bluuebunny/crossref_metadata_2025 huggingface dataset:
EPID-15. SEX-SPECIFIC DIFFERENCES IN GLIOBLASTOMA IN THE RESPOND CONSORTIUM
Authors: Gongala Sree , Garcia Jose , Korakavi Nisha , Patil Nirav , Akbari Hamed , Tippareddy Charit , Sloan Andrew , Barnholtz-Sloan Jill , Bakas Spyridon , Kazerooni Anahita Fathi , Sako Chiharu , Baid Ujjwal , Brem Steven , Lustig Robert A , Capellades Jaume , Nasrallah MacLean , O'Rourke Donald M , LaMontagne Pamela , Marcus Daniel S , Balana Carmen , Puig Josep , Waite Kristin , Colen Rivka , Choi Yoon Seong , Lee Seung-Koo , Dicker Adam P , Flanders Adam E , Shi Wenyin , Griffith Brent , Poisson Laila M , Rogers Lisa R , Booth Thomas C , Jain Rajan , Chakravarti Arnab , Palmer Joshua , Mohan Suyash , Tiwari Pallavi , Aboian Mariam , Ahn Sung Soo , Davatzikos Christos , Badve Chaitra
Published: November 2023

AIM

The goal of this study was to understand sex-specific differences in the molecular, clinical and radiological tumor parameters and survival outcomes of Glioblastoma (GBM) patients within the international GBM dataset, known as the ReSPOND (Radiomic Signatures for PrecisiON Diagnostics) consortium.

METHODS

Sex-based differences were retrospectively studied in 1922 GBM patients from the ReSPOND consortium which includes information from over 14 institutions across 3 continents. The parameters include age, Methylguanine-DNA Methyltransferase (MGMT) promoter methylation status, isocitrate dehydrogenase 1 (IDH1) mutation status, Karnofsky performance status (KPS), extent of resection (EOR), tumor epicenter, volumes, laterality and spatial extent. Non-parametric tests, log-rank test and cox-proportional hazard analysis were performed to understand sex-based differences in tumor parameters, survival rates and hazard ratios. Spatial atlases were generated to understand radiological parameters such as tumor spatial extent.

RESULTS

GBM in was diagnosed at a median age of 62.6 years in females compared to 61 years in males (p = 0.001). Additionally, 44% females compared to 37% males (p = 0.04) had methylated MGMT and 79% females compared to 73% males (p = 0.004) had IDH1 wildtype. The tumor volumes were smaller in females (necrotic core, edema, and enhancing tumor) compared to males. Females exhibited a higher prevalence of right hemisphere (39.6%) and right temporal lobe tumors (19.7%), while males showed a higher prevalence of left hemisphere (40.3%) left temporal lobe tumors (23.7%). No significant sex-based differences in OS and PFS was observed in overall sample, although longer PFS was observed in elderly (above 60 years) female patients.

CONCLUSION

This is a first international large cohort study looking at sex-based differences in GBM patients using the ReSPOND consortium data. Several sex-specific differences in the distribution of various tumor phenotypes were noted, however sex was not a contributing factor in OS and PFS.
EPID-29. ASSOCIATIONS BETWEEN PM2.5, VEGETATION DENSITY AND CHILDHOOD BRAIN TUMORS: A CASE-CONTROL REGISTRY-BASED STUDY FROM TEXAS 1995-2011
Authors: Williams Lindsay , Haynes David , Sample Jeannette , Hossaini Ali , McGuinn Laura , Hoang Thanh , Lupo Philip , Scheurer Michael
Published: November 2023

BACKGROUND

Air pollution has been reported to be associated with childhood leukemia, and increasing vegetation density (greenness) has been inversely associated with adult cancer incidence. However, the interplay between air pollution and greenness in childhood brain tumor (CBT) etiology is unclear. We sought to estimate the association between prenatal exposure to air pollution, greenness, and CBTs in Texas (1995-2011). Materials and

METHODS

We included 1,316 individuals with a CBT diagnosed ≤ 16 years of age and 109,762 age- and sex-matched controls. We linked birth certificate residential address to census tract annual average particulate matter 2.5 µg/m³ (PM2.5) and Normalized Difference Vegetation Index (NDVI) to approximate prenatal exposure to air pollution and greenness. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) between CBTs, PM2.5 and NDVI interquartile range (IQR) increases. Models were adjusted for birth year, sex, race/ethnicity, and area-level socioeconomic status.

RESULTS

Ependymoma (n=136), astrocytoma (n=619), medulloblastoma (n=187), PNET (n=57), ATRT (n=54), and other gliomas (n=263) were included. Average birth year PM2.5 and NDVI exposure levels were similar in cases and controls, 11 µg/m³ and 0.4, respectively. Each IQR increase (2.6µg/m³) in PM2.5 was associated with ependymoma (OR: 1.27, 95% CI: 1.01-1.60), adjusting for NDVI. After adjusting for PM2.5 quartiles, each IQR increase in NDVI (0.13) was inversely associated with ependymoma in those diagnosed at 0-4 years of age (OR: 0.75, 95% CI: 0.56-0.97) and medulloblastoma in those aged 0-16 years at diagnosis (OR: 0.75, 95% CI: 0.62-0.91). There was no evidence of statistical interaction for any CBT.

CONCLUSIONS

Increasing air pollution during the prenatal period increased risk of childhood ependymoma, independent of greenness. Conversely, increasing greenness prenatal exposure decreased the risk of ependymoma and medulloblastoma, independent of PM2.5. These findings highlight the complex relationship between air pollution and greenness in CBT etiology.
EPID-33. MORTALITY AND CAUSE OF DEATH RELATED TO CLINICAL AND GENETIC SEVERITY IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2 – SCHWANNOMATOSIS
Authors: Weigert Lisa , McLean Anna Lawson , Freier Anna , Farschtschi Said , Rosahl Steffen
Published: November 2023

OBJECTIVES

This study aimed to investigate the circumstances of death in NF2 patients, focusing on clinical and genetic severity.

