bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCO-52. SUBTYPES AND SURVIVAL ANALYSIS OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA WITH RADIOMICS FEATURES
Authors: Barillot Noemie , Alentorn Agusti , Hernandez Isaias , Mokhtari Karima , Hoang-Xuan Khe , Mathon Bertrand 
Published: November 2023

Abstract
Primary Central Nervous System Lymphoma (PCNSL) is a rare and heterogeneous disease with dismal prognosis. Recently, four molecular clusters with clinical relevance have been identified with different potential therapeutic targets in each group. Nevertheless, multi-omics data collection and analysis are expensive and not adapted for clinical practice. Therefore, the identification of surrogate markers to identify PCNSL subtypes from routine data is required, like using hematoxylin and eosin slides from brain biopsies. We used a cohort of 108 patients and we selected the 5000 nuclei for each patient among roughly 1,500,000 nuclei. Once hematoxylin and eosin slides have been digitized, tessellated, normalized and the nuclei have been segmented and filtered with the computation of a solidity score, the PyRadiomics package provides us with more than 800 features for each nuclei. Firstly, we were interested in survival analysis. In a second time, we also used these features for training classification models. We used a partial least squared Cox model, which is a classic Cox model applied to latent components constructed by using linear combinations of the original variables. RESULTS: for our first cohort are promising (C-index of 0.87, std 0.01), with a significant increase compared to the clinical features model (C-index of 0.68, std 0.03). We are now challenging these results with three other cohorts of brain and systemic lymphoma. This study paves the way for a stratification of the clinical evolution based on the machine learning analysis of digital pathology in PCNSL that could be easily translated to a broad range of diseases or other brain tumors.
DISP-12. BRAIN CANCER CANADA FUNDS CRITICALLY NEEDED RESEARCH AND ADVOCATES FOR PATIENTS, WITH THE AIM TO IMPROVE OUTCOMES FOR CANADIANS DIAGNOSED WITH PRIMARY MALIGNANT BRAIN TUMOURS
Authors: Soares Jessica , Angelini Anita , Ladak Ali , Devan Kaviya , Loebenberg Lia , de Arujo Elvin , Power Jason , Leong Russell , Ayyadhury Shamini , Hoang Yung , Peeters Marc , Scalisi Angela , Canada Brain Cancer 
Published: November 2023

Abstract
Brain Cancer Canada (BCC) is a national, volunteer-driven charity supporting paediatric and adult primary malignant brain tumour research and patient advocacy. To achieve these goals BCC 1) awards grants to Canadian doctors and scientists advancing brain cancer research, and 2) advocates for equitable pharmacare for brain cancer patients. BCC is committed to funding innovative research projects, with the aim to improve treatment options for patients. Led by its Scientific Advisory Committee, submissions are reviewed, screened, and undergo a systematic evaluation by the panel. Recommendations on successful proposals are provided to the board for approval. This May, the charity awarded 5 research grants, totaling $380,000 CAD. These projects include supporting the acquisition of a next-generation DNA Sequencer, advancing FET-PET/MRI imaging, pioneering a novel approach to combat Diffuse Intrinsic Pontine Glioma (DIPG), developing a novel dual-hit therapeutic approach for glioblastoma, and other projects focusing on precision medicine. BCC has taken a deliberate and firm stand in highlighting the drug coverage disparities that exist for patients afflicted with brain cancer BCC’s Pharmacare Advocacy Committee has found that disparities exist owing to the lack of a national drug program, and a patchwork of alternative schemes varying by province/territory. These findings are well documented by others. For example, our research shows that temozolomide (TMZ), the global standard of care for treating gliomas, is not covered in 4 provinces. Our pharmacare research on TMZ and 5 other drugs further confirm the disparity in coverage that hinders patient welfare and imposes a confusing and detrimental strain on the healthcare system. With, the dependence on take-home medication increasing, it is critical we take immediate action in supporting this marginalized group. With the support of The Society for Neuro-Oncology, Brain Cancer Canada will be better positioned to reach its goals and support people affected by primary malignant brain tumours.
IMMU-07. THE CXCL16/CXCR6 AXIS REGULATES CD8+ T-CELL RECRUITMENT AND FUNCTION IN GLIOBLASTOMA
Authors: Chia Tzu-Yi , Billingham Leah , Boland Lauren , Wan Hanxiao , Wang Si , Katz Joshua , Hou David , Cervantes Gustavo Ignacio Vazquez , Han Yu , Lopez-Rosas Aurora , Zhang Peng , Lee-Chang Catalina , Miska Jason 
Published: November 2023

