bluuebunny/crossref_metadata_2025 huggingface dataset:
EPCO-53. MULTI-SCALE REGULATION OF SIGNALING CASCADES AND TUMOR EVOLUTION IN HIGH GRADE ASTROCYTOMAS
Authors: Chheda Milan , Liu Jingxian , Cao Song , Imbach Kathleen , Gritsenko Marina , Lih Tung-Shing , Kyle Jennifer , Yaron Tomer , Li Yize , Strunilin Ilya , Binder Zev , Wang Yi-Ting , Tsai Chia-Feng , Ma Weiping , Chen Lijun , Clark Natalie , Wyczalkowski Matthew , Wang Liang-Bo , Deen Nataly Al , Caravan Wagma , Houston Andrew , Rykunov Dmitry , Cottingham Sandra , Chu Rosalie , Weitz Karl , Moore Ronald , Wiznerowicz Maciej , Hostetter Galen , Jewell Scott , Newton Chelsea , Ketchum Karen , Thangudu Ratna , Barnholtz-Sloan Jill , Wang Pei , Fenyö David , An Eunkyung , Nasrallah MacLean P , Thiagarajan Mathangi , Robles Ana , Mani D R , Smith Richard , Porta-Pardo Eduard , Cantley Lewis , Iavarone Antonio , Mesri Mehdi , Zhang Hui , Resnick Adam , Rodland Karin , Liu Tao , Ding Li
Published: November 2023

The National Cancer Institute Clinical Proteomic Atlas Consortium (CPTAC) herein reports our deep characterization of 228 grade IV IDH1 WT and mutant astrocytomas (including 28 matched primary and recurrent GBMs) using 15 proteogenomic and metabolomic platforms. Major advances over our first CPTAC GBM report (Wang et al., 2021, Cancer Cell), are the inclusion of many more samples including paired primary and recurrent tumors, application of new platforms, including glycoproteomics and targeted mass spectrometry methods, development and application of new computational techniques, and the integration of an atlas of experimentally determined, functional, kinase substrate interactions from Kinase Library. Paired primary-recurrent GBM analyses showed increased clonal diversity in recurrent tumors as a function of time, and treatment-induced mutation signatures. Proteomic and metabolomic analyses showed that different drivers can cause similar downstream effects. Only EGFR altered tumors were associated with dual EGFR glycosylation (N352 and N603) and EGFR phosphorylation (Y316) events. IDH1 mutation was associated with activated RTK signaling and decreased hypoxia pathway activities, concordant with epigenetic and metabolic profiles. Protein-protein interaction and kinase/phosphatase-substrate analyses uncovered detailed signaling events from different upstream drivers (e.g., EGFR, PDGFRA, and IDH1) converged through a PTPN11 hub to downstream effectors, including GAB1, IRS1, MAP3K5, and PTK2B. In summary, this multiscale resource presents new and deeper biological insights regarding treatment impact on tumor evolution, shared downstream consequences of independent drivers, and the potential importance of PTPN11 signaling circuitry across high-grade gliomas. We hope that reporting this new international resource to the SNO community will advance therapeutic development, including targeted therapies that may avoid known mechanisms of resistance.
DISP-01. THE IMPACT OF COVID-19 PANDEMIC ON THE HEALTHCARE DELIVERY OF RACIAL/ETHNIC MINORITIES WITH BRAIN METASTASIS BY FACILITY TYPE
Authors: Zhu Ping , Chen Clark ,   NC Consortium
Published: November 2023

OBJECTIVES

Brain metastases (BM) are the most common form of adult brain cancer and one of the most devastating complications of cancer. We propose to characterize the effect of the pandemic on health care delivery for racial/ethnic underserved populations on BM care in general and stratifying by facility type.

METHODS

We utilized two national-scale datasets - the National Cancer Database (NCDB) and one of the largest COVID-19 real-time centralized data in the world - the National COVID Cohort Collaborative (N3C) database. Multivariable binary logistic regression models were performed to determine whether the pandemic (three-dimensional measures: pre-pandemic vs. during-pandemic, COVID-19 positivity, and density of COVID-19 prevalence) influence BM care delivery [including stereotactic radiosurgery (SRS), chemotherapy, and immunotherapy], especially for race/ethnicity minorities and patients receiving treatments at non-academic centers (NACs).