METHODS

Data from three major German NF2 centers were analyzed retrospectively. A total of 199 patients were included, with follow-up periods ranging from 6 months to 30 years. Disease severity was assessed using clinical and genetic classification scales with three grades each. At the time of data analysis, 36 patients had died in all three centers combined.

RESULTS

Of the 36 deceased patients, 47.2% had moderate clinical severity, 38.9% had severe disease, 13,9% were classified as grade 1. Genetic severity could be determined for 15 patients with 66.7% categorized as a moderate NF2 and 20.0% as genetically severe NF2. Only 13.3% had tissue mosaicism associated with a mild genetic severity. Patients with moderate clinical severity died at a mean age of 44.5 years (± 20.97), patients in grade 3 died at 46.89 years (± 11.71), and grade 1 patients died at 35.1 years (± 31.36) in this cohort. Patients with the highest genetic severity score died earlier (mean age = 35.5 years ± 2.29) than those with a moderate severity (51.3 years ± 21.65). The most common causes of death were malignant neoplasms, cerebral insults, and pneumonia, each accounting for three of the cases. Other causes of death included road traffic fatalities, septic shock, cerebral compression, and suicide, with 16.6% of cases involving attempted suicide.

CONCLUSIONS

The study emphasizes the need for a wider registry to assess prognosis, to stratify major risk factors causing mortality in NF2 and to verify correlations to clinical and genetic severity scales. Increased suicide and attempted suicide rates among NF2 patients highlight the importance of psychological counseling in patient management.
EPCO-29. SEXUALLY DIMORPHIC EFFECT OF H-FERRITIN GENETIC MANIPULATION ON SURVIVAL AND IMMUNE CELL INFILTRATION IN A MOUSE MODEL OF GLIOBLASTOMA
Authors: Shesh Bhavyata (Pandya) , Walter Vonn , Slage-Webb Becky , Neely Elizabeth , Connor James R
Published: November 2023

Iron plays a crucial role in promoting tumor growth. Recent research has shown that H-ferritin (FTH1), traditionally recognized as an iron storage protein, can transport iron to GBM cancer stem cells, reducing their invasion activity. Moreover, binding of extracellular FTH1 to human GBM tissues, and brain iron delivery in general, has been found to have a sex bias. This raises questions addressed in this study about whether H-ferritin levels extrinsic to the tumor can affect tumor cell pathways and if this impact is sex-specific. Systemic Fth1+/- mice were orthotopically implanted with mouse GBM cells (GL261). Littermate Fth1 +/+ mice were controls. Survival was evaluated and the tumors were subjected to next-generation sequencing protocols. We analyzed resulting data utilizing murine Microenvironment Cell Population (mMCP) method. mMCP estimates abundance of tissue infiltrating immune and stromal populations based on cell-specific gene signatures. Female Fth1+/- mice had significantly poorer survival than control females. Fth1 genetic status had no effect on survival in males. mMCP analysis revealed a significant reduction in T cells and CD8+ T cell infiltration tumors of Fth1+/- females as compared to Fth1+/+. Mast and fibroblast cell infiltration was increased in females and males with Fth1+/- background, respectively, compared to Fth1+/+ mice. Genetic manipulation of Fth1 which leads to reduced systemic levels of FTH1 protein had a sexually dimorphic impact on survival. Fth1+/- significantly worsened survival in females but not in male GBMs. Furthermore, genetic manipulation of Fth1 significantly affected tumor infiltration of T-cells, CD8+ T cells, fibroblasts, and mast cells in a sexually dimorphic manner. These results demonstrate a role for FTH1 and presumably iron status in establishing the tumor cellular landscape that ultimately impacts survival and further reveals a sex bias that may inform the population studies showing a sex effect on the prevalence of brain tumors.
EPCO-39. CLARIFYING THE MOLECULAR CONSEQUENCES OF ONCOGENIC MUTATIONS THROUGH MULTISCALE AND MULTIOMIC ANALYSIS OF INDIVIDUAL TUMORS
Authors: Schupp Patrick , Shelton Samuel , Brody Daniel , Eliscu Rebecca , Johnson Brett , Mazor Tali , Kelley Kevin , Potts Matthew , McDermott Michael , Huang Eric , Lim Daniel , Pieper Russell , Berger Mitchel , Costello Joseph , Phillips Joanna , Oldham Michael
Published: November 2023

Understanding the molecular consequences of oncogenic mutations is an important goal that may reveal essential features of malignant cells and new therapeutic targets for diverse cancers. However, this task is complicated by substantial inter- and intra-tumoral heterogeneity, which obscure the molecular consequences of oncogenic mutations in malignant cells. Although single-cell methods hold promise for this task, it remains non-trivial to isolate DNA and RNA from the same cell at scale. Here we describe a statistically motivated strategy that controls for inter-tumoral heterogeneity and exploits intra-tumoral heterogeneity to reveal the most consistent molecular phenotypes of malignant cells. By combining deep, multiscale sampling of IDH-mutant astrocytomas with integrative, multiomic analysis, we reconstruct and validate the phylogenies, spatial distributions, and molecular profiles of distinct malignant clones. Importantly, by genotyping nuclei for driver mutations, we show that existing strategies for inferring malignancy from gene expression profiles of single cells may be inaccurate. We identify genes that are consistently upregulated in the truncal clone of IDH-mutant astrocytomas, which are significantly enriched with genes involved in RNA splicing, mRNA transport and the nuclear pore, and WNT / MYC signaling. Furthermore, we find that expression phenotypes of malignancy persist despite loss of the mutant IDH1 protein following chr2q deletion in a subset of malignant cells. More broadly, our work provides a generalizable strategy for precisely deconstructing intra-tumoral heterogeneity and determining the most robust molecular consequences of oncogenic mutations in any kind of solid tumor.
EPCO-45. CELLULAR HIERARCHIES OF ETMR ARE SHAPED BY ONCOGENIC MICRORNAS AND RECEPTOR-LIGAND INTERACTIONS
Authors: Gabler Lisa , Beck Alexander , Cruzeiro Gustavo , Lambo Sander , Englinger Bernhard , Shaw McKenzie L , Hack Olivia , Chi Susan , Alexandrescu Sanda , Gojo Johannes , Kool Marcel , Hovestadt Volker , Filbin Mariella
Published: November 2023

Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive brain tumor that predominantly occurs in children under the age of four years. Most children succumb within 10 months of diagnosis, typically due to invasive tumor growth and therapy-refractory behavior. 95% of ETMR harbor activating genetic alterations of the chromosome 19 microRNA cluster (C19MC). Despite the identification of this presumed oncogenic driving event, its biological consequences remain understudied and targeted therapy options are lacking. Here, we set out to further explore the intracellular heterogeneity of ETMR and shed light onto its oncogenic mechanisms with the goal to identify novel therapeutic targets for this dismal disease. We have compiled and analyzed a cohort of 11 ETMR tumors using single-cell RNA sequencing and multiplexed spatial imaging. We reveal a common, spatially distinct cellular hierarchy, closely resembling physiological brain development. This hierarchy spans a highly proliferative neural stem cell-like population that gives rise to more differentiated neuron-like cells. C19MC, predominantly expressed in the malignant stem-like population, controls a transcriptional network governing stemness and lineage commitment, as resolved by genome-wide analysis of microRNA-mRNA interactions. Targeting specific C19MC members by antisense oligonucleotides results in reduced cell proliferation, suggesting potent new avenues for future therapeutic approaches. Seeking more immediate therapeutic targets, we performed comprehensive cell-cell interaction analyses and reveal that FGF-FGFR and Delta-Notch interactions are important to maintain oncogenic signaling across malignant cell populations. These interactions were successfully targeted using small molecule inhibitors in preclinical models and in one ETMR patient. Taken together, we identify different malignant ETMR cell populations that follow a common developmental hierarchy, explore the regulatory reach of C19MC activation, and identify an oncogenic receptor-ligand interaction network. Targeting this interaction network opens a powerful new rationale for more effective ETMR therapies.
DISP-04. EXPLORING ENGAGEMENT IN LOW GRADE GLIOMA GENOMIC RESEARCH: A COMPARATIVE ANALYSIS OF THREE APPROACHES
Authors: Kwan Bethany , Barnard Juliana , Ritger Carly , Begum Anowara , Salmi Liz , Fischmann Rudy , Garcia-Hernandez Sandra , Gay Nestelynn , Gonzalez-Fisher Ricardo , Helmkamp Laura , Johnson Kevin , Lennox Lindsay , Lipof Guy , Ostmeyer Jasmyn , Perkins Ifeoma , Pyle Laura , Reno Jenna , Roth Taylor , Claus Elizabeth , Verhaak Roel , DeCamp Matthew
Published: November 2023

BACKGROUND

Engaging patients and care partners in research planning and conduct improves equity and patient-centeredness of research. Determining the most effective engagement methods remains challenging. This study evaluated participation and experience using three engagement methods with the Low Grade Glioma (LGG) Registry’s OPTIMUM project, part of the Participant Engagement in Cancer Genome Sequencing (PE-CGS) Network.

METHODS

We evaluated participation and experience among participants in LGG Registry Research Advisory Council (RAC) meetings, Twitter (“tweet chats”), and Facebook discussions across four engagement activities. Participants completed validated engagement experience surveys, including the Public & Patient Engagement Evaluation Tool (PPEET), Research Engagement Survey Tool (REST), Patient Engagement in Research Scale (PEIRS-22), and the Trust in Medical Researchers scale. Researchers recorded discussions and performed qualitative analyses across groups.

RESULTS

RAC engagements involved 25 unique participants representing diverse backgrounds, while tweet chats and Facebook discussions had 197 and 133 participants, respectively. Post-engagement surveys (n = 52 post-engagement 1; n = 40 post-engagement 4) showed no statistically significant differences between engagement approaches in the overall meaningfulness of engagement on PEIRS-22 or REST scales, nor were there differences in post-engagement 1 trust. RAC members rated PEIRS-22 procedural requirements more positively and reported recalling a wide range of expressed views more than social media participants. Conversely, RAC members gave less positive ratings on PPEET items related to feeling heard. Qualitative findings highlighted differences in the nature of interactions across groups, but agreement around trust and similar recommendations for promoting participation in genomic research across engagement methods.
DISP-17. BUILDING A MODEL PEDIATRIC NEURO-ONCOLOGY PROGRAM IN SUB-SAHARAN AFRICA AND ITS IMPACT
Authors: Katasi Victoria Mwebe , Munube Deo , Namazzi Ruth , Nabaggala Cathy , Israel Luutu , Ssekabunga Julie , Ssenyonga Peter , Mwesigye Angelina Kakooza , Chintagumpala Murali , Muwonge Peter Wasswa , Akullo Ann , Nakirulu Annet , Kasirye Phillip , Naitala Ronald , Piloya Theresa
Published: November 2023

BACKGROUND

Central nervous system tumors are the most common solid tumors in children and the second commonest childhood cancer globally. We describe the establishment of the first dedicated comprehensive pediatric neuro-oncology treatment center that may serve as a model for others in low-resource settings and the impact of this initiative.

