bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-08. EOSINOPHILS ARE IMPORTANT MODULATORS OF AN IMMUNE-RESPONSIVE TUMOR-MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Herold-Mende Christel , Heiland Dieter Henrik , Fermi Valentina , von Deimling Andreas , Unterberg Andreas , Warta Rolf 
Published: November 2023

Abstract
Eosinophils, bone marrow-derived granulocytes involved in allergic asthma and autoimmunity, have attracted increasing attention due to their assumed role in effective responses to immune checkpoint blockade in some extracranial tumors. However, the role of this rare type of immune cells in immunologically cold tumors such as glioblastoma (GBM) has not been studied so far. When quantifying immune infiltrates and levels of 30 immune-relevant cytokines in 60 matched pairs of human primary and recurrent GBM, strongest correlations (r= 0.71-0.93) were observed for the eosinophil-associated cytokines Eotaxin and Il-5 as well as for TNFa, IFNg and Il2 which are important cytokines for cytotoxic T cell responses. A combined score of these cytokines (Eo score) turned out to be an independent prognostic marker for improved overall survival of GBM patients. Furthermore, multicolor immunofluorescent staining revealed that Eo score high GBM are significantly higher infiltrated by effector T cells and show a significantly lower infiltration with anti-inflammatory M2-like tumor-associated macrophages / microglia cells (M2-TAM) in recurrent GBM. Flowcytometry analysis of GBM-derived single cell suspensions confirmed a positive correlation of higher eosinophil numbers with higher numbers of tumor-infiltrating T cells, while an inverse relation between eosinophils and monocytes could be demonstrated in the TCGA data set. Spatial transcriptomic data of human GBM confirmed that areas with a higher eosinophil infiltration showed higher numbers of T cells and pro-inflammatory M1-TAM, lower numbers of M2-TAM and a remarkable vessel normalization. Finally, in a newly developed patient-derived GBM organoid model we could corroborate the functional impact of eosinophils on the tumor-microenvironment. An increase of eosinophil numbers in these patient avatars resulted in a significantly decreased number of M2-TAM. Altogether, tumor-infiltrating eosinophils seem to be a novel type of immune-modulator in GBM and may enhance immune responses by shaping the tumor niche from an immunosuppressive to an immunepermissive microenvironment.
IMMU-18. ESTABLISHMENT OF CAR-NK CELL THERAPY TARGETING B7-H3 AGAINST GLIOBLASTOMA
Authors: Tachi Tetsuro , Kijima Noriyuki , Kuroda Hideki , Ikeda Shunya , Murakami Koki , Hirayama Ryuichi , Okita Yoshiko , Kagawa Naoki , Hosen Naoki , Kishima Haruhiko 
Published: November 2023

Abstract
Glioblastoma (GBM) has a poor prognosis despite intensive treatment by surgery, radiation, and chemotherapy, thus new therapeutic strategies are urgently needed. Recently, CAR (chimeric antigen receptors) -T cell therapy, which uses genetically engineered T cells to express CAR has been extensively investigated. However, although CAR-T cell therapy has shown some efficacies in preclinical GBM models, it exhibited limited efficacy and undesirable side effects such as graft-versus-host disease when adapted for clinical trials. In contrast, cord blood-derived natural killer (NK) cells show a robust safety profile in preclinical models and CAR-NK cell therapy is an attractive therapeutic option for cancer treatment. In this study, we aim to analyze the therapeutic efficacy of CAR-NK therapy against GBM. We used B7-H3 as a target antigen for CAR-NK cell therapy because B7-H3 has recently been reported to be a tumor specific antigen for GBM. First, we generated CAR-T cells expressing CAR targeting B7-H3. We found that CAR-T cells targeting B7-H3 produced IL-2 and IFNɤ and exerted cytotoxicity to GBM cells by chromium 51 release assay. In addition, in an orthotopic mouse model, CAR-T cells targeting B7-H3 showed survival benefits compared with control CAR-T cells. Next, we generated CAR-NK cells targeting B7-H3 from cord blood-derived NK cells and found robust cytolytic activity against GBM cells in vitro. These results suggest that cord blood-derived CAR-NK cells targeting B7-H3 may be a promising therapy for GBM and further studies are necessary to examine whether cord blood-derived CAR-NK cells targeting B7-H3 could be a therapeutic strategy against GBM.
IMMU-30. NOVEL HYPOMETHYLATING AGENT GSK-3484862 SENSITIZES GLIOBLASTOMA TO NY-ESO-1 SPECIFIC IMMUNOTHERAPY
Authors: Li Kevin , Lai Thomas , Prins Robert , Everson Richard 
Published: November 2023