RESULTS

Compared to pre-pandemic years, the proportions of receiving BM care significantly decreased across all racial/ethnic groups during the pandemic using two nationwide datasets (NCDB: N=5238; N3C: N=13106), but non-white patients were still significantly less likely to undergo SRS than non-Hispanic whites (NHW) in N3C (total: aOR-0.76, p< 0.001; Black: aOR-0.78, p< 0.001, Hispanic: aOR-0.75, p=0.013; APAA: aOR-0.62, p=0.002) and NCDB (Black: aOR-0.78, p=0.006). Similarly, the odds of receiving chemotherapy for race/ethnicity minorities BM patients were significantly lower than NHW in N3C (Black: aOR-0.71, Hispanic: aOR-0.63, APAA: aOR-0.46, all p< 0.001) and NCDB (Black: aOR-0.86, p=0.028). Furthermore, such inequality in SRS receipt by race/ethnicity was exacerbated during the pandemic at NACs over academic centers (ACs) (esp. Hispanic vs. NHW at NACs: aOR-0.58, p=0.004; Hispanic vs. NHW at ACs: aOR-0.88, p=0.380) in NCDB.

CONCLUSION

Our study suggests that BM healthcare delivery has been significantly reduced in general during the pandemic, but racial/ethnic disparities in BM care and inequality in healthcare access by facility type still exist and have been even exacerbated.
DISP-06. EXAMINING THE INFLUENCE OF NEUROSURGICAL ONCOLOGY PROVIDER ACCESS ON DIFFUSE GLIOMA SURVIVAL OUTCOMES: A NATIONWIDE COUNTY-LEVEL APPROACH
Authors: Sibih Youssef , Perera Sudheesha , DiGiorgio Anthony , Hervey-Jumper Shawn
Published: November 2023

Neuro-oncology as a field has markedly improved understanding of the molecular underpinnings of brain cancer, yet fundamental concepts driving patient outcomes such as access to neuro-oncology subspecialty care remain poorly understood. The aim of this study was to determine the density of neuro-oncologist in the US and correlate disease-specific mortality with provider density. The data was calculated from two national data registries: Centers for Medicare & Medicaid Services (CMS) and Surveillance, Epidemiology, and End RESULTS: (SEER) database. Linear regression modeled three primary outcomes of interest: neurosurgical oncologist per capita, average distance to subspecialist care, and incidence-based mortality of diffuse glioma. Neurosurgical oncologists were classified as providers who billed for CPT code “61510” with at least 10 total services per year over the 5-year duration. In the US, a total of 113 catchment areas were constructed. Mean number of subspecialty providers per capita was 1.80 and the average distance traveled to the nearest provider across the US was 49.9 miles (range 5–151 mi). The mean age-adjusted incidence-based mortality rate among all catchment areas represented was 5.42 deaths per 1000 person-years. Catchment areas with a higher average income were associated with a greater number of subspecialty providers (95% CI 2.13 to 3.44, p < 0.027). Among all US regions, there was no correlation between mortality and provider density or average distance to care. However, Hispanic ethnicity displayed highest incidence-based mortality (r = 0.601, 95% CI -5.02 to -0.944, p < 0.0051). US regions associated with higher poverty and lower average income were associated with greatest mortality (r = 0.45, p < 0.0058). This population study illustrates differences in provider density throughout the United States. Additional research is needed to devise strategies that ensure equitable geographic access in order to optimize patient care and reduce disease burden.
DISP-09. HISTOPATHOLOGIC AND MOLECULAR PROFILE OF GLIOMAS: A 9-YEAR RETROSPECTIVE STUDY OF CASES DIAGNOSED IN LAGOS NIGERIA
Authors: Odukoya Lateef , Kollmeyer Thomas , Eckel-Passow Jeanette , Ida Cristine , Lachance Daniel , Fonkem Ekokobe , Badmos Kabir , Bankole Olufemi , Kitange Gaspar , Daramola Adetola , Anunobi Charles , Jenkins Robert
Published: November 2023

BACKGROUND

The diagnosis and management of patients with brain tumors currently uses WHO defined morphologic and molecular features. However, neuro-oncology practice in low resource settings relies on histomorphology. This study aims to reclassify glioma cases diagnosed in the Department of Anatomic and Molecular Pathology Lagos University Teaching Hospital using the 2021 WHO classification.