METHODS

This is a descriptive interim report of a pediatric neuro-oncology capacity building program in the SSA setting established in March 2019 at Mulago National Referral Hospital in Uganda, including a retrospective study conducted at Mulago National referral Hospital, in patients below 18 years of age admitted with a radiological diagnosis of a brain tumor from March 2019 to March 2023, to demonstrate the impact of this program. The program is a collaboration between Makerere University, Mulago National Referral Hospital, Texas children's Hospital/Baylor College of Medicine, and other academic and philanthropy partners in North America and Europe.

RESULTS

A total of 14 pediatric oncologists have been trained over 6 years, with one further training in neuro-oncology. Multidisciplinary management involving local experts from Uganda and experts from Texas Children's Hospital has been strengthened. Between March 2019 and March 2023, 121 children were diagnosed radiologically with brain tumors. Majority (57%) of these patients were males. The commonest symptom at presentation was headache (42%). Most of the patients (52%) had infratentorial tumors. The commonest diagnosis was glioma (38%), craniopharyngioma (26%), medulloblastoma (11%). Fifty-two patients had surgical resection and a histological diagnosis. Ten percent of patients had no diagnosis. Radiotherapy was received by 24(20%) patients. Twenty patients received chemotherapy. Sixty-six are alive and attending clinic. The overall one-year survival was 63%(95%CI(50.3-73.4).

CONCLUSION

Capacity to improve the suspicion, referral, diagnosis and comprehensive care for children with central nervous system tumors in low-resource settings can be improved through innovative collaborations.
IMMU-06. THE ROLE OF BRAIN TUMOR MICROENVIRONMENT ON T CELL TELOMERE SHORTENING
Authors: Cervantes Gustavo Ignacio Vazquez , Katz Joshua , Lopez-Rosas Aurora , Han Yu , Lee-Chang Catalina , Miska Jason , Lesniak Maciej
Published: November 2023

INTRODUCTION

Glioblastoma (GBM) stands as the most frequent and the most aggressive of the primary brain tumors. GBM-driven immunomodulatory mechanisms induce T-cell exhaustion or senescence leading to impaired anti-tumor responses. Telomeres are nucleoprotein complexes located at the ending regions of eukaryotic chromosomes that become shorter during each cell cycle or due to cellular stress leading to DNA damage response and cell cycle arrest. Tumor-associated T-cell senescence associated with telomere loss on different tumor models still represents a barrier to the success of T-cell-based tumor immunotherapies. However, the mechanisms through which the GBM microenvironment promotes T-cell telomere loss remain poorly understood.

METHODS

We evaluated the expression profile of telomere maintenance-related gene sets of single-cell RNA sequencing from public datasets of GBM patients matched with the peripheral blood. We determined the telomere length, telomere-associated DNA secondary structures (G-quadruplex), β-galactosidase activity, and reactive oxygen species (ROS) production of CD8+ T-cells after 72 h exposure to the conditioned media of malignant glioma murine cell cultures CT2A and GL261. We analyzed the telomere length and G-quadruplex abundance in peripheral and tumor-infiltrated T-cells at different time points of tumor-bearing mice injected with CT2A and GL261 cells.

RESULTS

CD8+ T-cells exposed to the malignant cell conditioned media showed a 20 % reduction of telomere length compared to controls (p< 0.05), a 1.5-fold increase of β-galactosidase activity (p< 0.05), and a 2-fold increase of ROS production (p< 0.05). Both tumor-infiltrated CD4+ and CD8+ T-cells presented a relative telomere shortening of 22 % compared to spleen CD4+ and CD8+ T-cells (p< 0.05). Besides, G-quadruplex abundance increased by 5-fold in tumor-infiltrated CD4+ and 3-fold in tumor-infiltrated CD8+ T-cells compared to peripheral T-cells (p< 0.05).

CONCLUSIONS

T-cell telomere maintenance is affected by malignant cell conditioned media. In vivo tumor microenvironment induced telomere shortening of tumor-infiltrated T-cells in a time-dependent fashion.
IMMU-10. VISUALIZING GBM SUCCESS: SOC + TRIPLE-ARMED IMMUNOTHERAPY CASE REPORT--FUTURE TRIAL DESIGN OPTIONS
Authors: Arbess Daniel , Khozin Sean
Published: November 2023

Pro-neural GBM IV patient's family-guided, provider-consulted N-of-1 journey from SOC through development and implementation of a triple-armed personalized immunotherapy combination. No tumor progression observed 4-years post-diagnosis, 3-years post-anti-tumor therapy. Therapeutic combination included SOC + (a) checkpoint inhibition, (b) patient tumor-specific-antigen peptide vaccine, (c) TME metabolic reprogramming; and (d) bioavailable supplements. Presentation will highlight inductive observations relevant to potential trial design and future practice, including (among others): Relative Benefits of Vaccine Technologies (lysate, TSA) & delivery vectors (DC, sub-q, mRNA); Suggested Order of Immunotherapy Components (TME metabolic, vaccine, CPI); Monitoring: Imaging Interpretational Challenges (distinguishing immune-inflammation from tumor progression); Ongoing Immunogenicity Analysis; Patient Wellbeing: Managing Treatment Effects (epitope spread/inflammatory overshoot); and Implications for Neuro-Immunotherapy Trial Design: Combining/comparing/optimizing elements of SOC, TME metabolic reprogramming, Vax & CPI.
IMMU-14. SINGLE CELL RNASEQ OF PBMCS FROM NEWLY-DIAGNOSED GLIOBLASTOMA PATIENTS
Authors: Dean Bayli DiVita , Yegorov Oleg , Figg John , Font Laura Falceto , Jin Dan , Francis Connor , Reid Alexandra , Mitchell Duane , Flores Catherine
Published: November 2023

INTRODUCTION

A multitude of recently published papers have found immunosuppression caused by glioblastoma (GBM) is not limited to the tumor microenvironment and impacts the peripheral immune system. Our group has recently reported an expansion of granulocyte macrophage precursors, a subset of hematopoietic stem and progenitor populations (HSPCs), in glioma-bearing mice relative to healthy, age-matched controls. Thus we sought to determine if GBM causes cell fate dysfunction in CD34+ HSPCs in patients.