Abstract

INTROUCTION
Immunotherapy is a promising mode of treatment due to its specificity and efficacy in eliminating tumors, but is limited in GBM due to the lack of immunogenicity and unique cancer antigen expression. Previous work from our group has shown that Decitabine (DAC), a demethylating agent, can improve the immunogenicity of Glioblastoma (GBM) for immuno-therapeutic targeting through the upregulation of immunogenic cancer testis antigens (CTA) such as NY-ESO-1 and altered expression of other immunoregulatory programs. However, immunosensitization using DAC is limited due to non-specific toxicity after prolonged administration. We hypothesize that a newly synthesized hypomethylating agent, GSK-3484862 (GSK), may be an effective alternative to DAC in promoting CTA expression in GBM with limited cytotoxic effects on surrounding immune cells.

METHODS
Human GBM cells and patient-derived glioma spheres were treated with GSK and DAC. We investigated the differential expression in NY-ESO-1 at a transcriptional level between DAC and GSK through quantitative real-time PCR. To assess whether these differences translated into heightened immune responses as a result of NY-ESO-1 upregulation, we co-cultured DAC and GSK-treated immortalized and primary cell lines with transduced NY-ESO-1 specific T-cell receptor T-cells.

RESULTS
Immortalized and primary glioma sphere cells demonstrated equivalent NY-ESO-1 gene upregulation after four days of treatment between 1 µM DAC and 5 µM GSK. Glioma spheres treated for three weeks at a dose of either 0.5 µM DAC or 2.5 µM GSK demonstrate equivalent NY-ESO-1 upregulation. Furthermore, xCELLigence data demonstrates that equivalent NY-ESO-1 expression achieved by the differential dosing between GSK and DAC leads to similar rates of NY-ESO-1 specific T-cell mediated killing, indicating a functional equivalence between GSK and DAC induced immunosensitization at equivalent NY-ESO-1 expression levels.

CONCLUSION
Our results demonstrate a preclinical rationale for the use of GSK as a viable pro-antigenic agent for the sensitization of GBM to targeted immune therapy.
IMMU-43. IN-DEPTH SINGLE-CELL ANALYSIS OF THE IMMUNE LANDSCAPE IN CHORDOMAS REVEALS T-CELL EXHAUSTION AND INFORMS RATIONAL IMMUNOTHERAPEUTIC INTERVENTION
Authors: Arrieta Victor , Benotmane Jasim K , Zhao Junfei , Dhiantravan Silpol , Hou David , Katz Joshua , Wang Si , Castro Brandyn , Pandey Surya , Cholak Meghan , Galbraith Kirstyn , Najem Hinda , Han Yu , Bettegowda Chetan , Snuderl Matija , Horbinski Craig , Miska Jason , Stupp Roger , Heimberger Amy , Lesniak Maciej , Sonabend Adam , Wolinsky Jean-Paul , Heiland Dieter Henrik , Lee-Chang Catalina 
Published: November 2023

Abstract
Chordomas are rare tumors that arise from remnants of the notochord. The standard of care for chordoma remains only surgery and radiotherapy. Though checkpoint inhibition therapy shows promise, recent immunotherapy trials failed to reach endpoints. This emphasizes the need to comprehensively understand the tumor and peripheral immune landscape of chordomas to establish a rationale for immunotherapeutic intervention. Here, we aimed to investigate the composition and functionality of the tumor and peripheral immunological landscape of chordomas using single-cell RNA-sequencing, TCR profiling, and multiplex immunofluorescence. We generated a comprehensive single-cell atlas of chordomas incorporating paired single-cell transcriptomic samples from the tumor and blood of five patients and single-cell TCR sequencing data to analyze the T-cell clonality. Furthermore, we analyzed and quantified the immune cell composition (CD3+, CD4+, CD8+, CD20+, and CD163+ cells) of 33 chordomas (14 clival and 19 spinal) through multiplex immunofluorescence. Our findings revealed that the CD8+ T-cell antitumoral immunity originates in the periphery, characterized by clonal expansion of cytotoxic and memory T cells in the blood. However, this immunity undergoes progressive exhaustion following tumor infiltration. Furthermore, we observed that CTLA-expressing central memory and Tregs constitute most of the CD4 T-cell tumoral landscape. Within the B cell compartment, regulatory B cells and plasma cells were the most abundant. Hierarchical clustering analysis of 33 chordomas identified 3 distinct clusters based on the relative abundance of T cells, B cells, and macrophages. Notably, a higher abundance of CD3+ T cells was found in newly diagnosed chordomas as opposed to recurrent cases. Our study provides crucial insights into the complex immune landscape of chordoma. The results of this work may be of foundational importance to understanding chordoma immunology and tailoring immunotherapeutic strategies for these tumors.
IMMU-49. BETA-ADRENERGIC BLOCKADE LICENSES THE USE OF IMMUNOTHERAPY IN PRIMARY AND METASTATIC BRAIN TUMORS
Authors: Lorrey Selena , Wachsmuth Lucas , Polania Jessica Waibl , Hoyt-Miggelbrink Alexandra , Neff Corey , Price Mackenzie , Finlay John , Cui Xiuyu , Wilkinson Daniel , Lerner Emily , Srinivasan Ethan , Hotchkiss Kelly , Ostrom Quinn , Fecci Peter 
Published: November 2023