METHODS

Fifty-six cases of glioma diagnosed between 2013 to 2021 were evaluated. Morphologic diagnosis was reassessed. Five-micron sections were obtained for immunohistochemistry (IHC), and genetic testing (DNA and RNA); after manual macrodissection for tumor enrichment using 10μm sections. IHC for IDH1-R132H, ATRX, BRAFV600E, P53,Ki67, and H3K27M and OncoScan chromosomal microarray analysis were performed. NGS mutation/fusion analysis and EPIC methylation array profiling are in progress.

RESULTS

Of 56 cases evaluated, median age was 22 years (range=1-60 years); 71% were males. The initial morphologic diagnosis include 21 pilocytic astrocytoma, 11 glioblastoma, 9 ependymoma, 7 diffuse astrocytoma, 3 anaplastic astrocytoma, 2 high-grade gliomas, 1 oligodendroglioma, 1 diffuse midline glioma, and 1 pleomorphic xanthoastrocytoma (PXA). Histomorphologic re-evaluation revealed discordant diagnosis in 29% (16/56) of cases. Of the 56 cases, 73% (41/56) had usable DNA yield and 38% (21/56) had DNA yield of ≥ 750ng. Chromosomal microarray analysis was completed for 50% (28/56) cases. The revised 2021 WHO diagnosis were: 5 glioblastoma, IDH-wildtype, 5 pilocytic astrocytoma, 4 glioma NEC, 3 posterior fossa ependymoma, group B, 3 PXAs, 3 astrocytoma, IDH-mutant, 2 pediatric low-grade glioma, 2 supratentorial ependymoma, ZFTA fusion-positive, 1 posterior fossa ependymoma, group A. In 71% (20/28) of cases, diagnosis was revised using the 2021 WHO criteria.

CONCLUSION

Most cases had usable DNA yield. Overall, hsitologic re-evaluation and molecular testing based on the 2021 WHO classification guidelines refined the diagnosis in 48% (27/56) of cases.
DISP-13. ENHANCING HISPANIC PARTICIPATION IN BRAIN TUMOR TRIALS
Authors: Tajera Dalissa , Marino Irene , De Gennaro Geoffrey , Martinez Adriana , Wright Leonela , Trent Jonathan , de la Fuente Macarena
Published: November 2023

BACKGROUND

Hispanics represent 18.9% of the U.S. population, 26.8% of Florida population, and is the fastest growing ethnicity in the country. Hispanic representation in clinical trials remains extremely low at less than 3%. Increasing the Hispanic participation rate in clinical trials has been a priority for the University of Miami (UM), who has implemented various initiatives to improve diversity and inclusion of underrepresented ethnic minorities (URM) within our clinical trials, especially brain tumor trials. Efforts such as community outreach raising awareness of clinical trials, translation of informed consents to Spanish, use of bilingual staff trained in cultural communication diversity and inclusion, dedicated social workers and community seminars have played a crucial role at enhancing Hispanic participation within our brain tumor studies. Method Retrospective review using UM’s clinical trial registry to analyze demographics of brain tumor patients consented to therapeutic/non-therapeutic trials between May 2017 to May 2023.

RESULTS

A total of 431 patients were consented of which 313 (72.4%) actively participated in therapeutic/non-therapeutic trials and 118 (25.1%) screened-failed. Of the accrued participants, 283 (90.42%) self-identified as White, 16 (5.11%) Black/African American, 5 (1.60%) more than one race, 4 (1.28%) Asian, 4 (1.28%) unknown/unreported and 1 (0.32%) American Indian/Alaskan Native. For ethnicity, 160 (51.12%) self-identified as Hispanic/Latino, 148 (47.28%) as non-Hispanic, and 5 (1.60%) were unknown/unreported. 143 (45.69%) were females and 170 (54.31%) were males. For age, 43 (13.73%) were 18-39, 191 (61.02%) 40-64 and 79 (25.24%) were 65 and over.