METHODS

CD34+ cells were magnetically isolated from peripheral blood of newly-diagnosed GBM patients and healthy age-matched donors and processed for single-cell RNA sequencing. CD34+ cells were magnetically isolated from peripheral blood of newly-diagnosed GBM patients and healthy age-matched donors and processed for single-cell RNA sequencing using the 10X Genomics platform. CellRanger was used for primary analysis with default parameters. After quality control removal of doublets, dead, and low quality cells automated cell type annotation was performed using the Azimuth Hubmap Consortium human bone marrow reference. The annotated single cell object was then read into R and Seurat was used for differential expression analysis and visualization.

RESULTS

AND

CONCLUSIONS

There we no significant expansions of stem and progenitor populations. GBM patient CD34+ samples had upregulation of VWF, a marker of myeloid-bias cell subset. Within the mature immune cell compartments, we observed a significant expansion of NK cells in GBM patients including 1,997 genes differentially expressed in the NK cell cluster between cohorts. This includes downregulation of SLAMF6, which triggers cytolytic activity in NK cells, in GBM patients. Upregulation of early NK cell activation markers CD69 and JUN were seen in GBM patient samples. These results strongly suggest NK are likely activated in the context of GBM, but may not be functional.
IMMU-29. A CHIMERIC ONCOLYTIC ADENOVIRUS CIRCUMVENTS NEUTRALIZING ANTIBODIES DEVELOPED BY PATIENTS WITH RECURRENT GLIOBLASTOMA TREATED WITH DELTA-24-RGD
Authors: Shin Dong Ho , Jiang Hong , Gillard Andrew , Fan Xuejun , Singh Sanjay , Lopez-Rivas Andres , He Jiasen , Gumin Joy , Lang Frederick , Gomez-Manzano Candelaria , Fueyo-Margareto Juan
Published: November 2023

Oncolytic virotherapy holds great potential to treat high-grade gliomas by harnessing virus-mediated oncolysis to stimulate anti-tumor immune responses. However, the efficacy of oncolytic adenoviruses can be hampered by neutralizing antibodies. In this study, we examined sera obtained from a phase 1 clinical trial using oncolytic adenovirus Delta-24-RGD to treat patients with recurrent malignant gliomas. We found that a single intratumoral injection of Delta-24-RGD induced the development of neutralizing antibodies in less than half of the patients but demonstrated remarkable outcomes, with 20% of the patients surviving beyond three years. Conversely, multiple injections of the oncolytic adenovirus induced neutralizing antibodies in 80% of patients (P=0.05) but resulted in no long-term survivors. This inverse correlation led us to further investigate the role of neutralizing antibodies during glioma virotherapy. Examination of Delta-24-RGD-treated murine brain tumors using immunofluorescence displayed colocalization of antibodies and viral proteins. To counteract virus neutralization and maximize oncolysis, we engineered a chimeric virus, Delta-24-RGD-H43m, by replacing the hypervariable regions of the hexon protein from the prevalent serotype 5-based Delta-24-RGD with those from the rare serotype 43. The infectivity, replication, and oncolytic capabilities of Delta-24-RGD-H43m were similar to those of the parental virus. Using clinical trial patient sera, we observed that Delta-24-RGD-H43m displayed significant resilience against the inhibitory effects of neutralizing sera from patients (P=0.01). In murine models with pre-existing immunity to adenovirus, Delta-24-RGD-H43m treatment led to a significantly extended median survival and resulted in a higher percentage of long-term survivors than the parental virus (P=0.005). These results underscore the effectiveness of hexon swapping as a strategy to overcome the dominant immune response against oncolytic viruses, provide valuable insights into the interaction between oncolytic viruses and the host immune system, and lay the foundation to translate to the clinical setting immune-evading virotherapies for glioma patients.
IMMU-33. PRECISION ANTIGEN-DIRECTED IMMUNOTHERAPY TREATMENT OF BRAIN TUMORS INCREASES TUMOR-INFILTRATING EFFECTOR LYMPHOCYTE RESPONSES
Authors: Trivedi Vrunda , Yang Changlin , Yegorov Oleg , Klippel Kelena , Von Roemeling Christina , Hoang-Minh Lan , Fenton Graeme , Ogando-Rivas Elizabeth , Castillo Paul , Moore Ginger , Dyson Kyle , Mitchell Duane
Published: November 2023

BACKGROUND

Despite considerable advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized tumor antigens expressed within brain tumors that can mediate tumor rejection; the limited mutational burden within these cancers that limits the abundance of targetable neoantigens; and the immunologically “cold” tumor microenvironment that hampers the generation of sustained and productive immunologic responses. Our OBJECTIVE is to develop a precision immunotherapy approach for brain tumor patients utilizing prospectively identified tumor-specific antigens using cancer immunogenomics and selective amplification of patients’ tumor-specific antigens for generating tumor antigen-specific lymphocyte therapy.

METHODS

We identified neoantigens and tumor-associated antigens that were uniquely expressed in preclinical glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (ORAN). A tumor antigen-specific RNA library was created for each tumor model and tumor-bearing animals were treated with ex vivo expanded tumor-specific lymphocytes and tumor antigen-specific RNA-loaded dendritic cell (tsRNA-DC) vaccines. In a different approach, animals were treated with a combination of tsRNA-DC vaccines and anti-PD-1 checkpoint-blockade therapy. Tumor progression and survival outcomes were determined. The immune cell response was evaluated using flow cytometry, TCR sequencing, and single-cell RNAseq.