Abstract

INTRODUCTION
Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a poor prognosis and no curative treatment. Immunotherapy, revolutionizing oncology, is currently ineffective for GBM due to the immunosuppressive tumor microenvironment. A critical driver is tumor-associated macrophages (TAMs) infiltration, which is correlated to T-cell deficiency and tumor progression. While the interactions between TAMs and T-cells are known to inhibit the antitumor functions, the mechanisms driving these interactions in GBM are still not established. Our data shows that the CXCL16/CXCR6 axis is likely the predominant chemokine-receptor interaction among TAMs and CD8+ T-cells population in GBM. Understanding the role of this axis is crucial in modulating antitumor immune functions in GBM.

METHODS
We designed several migration and adhesion assays to determine how the CXCL16/CXCR6 axis influences: CD8+ T-cell migration, TAM: CD8+ T-cell interactions, and CD8+ T-cell dysfunction in GBM. In addition, long-term survival with immune checkpoint treatment was done to understand the influence of the axis on murine tumor growth.

RESULTS
While CXCR6 deficiency prevented T-cell infiltration into tumors, the CD8+ T-cells cells within the tumors expressed more markers associated with cytotoxicity and exhaustion. Furthermore, CXCR6 deficient CD8+ T cells were less adherent to immunosuppressive TAMs. Importantly, CXCR6 deficiency worked in concert with anti-PD1 to promote tumor rejection in the CT2A tumor-bearing model of GBM.

CONCLUSION
Our data show that while CXCR6 is crucial in trafficking CD8+ T-cells to tumors from the periphery, it promotes immunosuppressive interactions between TAMs/CD8+ T-cells within tumors. Thus, the CXCR6 axis exerts opposing roles in anti-tumor immunity in GBM.
IMMU-16. PUBLIC TUMOR-WIDE NEOANTIGENS DERIVED FROM CLONAL ABERRANT SPLICING EVENTS DRIVE TUMOR-SPECIFIC T-CELL RESPONSES
Authors: Kwok Darwin , Stevers Nicholas , Nejo Takahide , Jung Jangham , Chen Lee , Lakshmanachetty Senthilnath , Etxeberria Inaki , Gallus Marco , Yamamichi Akane , Ramos Emilio , Hong Chibo , Colton Maggie , Chan Gary , Du Aidan , Woo James , Wiita Arun , Klebanoff Christopher , Costello Joseph , Okada Hideho 
Published: November 2023

Abstract

BACKGROUND
Immunotherapy in gliomas is limited by tumor heterogeneity and low mutational burden. We developed a novel comprehensive in silico pipeline for detecting tumor-specific splicing events (neojunctions) across multiple cancer types, and in gliomas, we successfully identified tumor-wide, public, alternatively spliced neoantigens (ASNs) that elicit CD8+ T-cell-mediated immune responses.

METHODS
Our pipeline identified recurring public neojunctions expressed in TCGA RNA-seq (positive sample rate (PSR) &gt; 10%) and not in GTEx normal tissue RNA-seq data (PSR &lt; 1%) across six cancer types. To characterize intratumorally-conserved neojunctions, we utilized multi-site RNA sequencing, and with gliomas, we analyzed approximately 10 maximally-distanced intratumoral sites within 56 patients (n=535). Tumor-wide public neojunction expression was subsequently validated in RNA-sequencing and mass spectrometry (MS) data from patient-derived cell lines (n=68) and samples (n=99). Two independent algorithms then predicted peptide processing likelihood and HLA-binding affinity of ASN candidates. In vitro sensitization (IVS) of healthy donor-derived CD8+ T-cells against high-confidence ASN candidates, followed by 10x VDJ scRNA-seq, was performed to identify ASN-specific TCR sequences. TCRs were transduced into triple-reporter Jurkat76s and co-cultured with ASN and HLA-expressing COS7 cells and glioma cell lines to evaluate TCR functionality.