CONCLUSION

There is extensive evidence that patients from URM’s groups may not be afforded the same opportunity to participate in clinical trials and thus benefit from advanced therapies offered via them. Efforts to ensure meaningful representations of Hispanics in our brain tumor trials have led to a high accrual rate of Hispanics above national norms to better represent our community's demographics.
DISP-14. THE ASSOCIATION BETWEEN MEDICAID ENROLLMENT CONTINUITY AND CHILDHOOD, ADOLESCENT, AND YOUNG ADULT BRAIN TUMOR SURVIVAL
Authors: Johnson Kimberly , Brown Derek , Thompson Tess
Published: November 2023

BACKGROUND

Disparities in younger cancer patient survival between individuals with Medicaid and private insurance have been reported. To further understand this association for brain tumor survival, we used Surveillance, Epidemiology, and End

RESULTS

(SEER)-Medicaid-linked data to test two hypotheses: 1) those enrolled in Medicaid have lower brain tumor survival than those not enrolled, and 2) those with discontinuous enrollment in Medicaid around the time of diagnosis have lower survival than those with continuous enrollment.

METHODS

SEER-Medicaid linked data on individuals diagnosed with a first malignant primary brain cancer between 0 to 39 years from 2006 to 2013 were obtained with follow-up through 2018. Medicaid enrollment was classified as continuous (enrolled six months before through six months after diagnosis) and discontinuous (enrolled non-continuously in the twelve months surrounding the diagnosis month). We used Kaplan-Meier (KM) curves and Cox Proportional Hazards (PH) regression models with SEs clustered on state to evaluate survival differences in association with Medicaid enrollment timing after adjusting for age, race/ethnicity, and a measure of census tract poverty.

RESULTS

Our analytic dataset included 10,110 children, adolescents, and young adults, including 3,148 brain tumor deaths. Consistently lower survival probabilities over time were observed for those enrolled in Medicaid, particularly those with discontinuous enrollment for both age groups. Higher hazards of death were observed for those enrolled in Medicaid vs. not enrolled (HR0-19 =1.66 95% CI 1.41-1.95; HR20-39=1.38, 95% CI 1.27-1.51) and with discontinuous vs. continuous in Medicaid enrollment (HR0-19 =1.60, 95% CI 1.43-1.81; HR20-39=2.03, 95% CI 1.75-2.36).

CONCLUSIONS

These results indicate Medicaid enrollment continuity has an impact on the risk of death, with discontinuous enrollment associated with an over two times higher risk of death for young brain tumor patients. These results further support the critical need for consistent health insurance coverage for children, adolescents, and young adults.
IMMU-04. LOW-INTENSITY PULSED ULTRASOUND ENHANCES CAR T CELL THERAPY BY INDUCING TWO-WAY IMMUNE CELL TRAFFICKING – T CELL INTO TUMOR AND MYELOID CELL INTO PERIPHERY IN A SYNGENEIC MOUSE GLIOBLASTOMA MODEL
Authors: Yamamichi Akane , Chen Tiffany , Phyu Su , Young Jacob , Kyewarabye Keith , Hatae Ryusuke , Gallus Marco , Canney Michael , Sonabend Adam , Okada Hideho
Published: November 2023

