bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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&lt; 0.05), a 1.5-fold increase of β-galactosidase activity (p&lt; 0.05), and a 2-fold increase of ROS production (p&lt; 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&lt; 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&lt; 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

Abstract
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

Abstract

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

Abstract
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

Abstract

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

Abstract

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 &lt; 0.05). SP-CD8 thymocytes were similarly enriched for HSCPD1KO progeny (41.1% vs 24.7%, p &lt; 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

Abstract
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

Abstract

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 (&lt; 18, 18–65, and &gt; 65 years).

RESULTS
Overall, 25,898 patients from the US, Europe, Israel, and Japan were included. Of these, 93 (0.4%) were &lt; 18 years (pediatric), 17,817 (69%) were 18–65 years (adult), and 7,808 (30%) were &gt; 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.