RESULTS
Our glioma-specific analysis identified 249 public neojunctions with varying intratumoral heterogeneity. 4 ASNs were concurrently identified in transcriptomic and proteomic glioma data and predicted to be presented by HLA-A*02:01 with high confidence. IVS and subsequent 10x VDJ scRNA-seq on expanded CD8+ populations identified TCR clonotypes reactive against neojunctions in RPL22 (n=7) and GNAS (n=1), the latter being highly intratumorally-conserved (detected in &gt; 90% of spatially-mapped biopsies across 17/56 patients (26.78%)). TCR-transduced T-cells demonstrated recognition and immunogenic activation against endogenously processed and presented neoantigens in glioma and transfected COS7 cells.

CONCLUSION
Our unique integrative pipeline identified novel public tumor-wide splice-derived neoantigen candidates and TCRs, offering a promising off-the-shelf immunotherapy approach for gliomas.
IMMU-21. LOW-INTENSITY PULSED ULTRASOUND PROMOTES THE PRESENTATION OF BRAIN-DERIVED ANTIGENS THROUGH ENHANCED TRAFFICKING OF ANTIGEN-PRESENTING CELLS FROM THE BRAIN INTO THE PERIPHERY
Authors: Gallus Marco , Arrieta Victor , Saijo Atsuro , Haegelin Jeffrey , Chuntova Pavlina , Yamamichi Akane , Chen Li , Habashy Karl , Gould Andrew , Amidei Christina , Chang Catalina Lee , Stupp Roger , Canney Michael , Sonabend Adam , Okada Hideho 
Published: November 2023