Abstract
Immunotherapy is less effective against intracranial metastases compared to extracranial metastases and ineffective against primary brain tumors such as glioblastoma. Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just locally at the tumor, but also outside the CNS. Importantly, systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Through this work we present a novel axis of immunosuppression in patients with intracranial tumors and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success.Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. We demonstrate that this survival benefit is driven by a remodeling of the tumor microenvironment with an increase in cDC1s and CD8+ T cells, as well as an increase in CD40-CD40L signaling, suggesting the immune system is poised to respond. Further, we demonstrate that beta-adrenergic blockade can overcome systemic immunosuppression to restore the capacity of T cells to respond to an immune stimulus. Further, using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently receiving beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of glioma, demonstrating that combining immunotherapy and propranolol, a widely-prescribed FDA-approved beta-blocker, extended survival. Moving forward, we suggest that combination therapy with beta-blocker and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.
INNV-01. ASSESSMENT OF SURVIVAL AND SAFETY FOLLOWING INTRATHECAL CHEMOTHERAPY VIA OMMAYA RESERVOIR FOR PATIENTS WITH LEPTOMENINGEAL DISEASE
Authors: Harahsheh Ehab , Shah Shiv , Butterfield Richard , Ariete Carl , Lyons Mark , Krishna Chandan , Zimmerman Richard , Fortin-Ensign Shannon , Bendok Bernard , Mrugala Maciej 
Published: November 2023

Abstract

BACKGROUND
Leptomeningeal disease (LMD) carries poor prognosis with an average survival of 3-6 months after diagnosis. Ommaya reservoirs (OR) are an accessible alternative to serial lumbar punctures for delivery of intrathecal chemotherapy (IC) and disease monitoring but are not widely used. Intraventricular administration of chemotherapy may be associated with superior efficacy and improved patient comfort. The purpose of this study was to assess safety and efficacy of IC and disease monitoring via OR in routine clinical practice.

METHODS
Patients who received at least one administration of IC via OR for LMD between 2017 and 2022 were included. Demographics, treatment type, complications and outcomes were recorded.

RESULTS
We identified 22 patients (17 females, 5 males) with mean age 50.9 ± 14.8 years. The primary tumors were: breast (12), leukemia (3), ovarian carcinoma (3), CNS lymphoma (1), urothelial carcinoma (1), spinal melanocytoma (1), and high-grade glioma (1). A total of 208 OR injections were performed [median was 9 OR injections per patient, interquartile range (IQR) (5, 13)]. Five patients (23%) experienced mild adverse events of grade 2 or lower by Common Terminology Criteria for Adverse Events. Overall risk of adverse event from injection was 3.4% (7/208). Eight patients (36.3%) converted into negative CSF cytology (median 1 month following first injection). Eighteen patients (82%) had clinical or radiological progression of their LMD (median 2 months following first injection). Eleven patients (50%) died of their LMD during follow-up. Median OS and PFS from the first injection were 5.3 months [95% CI 4.8-NE (not estimable)] and 4.3 months [95% CI 1.8-16.0], respectively.