RESULTS

Our results demonstrate the effectiveness of tsRNA-DC vaccines in eliciting robust anti-tumor immune responses in combination with adoptive cellular therapy and checkpoint blockade therapy. Additionally, our findings substantiate a robust increase in tumor-infiltrating lymphocytes characterized by enhanced effector function both intratumorally and systemically after tumor antigen-specific RNA-directed immunotherapies.

CONCLUSION

This powerful approach to generating immunotherapy recognizing a plurality of tumor antigens uniquely addresses the challenge of dealing with tumor antigenic heterogeneity and confronting the reality of patient-to-patient variation in antigen expression in the development of antigen targeting strategies.
IMMU-36. PD-1KO HEMATOPOIETIC STEM CELLS RAPIDLY DIFFERENTIATE INTO GLIOMA-INFILTRATING EFFECTOR T-CELLS
Authors: Francis Connor , Dean Bayli DiVita , Font Laura Falceto , Figg John , Long-James Kaytora , Reid Alexandra , Jin Dan , Hilferty David , Moore Ginger , Mitchell Duane , Flores Catherine
Published: November 2023

INTRODUCTION

We previously published that hematopoietic stem cell combination therapy (HSC+aPD1) extends survival in murine CNS malignancies, including glioma. To better understand lymphoid-specific mechanisms, we analyzed various lymphoid tissues in a murine glioma model. We hypothesize early PD-1 blockade in HSCs influences later differentiation trajectories. Transferred HSCs differentiate into T-cells within the thymus and then migrate to the intracranial tumor microenvironment as anticipated. Indeed, blocking PD-1/PD-L1 signaling during HSC differentiation significantly impacts subsequent T-cell maturation. Remarkably, TILs derived from HSCPD1KO cells were biased towards CD4+ Treg or CD8+ effector lineages, whereas HSCPD1+/+ progeny leaned toward immature/naïve cell states.

METHODS

HSCs were prepared from constitutive GFP-expressing (CD45.2+) and PD1KO (CD45.2+) mice and transferred into CD45.1+ hosts. Sublethal 5Gy total body irradiation was administered day 5 post-intracranial tumor implantation. The next day, 1e6 HSCs from a 1:1-GFP:PD1KO cocktail were injected intravenously. Descriptive statistics are reported as mean ± SD. Transferred HSCs engraft, expand, differentiate, tended and migrate to form approximately 25% of the TIL compartment in only 15 days.

RESULTS

We found that, 56.2% ± 20.3 of CD3+ TILs display an immature CD4+CD8+ (DP) phenotype in early disease, and 43.8% ± 17.4 of these DP-TILs are HSC-derived. DP-TILs were virtually absent in advanced disease 29 days after treatment, but HSC-derived TILs most commonly fell within the single-positive (SP) TIL subsets, comprising 9.8% ± 5.6 of SP-CD8+ TILs. Notably, HSCPD1KO-derived cells were 4x more abundant amongst SP-CD8 TILs when compared to HSCGFP-derived cells (6.5% vs 1.6%, p < 0.05). SP-CD8 thymocytes were similarly enriched for HSCPD1KO progeny (41.1% vs 24.7%, p < 0.05) suggesting that PD-1 blockade impacts thymopoiesis directly.

CONCLUSION

PD-1 signaling modulates thymic output. Blocking the PD-1/PD-L1 axis during thymopoiesis increases the abundance of HSC-derived CD8+ effectors at the tumor site. HSC+aPD1 therapy is uniquely positioned to leverage thymus-dependent anti-tumor immunity.
IMMU-57. EFFECT OF THE ONCOMETABOLITE D2HG ON MYELOID-DERIVED SUPPRESSOR CELL POPULATIONS
Authors: Pumar Oriana Teran , Figueroa Maria , Bayik Defne
Published: November 2023

Mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) enzyme correlate with better prognosis of gliomas, partly due to enhanced infiltration of nonimmunosuppressive granulocytic cells compared to IDH wild-type (IDHwt) tumors. Altered cytokine/chemokine secretion from tumor cells and reprogramming of myeloid cell metabolism are among the factors that drive differences in immune profiles of IDHwt vs. IDHmut tumors. IDH mutant protein produces the oncometabolite D-2-hydroxyglutarate (D2HG) instead of the canonical alpha-ketoglutarate (αKG), a co-factor for histone and DNA demethylases. Since D2HG is known to be secreted into the tumor microenvironment (TME), we interrogated the effect of this metabolite on the epigenetic landscape and behavior of granulocytic and monocytic myeloid-derived suppressor cells (g/mMDSCs). Co-culturing bone marrow cells with either IDHmut or IDHwt glioma cells demonstrated that mMDSCs, which we previously showed to be the abundant tumor infiltrating MDSC subtype in IDHwt tumors, but not gMDSCs specifically experience higher levels of apoptosis when exposed to IDHmut cells. Treatment of bone marrow cells with physiologically relevant concentrations of either D2HG or αKG demonstrated that D2HG re-capitulates the pro-apoptotic effect on mMDSCs. Furthermore, co-cultures of IDHmut glioma cells and bone-marrow cells induced a pronounced increase in global methylation on mMDSCs specifically, and we observed that mMDSCs and gMDSCs differentially express histone demethylases via western blotting. Collectively, these results suggest that D2HG can differentially impact mMDSC vs gMDSC biology by epigenetic reprogramming. Future studies will elucidate the specific targets of D2HG in mMDSCs that renders these cells more susceptible to apoptosis with the goal of identifying the mechanisms that can be modulated to down-regulate mMDSC infiltration and/or survival within the TME.
INNV-08. LONG-TERM GLOBAL POST-MARKETING SAFETY SURVEILLANCE DATA FROM PEDIATRIC, ADULT AND ELDERLY PATIENTS WITH CENTRAL NERVOUS SYSTEM MALIGNANCIES TREATED WITH TUMOR TREATING FIELDS (TTFIELDS) THERAPY
Authors: Mrugala Maciej , Shi Wenyin , Iwamoto Fabio , Lukas Rimas , Palmer Joshua , Suh John , Glas Martin
Published: November 2023

BACKGROUND

Glioblastoma (GBM) is an aggressive central nervous system (CNS) malignancy with poor prognosis. TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability. TTFields therapy is approved for recurrent and newly diagnosed GBM, and pleural mesothelioma. We report long-term safety data from pediatric, adult and elderly patients with CNS malignancies receiving TTFields, from a global post-marketing surveillance (PMS) dataset.