Chimeric Antigen Receptor (CAR) T-cell therapy has been successful against hematological malignancies. However, it has not established efficacy in glioblastoma (GBM) patients. Significant challenges currently limiting the effectiveness of CAR T-cell therapy for patients with GBM include poor CAR-T cell trafficking to GBM due to the blood-brain barrier, and the presence of highly immunosuppressive and pro-tumoral tumor-associated macrophages (TAMs) in the tumor microenvironment. Furthermore, the heterogeneous expression of target antigens in GBM can lead to antigen escape and therapeutic resistance. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) has been shown to enhance CAR T-cell trafficking and improve survival in immunocompromised xenograft mice GBM models. In this study, we investigated whether multiple rounds of LIPU/MB can improve not only CAR T-cell but also endogenous T-cell infiltration into the tumors and induce myeloid cell trafficking into lymph nodes (LNs), thus enhancing CAR T-cell therapy against GBM in the immunocompetent syngeneic mice model. We recently developed a novel immunocompetent transgenic (Tg) mouse that expresses an anti-EGFRvIII CAR on T-cells and enables us to investigate the interaction between CAR T-cells and the endogenous immune environment. C57BL6/J mice bearing intracerebral EGFRvIII+ GBM received an intravenous administration of anti-EGFRvIII CAR T-cells derived from Tg-mice. The mice were stratified to receive single-LIPU (1 min before CAR T-cells administration) or triple-LIPU/MB (1 min before CAR T-cells administration, then two and four days later). Triple-LIPU/MB significantly suppressed tumor growth and improved survival and was associated with increased CAR T-cells and endogenous T-cells infiltration into the tumors compared with single-LIPU/MB or without LIPU. Furthermore, draining cervical LNs showed increased macrophages trafficking after triple-LIPU/MB. Moreover, TAMs isolated from triple-LIPU/MB mice brains showed higher levels of MHC-II expression. These results suggest that LIPU/MB may promote the tumor antigen presentation to endogenous T-cells and enhance the efficacy of CAR T-cell therapy for GBM.
IMMU-05. CD8 IMMUNOPET IMAGING IS ABLE TO MONITOR THE IMMUNE RESPONSE SENSITIVELY AND SPECIFICALLY IN GBM PATIENTS FOLLOWING NEOADJUVANT CHECKPOINT BLOCKADE IMMUNOTHERAPY
Authors: Prins Robert , Konik Arda , Sun Lu , Markus Lauren , Herrera Gilbert , Qin Lei , Everson Richard , Lee Eudocia , Reardon David , Shah Hina , Huang Raymond Y , Ellingson Benjamin , Cloughesy Timothy , Wen Patrick , Van den Abbeele Annick D
Published: November 2023

The sensitive and specific evaluation of treatment response in glioblastoma (GBM) patients following immunotherapy is a clinical dilemma. Traditional MRI assessments to visualize and quantify intracranial tumor burden following immunotherapy cannot reliably differentiate tumor progression and pseudo progression remains a complicating factor. In this study, we provide an early report on the use of an investigational new functional imaging PET tracer (CD8 ImmunoPET, 89Zr-crefmirlimab berdoxam, ImaginAb) prior to and immediately following neoadjuvant checkpoint blockade immunotherapy in five patients with recurrent GBM. Tumor samples were collected from each patient at surgery following a two-week neoadjuvant checkpoint blockade to assess gene expression changes and TIL density. We then evaluated how such tumor measurements correlated with PET metrics obtained at baseline and within 2 weeks after treatment initiation which included standardized uptake values (SUVmax, SUVpeak, and SUVmean), and two proposed new metrics indicating the Volume of Immunometabolism (VIM), and the Total Lesion or Lymph nodes’ T cells called TLTc (TLTc = VI x SUVmean) in the tumor bed and lymph node basins (neck, axillae, and inguinal regions). CD8 ImmunoPET demonstrated tracer uptake in the intracranial tumor at both time points, as well as specific physiologic uptake in lymph node basins, spleen, liver, and bone marrow. Neoadjuvant checkpoint blockade with PD-1 +/- CTLA-4 mAb (Nivolumab, Ipilimumab, BMS) at 2 weeks induced variable changes in SUV, but in four of the five initial patients studied in this clinical trial, an increase in VI and TLTc was observed within the tumor bed. Tracer uptake was associated with elevated T cell infiltration into the tumor bed and gene expression changes indicative of interferon signaling and immune cells in these same patients. Our early findings identify a noninvasive functional imaging platform to evaluate the immunometabolism secondary to T cell infiltration and/or activation changes following immunotherapy in GBM patients.
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

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

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

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

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

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

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

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

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

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

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.
INNV-41. SUCCESSFUL TREATMENT OF EXTREMELY RARE CASE OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOPLASMACYTIC LYMPHOMA WITH BENDAMUSTINE-RITUXIMAB REGIMEN: A CASE REPORT
Authors: Sy Kaitlyn , Mogla Sunveer , Singh Jaswinder , Shhwartz Eston , Dixit Sakshi , Kalra Amandeep
Published: November 2023