CONCLUSION
Use of OR in routine clinical practice is a safe and feasible option and should be strongly considered for treatment and monitoring of patients with LMD. The median OS in our cohort is comparable to prior published series.
INNV-03. INSTITUTION SPECIFIC CLINICAL TRIAL MATCHING WEB APPLICATION FOR CENTRAL NERVOUS SYSTEM METASTASES
Authors: Gilbert Marissa , Zhu Simeng , Shah Mira , Siddiqui Salim , Rogers Lisa R , Siddiqui Farzan 
Published: November 2023

Abstract

BACKGROUND
Current clinical trials evaluating treatment options for patients with brain metastases are tailored to a number of clinical factors, including type of underlying cancer, number of brain metastases, size and volume of brain metastasis, prior treatment, and genomic characterization. A multidisciplinary brain metastasis tumor board was established at our institution in January 2023. Subsequently, an institution specific clinical trial matching web application was developed in-house to screen and match subjects for trials accruing at our institution.

METHODS
We reviewed our institution’s list of phase III surgical, radiation, and medical oncology clinical trials specific for brain metastasis to identify the most discriminating inclusion criteria that can be used as a basis for branching and differentiation. These disease specific trials were then individually assessed according to these criteria and these results were populated in a common separated value (CSV) file.

RESULTS
A web application was created using Python for analysis of the CSV and incorporating branching logic. HTML, CSS, and JavaScript were used for building the webpage interface. The web application is hosted on our institutional server and can be utilized to search available clinical trials for each patient being presented during tumor board.

CONCLUSION
We developed an institution specific web application that can be used to screen patients for various clinical trials. By developing this application and hosting it internally, we are able to edit the components at our discretion. The methodology for this web-build can be applied to other disease sites or institutions. This web application is useful for screening our institution’s clinical trial portfolio to identify potential gaps, and can also be used to avoid competing trials. This web application significantly reduces the time to identify protocol eligibility and has increased clinical trial enrollment.
INNV-10. GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS – EXPERIENCE OF CASES PRESENTED AT NATIONAL AYA MULTI-DISCIPLINARY ROUNDS
Authors: Bennett Julie , Massey Natalie , Das Sunit , Climans Seth , MacDonald Maria , Perreault Sébastien , Vanan Magimairajan Issai , Yip Stephen , Lapointe Sarah , Tsang Derek , Tabori Uri , Hawkins Cynthia , Lim-Fat Mary-Jane 
Published: November 2023

Abstract

INTRODUCTION
Gliomas are the most common brain tumor in adolescents and young adults (AYA). IDH mutations are common in this population, though up to 30% of gliomas in AYA harbor a pediatric-type alteration including alterations in RAS/MAPK pathway and histone mutations. These can present a diagnostic and management dilemma in young adults given the limited data in this population. Here, we aim to describe glioma cases submitted for multi-disciplinary AYA rounds.

METHODS
Gliomas presented at the Canadian AYA Neuro-Oncology Network (CANON) rounds between April 2021 and June 2023 were compiled. Patient demographics, tumor histology and molecular alterations are described. Recommendations and themes from the multi-disciplinary rounds were summarized.

RESULTS
Of 132 cases presented, 96 were gliomas. Median age was 28 years (range 15-59). Twelve (12.5%) cases were IDH-mutant. Remaining cases included low grade glioma (LGG, n=37, 38.5%), IDH-WT high grade gliomas (HGG, n=22, 22.9%) and diffuse midline glioma (n=13, 13.5%). Of the LGGs, 13 gliomas had FGFR-alteration, 9 had BRAF-alteration, 3 had NF-1 with 4 having rare alterations typically seen in children (KRAS, NTRK fusion, PDGFRa K385-mut). Recommendations included discussion to start targeted therapy or management of toxicities due to targeted inhibitors in 16 cases. Of the HGGs, 7 (31.8%) had underlying cancer predisposition syndrome (NF-1 n=4, mismatch repair deficiency n=3). Management questions included role of re-resection, timing of radiation, duration of targeted therapies and access to targeted agents through clinical trials or compassionate access programs.

CONCLUSION
Within national rounds, there was enrichment of pediatric-type tumors and patients with cancer predisposition syndromes. Targeted agents are available for many of these driver mutations with potential improved outcomes; however, access to these agents in AYA may be limited. Clinicians face complex management questions in this population and underscores the need for a multi-disciplinary approach along with clinical trial opportunities for these patients.
INNV-20. PREDICTING RESPONSE TO CHEMOTHERAPY IN HIGH GRADE GLIOMAS USING EX VIVO 3D CELL CULTURE FUNCTIONAL PRECISION ONCOLOGY PLATFORM – A MULTI-INSTITUTIONAL EXPERIENCE
Authors: Mrugala Maciej , Hrachova Maya , Sherman Wendy , Ensign Shannon Fortin , Blomquist Mylan , Porter Alyx , Thompson Tracy , Greene DeNia , Anastasiadis Panos , Vasmatzis George , Lin Wan-Hsin , Dunn Ian , Quiñones-Hinojosa Alfredo , Zimmerman Richard , Swanson Kristin , Bendok Bernard 
Published: November 2023

Abstract

BACKGROUND
Treatment of high-grade glioma (HGG) remains a challenge. Several groups have developed ex vivo drug sensitivity assays to evaluate susceptibility of the tumor tissue to specific chemotherapeutics. This tool, in addition to molecular analysis of tumors might provide another layer of confidence in choosing treatments for patients with high-grade gliomas.