Abstract
The central nervous system, immunologically unique due to specialized lymphatics and anatomical barriers, often conceals brain neoplasm from the peripheral immune system. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) enables transient opening of the BBB, allowing drug transport and immune cell trafficking into brain tumors. However, it remains unclear whether BBB opening promotes immune cell trafficking from the brain to the periphery. To investigate this, we performed intravital imaging of Colony-stimulating factor receptor 1 (CSFR1) and CX3CR1 reporter mice to visualize antigen-presenting cell locomotion in the brain before and immediately after LIPU/MB using two-photon microscopy. Within one hour after LIPU/MB, we observed the exiting of CSFR1+ and CX3CR1+ immune cells from the brain parenchyma and perivascular space into the bloodstream, a phenomenon we did not observe prior to LIPU/MB treatment. To further evaluate the immunological effects of LIPU/MB on brain antigen presentation, we performed LIPU/MB in novel transgenic mice that express a minigene encoding for 4 immunogenic peptides under the glial fibrillary acidic protein (GFAP) promotor. We observed significant proliferation of naïve antigen-specific CD8 T cells targeting one of the peptides in the cervical lymph nodes one week after LIPU/MB treatment, but not in the animals that received T cells but did not undergo LIPU/MB. These data indicate that LIPU/MB facilitates the presentation of brain-localized antigens to antigen-reactive T cells in the systemic circulation. In 3 out of 5 GBM patients that underwent LIPU/MB plus doxorubicin and anti-PD-1 blocking antibodies, we observed CD11b+CD14+P2YR12+ microglia in blood samples collected after sonication. This increase was present in cycles 3-6 of this treatment. We did not observe the presence of this immune cell population in blood samples from healthy donors. Taken together, our results indicate that LIPU/MB could be a novel approach to enhance brain-antigen presentation in the periphery.
IMMU-22. BLOCKADE OF CD47 RESULTS IN METABOLIC REPROGRAMMING TO ENHANCE IMMUNE CELL-MEDIATED CYTOTOXICITY OF GLIOBLASTOMA
Authors: Tsai Yu-Ting , Lesser Glenn , Soto-Pantoja David R 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most aggressive and malignant brain tumor. There is growing interest in using immunotherapy to treat GBM, however, clinical trials with immune checkpoints have shown little efficacy, likely due to significant GBM-associated systemic and intra-tumoral immunosuppression. The expression of the transmembrane protein CD47 contributes significantly to immunosuppression limiting innate and adaptive anti-tumor responses. Our new data shows that patient biopsies showed strong immunoreactivity to CD47 in GBM compared to normal adjacent tissue. Furthermore, high CD47 expression in GBM patients resulted in poor survival, indicating that CD47 may be a potential target for GBM treatment. Beyond the “don’t eat me signal”, CD47 facilitates its intracellular signaling through PLIC1 and it still unknown how CD47-related can influence metabolic reprogramming in the tumor microenvironment. Previous studies that upregulated fatty acid oxidation (FAO) provide GBM cells with metabolic plasticity to accommodate its dynamic nutrient microenvironment. Respirometry data revealed that blocking CD47 in murine cell line (CT2A) reduces mitochondrial function and ATP production by over 40-50% respectively (p*&lt; 0.02). The reduction in mitochondrial respiration is linked to an over 50% reduction in FAO (*p&lt; 0.004). This was associated with significant decreases in CPT1a, FASN, ATGL, and CD36 indicating a reduction in FA metabolism mediators. On the other hand, blocking CD47 on murine microglia (SIMA9), showed an opposite result from cancer cells, with increasing mitochondrial respiration and FAO. Initial shows differential responses may be due to the engagement of PLIC1 to CD47. Furthermore, blocking CD47 on microglia increased three-fold of the immune cell-mediated GBM cell cytotoxicity (*p&lt; 0.005), suggesting that metabolic reprogramming associated with CD47 blockade could result in the improvement of immune adaptive responses in the GBM microenvironment. Taken together, our data indicated that CD47 blockade may be a prospective treatment to reduce GBM metabolic plasticity and increase microglia-mediated GBM killing.
IMMU-26. MRNA CAR T CELL TRAFFICKING FOLLOWING INTRA-VENTRICULAR ADMINISTRATION IN PRECLINICAL MODELS OF DIFFUSE MIDLINE GLIOMA
Authors: Al-atrache Zein , Mcmanus Olivia , Harvey Kyra , Dickson Conor , Patterson Luke , Beaubien Ezra , Wilson Cullen , Hajeebu Sreehita , Keil Samantha , Braun Molly , Meechan Michael , Vitanza Nicholas , Iliff Jeffrey , Madsen Peter , Foster Jessica 
Published: November 2023

Abstract

BACKGROUND
GD2-directed chimeric antigen receptor (CAR) T cells have shown promise as a potential therapeutic for diffuse midline glioma. We have previously shown intra-tumoral infusions of mRNA CAR T cells result in tumor regression with improved safety and toxicity profile in murine models. For human trials, the optimal route of CAR T cell administration into the central nervous system should maximize in vivo potency while minimizing procedural morbidity. Prior mRNA CAR T literature has reported decreased solid tumor infiltration with systemic delivery, so we sought to determine mRNA CAR T cell trafficking into pontine tumors from the cerebral spinal fluid to inform clinical translation of this therapy.

METHODS
Mice engrafted with SU-DIPG13P* tumor cells in the pons were treated with 5x106 mRNA CAR T cells into the lateral ventricle (LV) and brains were harvested 24 hours later. Tumor and T cells were analyzed using confocal microscopy to determine the migration of CAR T cells.

RESULTS
LV injection of GD2-directed CAR T cells resulted in T cell trafficking to the subarachnoid spaces, tumor site, and surrounding parenchyma. The highest concentration of T cells was in the subarachnoid space directly adjacent to the tumor (p&lt; 0.0001) and decreased on a gradient to subcortical tumor. Even at 24 hours after injection, T cells were identified within the center of the tumor mass. CD19-directed control CAR T cells showed similar distribution within the subarachnoid with significantly decreased T cells at the tumor site.