METHODS

Unsolicited PMS data were collected from patients receiving TTFields (October 2011–October 2022). AEs were categorized using MedDRA version 25.1, and data stratified by age group (< 18, 18–65, and > 65 years).

RESULTS

Overall, 25,898 patients from the US, Europe, Israel, and Japan were included. Of these, 93 (0.4%) were < 18 years (pediatric), 17,817 (69%) were 18–65 years (adult), and 7,808 (30%) were > 65 years (elderly). Two-thirds (66%) of all patients were male. Demographic characteristics were therefore consistent with a typical GBM population. Of pediatric patients, 62% experienced ≥ 1 AE, with 53% related to TTFields. This was comparable in adults (72% and 56%, respectively), and elderly patients (75% and 57%, respectively). The most common TTFields-related AEs were skin reaction (pediatric: 39%; adult: 42%; elderly: 45%), heat (warmth) sensation (pediatric: 14%; adult: 12%; elderly: 12%), and electric (tingling) sensation (pediatric: 10%; adult: 15%; elderly: 10%). All-cause serious AEs occurred in 14%, 21% and 25% of pediatric, adult and elderly patients, respectively. No systemic toxicities were reported, regardless of age.

CONCLUSIONS

These long-term, real-world PMS data demonstrate that TTFields has a tolerable safety profile in pediatric, adult and elderly patients with CNS malignancies, with no new safety signals in any age group. Most AEs were localized skin reactions which are manageable. These data provide supportive evidence of the safety and broad applicability of TTFields, regardless of patient age.
INNV-27. LOW/ULTRA-LOW RADIO FREQUENCY MAGNETIC FIELD THERAPIES FOR THE TREATMENT OF CNS TUMORS: RGBM AND DIPG – PAST AND CURRENT RESULTS USING THE EMULATE THERAPEUTICS INC. TECHNOLOGY
Authors: Figueroa Xavier
Published: November 2023

EMulate Therapeutics, Inc. (EMTx) has developed a technology that emulates the effects of chemical compounds, via an alternating magnetic field. Our research has led to the development of a radio frequency energy (RFE) signal (A1A) that emulates the effects of paclitaxel. Pre-clinical and animal studies demonstrate an effect in slowing down and inhibiting tumor growth. EMTx has developed a portable medical device that allows for continuous delivery of our A1A signal for up to 14 hours before recharging. The device can be used in combination with current best-supportive-care (BSC) and new investigational treatments. Our technology has been tested in recurrent glioblastoma (rGBM) with very encouraging results in overall survival (OS), especially in combination with BSC. Phase II OS alone was equivalent to BSC (7.2 months BSC OS vs. 7.0 months A1A alone OS) and a considerably improved OS when combined with conventional drug treatment (7.2 months BSC OS versus 10.0 months A1A + BSC OS). EMTx is in the process of seeking humanitarian device exemption (HDE) from the US Food & Drug Administration (FDA) for the Hælo® therapeutic system, our pediatric treatment option. Diffuse intrinsic pontine gliomas (DIPG) are a rare pediatric central nervous system (CNS) tumor. Survival is measured in under 12 months, with no clinical trials demonstrating a significant increase in overall survival in 20 years (9 months median survival post radiation therapy). EMTx’s compassionate use program demonstrated safety and suggested a clinical benefit, with 12 of 14 patients surviving more than 12 months. EMTx is committed to run and complete a pivotal pediatric trial for children diagnosed with DMG/DIPG. The trial will recruit study patients from both the US and India. A total of 35-40 patients will be recruited to participate in this pediatric neuro-oncology trial, which will be a best-supportive-care + single therapy (Hælo®) clinical trial.
INNV-32. RELIABILITY OF SERIAL NEUROPATHOLOGICAL ASSESSMENT TO DIFFERENTIATE TUMOR PROGRESSION FROM PSEUDO-PROGRESSION IN GLIOMA
Authors: Khoury Lara , Harrison William , Ramkissoon Shakti , Stogner-Underwood Kimberly , Mott Ryan T , Miller James , Lesser Glenn , Chan Michael , Cramer Christina , Tatter Steven , Laxton Adrian , White Jaclyn , Tavolara Thomas , Hsu Fang-Chi , Strowd Roy
Published: November 2023