Lymphoplasmacytic lymphoma (LPL) is an uncommon low-grade non-Hodgkin B-cell lymphoma, with an annual incidence rate of 3 to 4 cases per million people. Primary central nervous system lymphoplasmacytic lymphoma (PCNSLPL) is even rarer, with fewer than 30 cases documented in the literature so far, to our knowledge. We report a case of a 40-year-old Caucasian male who presented with headaches and mild short-term memory problems. CT was suggestive of a right parietal mass. MRI revealed a right parietal homogeneously contrast-enhancing mass with T2 and flair changes extending to the right lateral ventricle, suggestive of vasogenic edema. An open biopsy was performed, and immunohistochemical analysis of the sample indicated lymphoplasmacytic lymphoma. PET scan was negative for hypermetabolic lesions. Bone marrow biopsy, serum protein electrophoresis, urine protein electrophoresis, and CSF analysis were unremarkable. A diagnosis of primary central nervous system lymphoplasmacytic lymphoma (PCNSLPL) was given after comprehensive workup. Treatment with 10 cycles of bendamustine and rituximab (BR regimen) resulted in a good response. The patient has been clinically stable and improving for over a year. Radiologically, there has been interval shrinkage of the right parietal mass and follow-up scans continue to be stable. The plan is to continue maintenance rituximab for 2 years. Although extremely rare, PCNSLPL should be considered in differential diagnoses of hematolymphoid tumors of the CNS and bendamustine with rituximab as induction treatment followed by maintenance rituximab might be considered.
PATH-02. NOVEL SOX10 INDEL MUTATIONS DRIVE SCHWANNOMAS THROUGH IMPAIRED TRANSACTIVATION OF MYELINATION GENE PROGRAMS
Authors: Williams Erik , Ravindranathan Ajay , Gupta Rohit , Stevers Nicholas , Suwala Abigail , Hong Chibo , Kim Somang , Yuan Jimmy , Wu Jasper , Barreto Jairo , Lucas Calixto-Hope , Chan Emily , Pekmezci Melike , Leboit Philip , Mully Thaddeus , Perry Arie , Bollen Andrew , Van Ziffle Jessica , Devine W Patrick , Reddy Alyssa T , Gupta Nalin , Basnet Kristen , Macaulay Robert , Malafronte Patrick , Lee Han , Yong William , Williams Kevin Jon , Juratli Tareq , Mata Douglas , Huang Richard , Hiemenz Matthew , Pavlick Dean , Frampton Garrett , Janovitz Tyler , Ross Jeffrey , Chang Susan , Berger Mitchel , Jacques Line , Song Jun , Costello Joseph , Solomon David
Published: November 2023

Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity due to their stereotypic intracranial and paraspinal locations. However, the molecular drivers responsible for a substantial subset remain unknown. Through genomic profiling of 96 schwannomas, we identified novel in-frame insertion/deletion mutations in the SOX10 gene in 29% of sporadic tumors which uniformly lacked alterations in known nerve sheath tumor genes including NF1, NF2, LZTR1, and SMARCB1. These indel mutations clustered at the C-terminal end of the HMG-box domain, the DNA binding motif of the SOX10 transcription factor critical for Schwann cell differentiation. Schwannomas arising from non-vestibular cranial nerves (e.g. facial, trigeminal, vagus) were highly enriched for SOX10 mutations, whereas the vast majority of vestibular schwannomas had NF2 inactivation. DNA methylation profiling revealed that SOX10 mutant schwannomas clustered together with schwannomas harboring NF2 mutation or SH3PXD2A-HTRA1 fusion, indicating that SOX10 indel mutations define a novel schwannoma molecular subtype and not a distinct nerve sheath tumor entity. To investigate the mechanism by which SOX10 indel mutations promote schwannoma development, we stably transduced human fetal glial cells with either wildtype SOX10 or two different tumor-derived insertion mutants. RNA sequencing revealed that both SOX10 indel mutants, in contrast to wildtype SOX10, failed to activate expression of myelination and glial differentiation gene programs, including PMP2 which encodes the major peripheral myelin protein in mature Schwann cells. Electrophoretic mobility shift assay revealed that the indel mutants retained their DNA binding capacity to the SOX10 binding site in the PMP2 promoter, while a luciferase reporter assay revealed transactivation at the PMP2 promoter by wildtype SOX10 but not by the mutants. In summary, we identified a new recurrent genetic event in 29% of sporadic schwannomas that we speculate drives schwannoma development through impaired transactivation of myelination gene expression programs causing blocked differentiation of immature Schwann cells.