CONCLUSION
Ventricular infusions of mRNA CAR T cells showed effective migration to pontine tumors within 24 hours. While CAR T cells did not fully penetrate the parenchyma within that timeframe, GD2-directed mRNA CAR T cells were detected within the center of the tumor mass, indicating ventricular administration may be sufficient for clinical delivery. Additional routes are being explored in ongoing work.
IMMU-35. G-AMINOBUTYRIC ACID DRIVES GLIOBLASTOMA IN FEMALES BY ACTIVATING THE COMPLEMENT SYSTEM
Authors: Bayik Defne , Pathak Asmita , Chin Diana , Lin Feng , Iavarone Antonio , Lathia Justin 
Published: November 2023

Abstract
Interaction between tumor and neural cells drives the progression of glioblastoma (GBM), which is characterized by enhanced immunosuppressive myeloid cell accumulation. Our previous results revealed that myeloid-derived suppressor cell subsets (MDSCs) play a central role in tumorigenesis in a sex-specific manner, with monocytic MDSCs (mMDSCs) accumulating in male tumors and granulocytic MDSCs (gMDSCs) correlating with a worse outcome in females. However, host factors governing sex differences in MDSC subset activity remained unknown. Here, we report that g-aminobutyric acid (GABA) receptor expression by gMDSCs informs their sex-specific behavior. We observed that only female gMDSCs but not male gMDSCs or mMDSCs from either sex respond to GABA by upregulating the antiviral innate immune pathway. As part of this signature, GABA-stimulated female gMDSCs had higher complement 1qa (C1qa) expression. To test the potential role of the GABA pathway on GBM outcome, we tested the GABA analogue pregabalin in preclinical models. Female mice treated with pregabalin succumbed to disease earlier, consistent with our previous observation that gMDSCs have a central role in GBM progression in females. In contrast, pregabalin treatment had no effect in male mice with tumors or immunocompromised female mice. To further evaluate whether C1q is a relevant physiological target, we performed single-cell sequencing of tumor-infiltrating versus circulating MDSC subsets and detected high levels of C1q expression in gMDSCs from tumors. C1q KO transgenic female mice had significantly better outcomes compared to wild-type littermates upon implantation with syngeneic mouse GBM lines, while C1q expression status did not impact the outcome in males. Correspondingly, only in female patients C1q expression correlated with poor prognosis. Collectively, these results identify a neuron-immune-cancer communication axis and indicate that GABA and C1q alter anti-tumor immune responses in a sex-specific manner. These results support the future assessment of the GABA pathway and complement inhibitors as potential immunotherapy agents.
IMMU-39. EFFICACY OF IMMUNE CHECKPOINT INHIBITORS IN GLIOBLASTOMA FROM REAL-WORLD DATA ANALYSIS
Authors: Stuhlmiller Timothy , Quinn Jameson , Awawda Alaa , Blondin Nicolas , Iwamoto Fabio , Nabors Burt , Redfern Charles , Wasserman Asher , Cole Zachariah , Shapiro Mark , Kesari Santosh 
Published: November 2023