Histopathology is the gold standard for distinguishing tumor recurrence from treatment-induced necrosis but differentiating pseudoprogression from true recurrence is challenging in tumors with ambiguous morphological features. Prior research reported a 36% inter-rater agreement during suspected recurrence (Holdhoff et al., 2019). While serial radiographic and laboratory assessments are common, serial histopathological assessments are not. This study evaluated agreement and factors influencing assessment of active and inactive tumors through single and multiple time-point histopathological assessments. Patients who underwent initial and subsequent reoperation were identified, and their available histology slides were examined retrospectively. Four independent neuropathologists conducted two types of reviews: single time-point reviews using most recent biopsy/surgery slides, and multiple time-point reviews comparing images from initial and repeat biopsies taken 1-3 months apart. Neuropathologists completed a questionnaire assessing various tumor characteristics. Assignments were categorized as "active tumor," "treatment effect," or "unable to classify." 324 assessments were conducted (108 single time-point, 216 multiple time-point). Intraclass correlation coefficients for single vs. multiple time-point assessments were 0.72-0.93 for active tumors and 0.57-0.86 for inactive tumors. Pathologists' assessment of % inactive tumor was influenced by mitotic activity (p= 0.0028), cellularity (p< 0.0001), hyalinized vessels (p= 0.0019), and necrosis (p= 0.0046). Evaluation of % active tumor was influenced by hyalinized vessels (p= 0.0006), mitotic activity (p< 0.0001), cellularity (p< 0.0001), and microvascular proliferation (p= 0.0093), with the latter three factors specifically affecting final sign-out pathology. Serial histopathological assessment didn’t affect determination of % active or inactive tumor. No association between % inactive tumor and fibrinoid necrosis for single time-point (p= 0.34) but a strong negative association was seen for serial assessment (p= 0.0006). Inter-rater agreement was higher for identifying active tumors than inactive tumors in both case reviews. Changes in necrosis between tissue samples in single vs. multiple timepoint assessments influenced pathologists' assessment of % inactive tumor.
INNV-35. IMPLEMENTATION OF A NATIONAL ADOLESCENT AND YOUNG ADULT MOLECULAR TUMOR BOARD: REPORT FROM THE CANADIAN AYA NEURO-ONCOLOGY NETWORK
Authors: Lim-Fat Mary-Jane , Das Sunit , Climans Seth , MacDonald Maria , Perreault Sébastien , Yip Stephen , Harrison Rebecca , Lapointe Sarah , Chan Aimee , Massey Natalie , Erker Craig , MacNeil Mary , Ironside Sarah , Tsang Derek , Hawkins Cynthia , Tabori Uri , Bennett Julie
Published: November 2023

BACKGROUND

The adolescent and young adult (AYA) population (15-39 years) is a unique and understudied population and their care requires multidisciplinary expertise. Current challenges in AYA neuro-oncology include fragmented care across pediatric and adult hospitals, low inclusion in clinical trials, unique survivorship considerations and a lack of standard-of-care therapies for this population.

METHODS

We will report on a two-and-a-half-year national effort from the Canadian AYA Neuro-Oncology Network (CANON) to implement national clinical and molecular AYA rounds. The aims of the rounds are to provide a platform for standardized diagnostics and multidisciplinary recommendations benefiting from the expertise of pediatric and adult providers across several tertiary and community centers.

RESULTS

Since April 2021, the Canadian national AYA rounds have occurred biweekly on a virtual secure platform. As of April 2023, 132 cases have been discussed from 25 sites; 15 cases (11%) involved pediatric patients and 117 (89%) were patients aged > 18 and treated at adult hospitals. Cases discussed included adult (n =34, 26%) and pediatric type (n = 22, 17%) low-(n=25, 19%) and high-grade (n=30, 23%) glioma, medulloblastoma (n=14, 10.5%), ependymoma (n=6, 5%) and other tumors (glioneuronal tumors, pineal tumors, germinoma). A total of 175 providers and 70 trainees across 32 Canadian institutions have attended the rounds, spanning adult and pediatric neurosurgery, neuropathology, neuro-oncology, radiation oncology and radiology. The updated results of an ongoing prospective database of cases presented at our AYA rounds, outlining themes around molecular characterization, choice of therapies and relevant clinical outcomes will be presented at the meeting.

CONCLUSIONS

Virtual national AYA-neuro-oncology multi-disciplinary rounds is an effective platform that has raised awareness of current gaps and has facilitated nation-wide solutions to improve the care of AYA brain tumors, leveraging research and clinical collaborations.
INNV-38. PREDICTING THE CLINICAL PHENOTYPE IN NF2 RELATED SCHWANNOMATOSIS PATIENTS
Authors: Borghi Arianna , Rosati Nayma , Paterra Rosina , Vetrano Igrazio , Nazzi Vittoria , Moscatelli Marco , Silvani Antonio , Eoli Marica
Published: November 2023

BACKGROUND

Different genetic scores have been proposed to predict the phenotype of NF2 related Schwannomatosis (NF2 -SCHW MIM # 101000) , a rare autosomal dominant familial cancer syndromes caused by pathogenic variants of the NF2 gene. The UK NF2 Reference Group proposed the Genetic Severity Score (GSS) based on the type and location of NF2 germline variant observed. Catasus et al. suggested a new score based also on a functional assay of Merlin and its downstream pathways (FGSS). Recently Teranish et al. used targeted deep sequencing to predict functional prognosis in those patients. Material and

METHODS

70 patients (median age 40) were identified by scanning the electronic NF2-SCHW patient database at Fondazione IRCCS C. Besta,. The median follow-up was 14 yrs. Clinical diagnosis was established following the Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis”. All patients underwent NF2, SMARCB1 and LZTR1 mutational screening by NGS and MPLA analysis using blood DNA or the tissue of two different tumors when available. NF2 gene germline pathogenic were found in 45 subjects (64%), in most cases NF2 point mutations, but in 4 cases and whole gene deletions was observed and in 2 a ring NF2 chromosome was identified, in four cases a mosaic NF2-SCH was identified and in 21 (30%) patients no pathogenic variant was found. We assessed NF2 clinical phenotype in relation to the UK GSS and FGSS to validate their use.

RESULTS

The disease phenotype differed significantly depending both on clinical and genetic factors.. GSS and FGSS showed significant correlation with several measures, allowing stratification of patients with severe and mild disease but not with moderate phenotype. Furthermore, we provided evidence on correlation between whole NF2 deletion extent and phenotype severity. Large cohorts of NF2-SCHW patients are needed to identify more accurate scores.