METHODS
3D PredictTM platform (Kiyatec, Greenville, SC, USA) was tested at three academic medical centers in the United States. Twelve patients with newly diagnosed and recurrent HGGs were included. Tumor spheroids created ex vivo were exposed to twelve pre-selected drugs. Responses were reported as: no response, moderate response and response. We analyzed: demographics, histopathology, stage of disease, success rate and results of the ex vivo assay and clinical implications.

RESULTS
Majority of patients were women (67%). Median age was 58.5. Histology: GBM-83%, HGGs-17%. Eighty three percent of the samples represented recurrent disease. Sixty percent represented first recurrence while the remaining 40% represented 2nd or 3rd recurrence. Eight out of 12 tissue samples (67%) were successfully tested ex vivo. In six cases (75%), the information was used for immediate clinical decision making. In 2 cases, the decision was deferred until the next progression of the disease. The drugs chosen for treatment based on assay results included: olaparib (the assay was positive for response to rucaparib), temozolomide, lomustine, carboplatin and irinotecan.

CONCLUSIONS
This platform is easy to use in a standard clinical setting, the success rate for creating viable spheroids for drug sensitivity testing is high and the information obtained can be useful in clinical practice. Addition of other agents to the assay, correlation with molecular testing of the tumor tissue and attempt to assess response to drug combinations should be considered in further development of this technology. Prospective clinical trial is needed to validate this approach for routine clinical use.
INNV-30. DEVELOPMENT AND IMPLEMENTATION OF A NOVEL, BRIEF NEUROCOGNITIVE SCREENING AND REHABILITATION SERVICE IN A CLINICAL NEURO-ONCOLOGY SETTING
Authors: Sheppard David , Goldberg Myron , McGranahan Tresa , Graber Jerome , Venur Vyshak , Figuracion Karl Cristie , Song Young Bin , Wefel Jeffrey , Noll Kyle , Ferreira Manuel , Halasz Lia , Taylor Lynne 
Published: November 2023

Abstract

BACKGROUND
Although neurocognitive dysfunction is common in patients with brain tumors, existing screening methods (e.g., Montreal Cognitive Assessment) lack sensitivity for detecting neurocognitive difficulties. Moreover, existing neurocognitive screens provide only modest clinical utility for characterizing individual neurocognitive strengths/weaknesses critical for treatment planning.

METHODS
Beginning in February 2023, the Alvord Brain Tumor Center at the University of Washington Medical Center (UWMC) implemented the Rehabilitation Neuropsychology Screening Service (RNSS). The RNSS is an internal outpatient service staffed by a rehabilitation neuropsychologist from the Department of Rehabilitation Medicine at UWMC. Neuro-oncologists and advanced practice providers placed referrals to the RNSS based on clinical need and cognitive symptoms. On average, 1-2 referrals per week were received.

RESULTS
Patients referred to the RNSS have included those with high- and low-grade gliomas with varying degrees of everyday functioning status (e.g., independence at home, goals to return to work/school) and neurocognitive symptoms. The goal of the RNSS is to explore inclusion and exclusion criteria that optimize patient experience and outcomes while maximizing outreach to patients in need of neurorehabilitation services. The RNSS includes brief, repeatable neuropsychological testing (90-minutes) and patient-reported outcomes (e.g., mood, quality of life). A separate feedback appointment is then held with patients to describe personal neurocognitive strengths/weaknesses and provide neurorehabilitation strategies or rehabilitation resources/referrals based on findings. In select cases, RNSS has served as a triage stage for stepped care towards referrals to a more comprehensive neuropsychological evaluation.

CONCLUSION
The development and implementation of this novel approach to neurocognitive screening and rehabilitation, including the rationale, workflow of patient care, and expected outcomes, is described. With additional quality assessment/improvement, the RNSS may serve as a model for integrating neurorehabilitation services into existing neuro-oncology clinics, and may be an additional guide for patients and families towards neurorehabilitation resources and education.