Abstract
Immune checkpoint inhibitors (ICIs) failed to show efficacy in a randomized trial in glioblastoma (GBM). We utilized the patient-led XCELSIOR platform (NCT03793088) to evaluate ICIs in real-world GBM treatment. XCELSIOR centralizes EMR data from all care sites, creating longitudinal, source-verified data. Identity verification permits accurate overall survival (OS) calculations. As of 6/8/2023, 726 GBM patients were enrolled in XCELSIOR. Median diagnosis date was 1/13/2021 and median age was 56. Seventy-five patients (10%) received ICIs: 53 received pembrolizumab (71%) and 26 received nivolumab (35%) including 12 with ipilimumab (16%). Median days from diagnosis to ICI initiation was 263 days with 22 patients treated at 1st line, 39 at 2nd line, and 14 at 3rd line or later. Data was annotated for 71 patients treated with ICIs and 394 patients not treated with ICIs (no-ICI). Median OS (mOS) from diagnosis for all ICI patients vs. no-ICI was 4.95 years (95% CI 2.18-NR) vs. 1.75 years (1.56-2.03, p &lt; 0.0001). Key features in the ICI cohort were 46% methylated MGMT, 47% gross total resection, 61% exposed to non-SOC agents besides ICI. Creating a propensity score matched cohort for these features, ICI vs. no-ICI had a numerically increased but non-significant mOS of 2.58 years (1.78-NR, n=62) vs. 2.05 years (1.76-2.61, n=113) but a 5-year survival rate of 44% for ICI vs. 16% for no-ICI. Optune use was similar, 39% ICI and 29% no-ICI. Common non-SOC agents used in the ICI cohort were everolimus (11%), osimertinib (8%), lenvatinib (7%), abemaciclib (7%), and neoantigen peptide vaccines (7%). Among unmethylated MGMT patients, mOS was 1.78 years for ICI vs. 1.8 years for no-ICI. These data suggest activity of ICIs for a subset of GBM patients, but do not support use in patients with unmethylated MGMT. Next steps will focus on discrete combination regimens in this evolving data.
IMMU-40. DECITABINE PRIMES GLIOBLASTOMA TO NY-ESO-1 SPECIFIC T-CELL CYTOLYSIS VIA DNA DEMETHYLATION OF NY-ESO-1, CANCER-TESTIS ANTIGENS, AND PRO-INFLAMMATORY SIGNATURES
Authors: Lai Thomas , Sun Lu , Treger Janet , Li Tie , Li Kevin , Prins Terry , Lai Albert , Prins Robert , Everson Richard 
Published: November 2023

Abstract

INTRODUCTION
Previous work has shown that the DNA hypomethylating agent, Decitabine (DAC), can improve the immunogenicity of Glioblastoma (GBM) for immuno-therapeutic targeting through the upregulation of cancer testis antigens (CTA). Specifically, our group has published preclinical proof of principle that DAC upregulates NY-ESO-1, a well-studied and highly immunogenic CTA, in GBM for targeting by systemic adoptive T-cell therapy. However, the exact mechanisms by which this DAC-induced immunogenic enhancement occurs in GBM remains to be elucidated. We hypothesize that hypomethylating agents like DAC enable targeted immune therapy to overcome low immunogenicity in GBM cells via CpG demethylation of antigens and subsequent upregulation of inflammatory and antigen presentation gene signatures.

METHODS
We induced NY-ESO-1 expression in vitro in immortalized GBM lines and primary gliomaspheres using DAC and investigated the response of DAC-treatment using targeted bisulfite sequencing and quantitative real-time PCR. To functionally assess for specific immune killing of DAC treated GBM cells, we co-cultured DAC-treated cell lines with T-cells transduced to express a NY-ESO-1 specific T-cell receptor. Lastly, we performed probe-based methylation array and bulk RNA sequencing to interrogate global transcriptomic and epigenomic changes resulting from DAC treatment.

RESULTS
Sustained exposure to low dose (0.5 uM – 1 uM) DAC in immortalized and primary cell lines resulted in time-dependent demethylation of the CpG island of NY-ESO-1 and the subsequent robust increase in mRNA expression. Upregulation of NY-ESO-1 rendered specific T cell recognition and lysis of immortalized and primary cell lines. DAC upregulated other pro-inflammatory and immuno-modulatory signatures via CpG demethylation to enhance T-cell mediated targeted cytolysis of GBM.

CONCLUSION
Hypomethylating agents like DAC upregulate immunogenic signatures in primary and immortalized GBM cells, rendering them susceptible to antigen specific T-cell targeting. These pleiotropic effects demonstrate strong preclinical rationale for use of DAC to sensitize GBM for targeting by immune therapies.