax-derived Ab were IgG isotype, while BNaive mainly produced IgM isotype. Transfer of IgG from BVax treated mice directly into tumors of recipient animals significantly prolonged their survival, demonstrating anti-tumor cytotoxicity directly through humoral immunity. Patient-derived BVax activated ex vivo showed a plasmablast phenotype and the Ab repertoire supports the previous findings seen in our murine model. Our work suggests BVax-derived IgGs role in antibody-dependent cellular cytotoxicity and improved survival in murine models. This function, in addition to its role in cellular immunity against GBM, renders BVax a potentially effective alternative immunotherapeutic option for GBM patients.
IMMU-35. INDUCTION OF ANTI-TUMOR IMMUNITY BY TUMOR TREATING FIELDS (TTFIELDS) IN GLIOBLASTOMA
Authors: Chen Dongjiang , Le Son , Hutchinson Tarun , Jin Dan , Sebastian Mathew , Liu Tianyi , Ghinaseddin Ashley , Rahman Maryam , Tran David 
Published: November 2021

Abstract

INTRODUCTION
The novel approved GBM treatment TTFields employs alternating, intermediate-frequency (200kHz) electric fields to disrupt mitotic macromolecules leading to chromosome mis-segregation and apoptosis. Emerging evidence indicates that TTFields may also induce inflammation; however, the mechanism and whether this can be harnessed as cancer immunotherapy remain unclear.

METHODS
Multiple GBM cell lines were treated with TTFields using Inovitro, an in vitro TTFields system and integrity of the nuclear envelope and content and activation of key DNA sensor inflammatory pathways analyzed by immunostaining, expression profiling, and protein assays. In a syngeneic orthotopic murine model, TTFields-treated GBM cells were used to provide an in-situ vaccination platform. For validation, we performed bulk and single-cell RNAseq of PBMCs from 12 newly diagnosed GBM patients treated with TTFields.

RESULTS
TTFields induce focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that recruit and intensely activate the 2 major DNA sensors – cGAS and AIM2, and their cognate inflammasomes, thereby releasing pro-inflammatory cytokines and type-1 interferons (T1IFNs) that promote development and maturation of DCs and cytotoxic T cells. In murine model, TTFields-treated GBM cells induce anti-tumor memory immunity both intratumorally and systemically, producing a cure rate of 40% and partial immunity in an additional 25% in a STING- and AIM2-dependent manner. In patients with newly diagnosed GBM patients, we sequenced a total of 193,760 PBMCs and detected robust post-TTFields activation of adaptive immunity via the T1IFN trajectory anchored by plasmacytoid DCs, which was strongly correlated with the TCRαβ clonal expansion index observed in 11 of 12 patients (Spearman coefficient r=-0.8, P=0.014). Importantly, we also defined a T cell-based gene signature predictive of TTFields effects on T cell activation and TCRαβ clonal expansion.

CONCLUSION
Collectively, these studies define a novel strategy using TTFields to improve immunotherapy in GBM and potentially other solid tumors.
IMMU-38. DEEP IMMUNOPROFILING OF HUMAN GLIOBLASTOMA (GBM) REVEALS DIFFERENCES IN THE TUMOR IMMUNE CELL INFILTRATE IN PATIENTS WITH HIGH VS. LOW PLASMA CELL-FREE DNA (CFDNA)
Authors: Bagley Stephen J , Alanio Cecile , Till Jacob , Abdalla Aseel , Binder Zev , Desai Arati , Brem Steven , O’Rourke Donald M , Carpenter Erica , Wherry E John 
Published: November 2021

Abstract

BACKGROUND
We have previously demonstrated that high baseline plasma cfDNA concentration is associated with poor survival in patients with newly diagnosed GBM. The mechanism of this association remains unknown. To explore whether differences in the immune landscape between high- vs. low-cfDNA patients may play a role in their divergent clinical outcomes, we phenotyped tumors from patients with high vs. low cfDNA using mass cytometry by time of flight (CyTOF).

METHODS
We performed CyTOF on frozen tumor infiltrate suspension from a pilot cohort of patients with previously untreated GBM with known baseline plasma cfDNA concentration (Bagley, Clin Cancer Res 2020). CyTOF was used to simultaneously measure expression of 39 molecules related to immune cell lineage, differentiation state, and function. Differences in immune cell infiltrates between high- and low-cfDNA patients were assessed using Mann-Whitney U tests.

RESULTS
Four patients with high cfDNA (median 57, range 33-90 ng/mL) were compared to six patients with low cfDNA (median 12, range 7-16 ng/mL). Immune cell infiltrates with increased adaptive cells (high monocytes and T cells, p=0.05) were present in high-cfDNA compared to low-cfDNA patients. While &gt; 70% of the infiltrating T cells were exhausted in both groups, the pattern of exhaustion was significantly different in high- vs. low-cfDNA patients, with less CXCR5+CD69+ and more CXCR5-CD69- (p=0.008) progenitor exhausted T cells in cfDNA-high patients.

CONCLUSIONS
In this GBM pilot study, we demonstrated differences in the tumor immune infiltrate in patients with high vs. low baseline plasma cfDNA concentration. Preclinical studies will be needed to determine if this explains the association between high plasma cfDNA and poor outcomes previously observed in patients. Our results may have implications for the use of cfDNA concentration as a predictive biomarker for immunotherapy, as tumors with more intermediate progenitor (CXCR5-CD69-) exhausted T cells may respond better to PD-1 checkpoint blockade.