bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-69. DEVELOPMENT OF A NOVEL, HUMAN ANTIBODY TO IMPROVE ONCOLYTIC VIRUS THERAPY FOR GLIOBLASTOMA
Authors: Murphy Sara , Sivaccumar Jwala , Li Leike , Swanner Jessica , Lewis Cole , Li Jiaqi , Lee Tae Jin , Sahu Upasana , Rivera-Caraballo Kimberly , Vazquez-Arreguin Karina , Zhang Ningyan , Sharma Ashok , An Zhiqiang , Kaur Balveen 
Published: November 2024

Abstract
Glioblastoma (GBM) is the most aggressive, malignant, primary brain tumor with abysmal overall survival. GBM is regarded as an “immune cold” tumor due to poor immune cell infiltration and immunosuppressive signaling in the tumor microenvironment (TME). Oncolytic herpes virus (oHSV) therapy has emerged as a possible therapeutic avenue for solid tumors such as GBM. We have observed that oHSV-treated tumor cells release extracellular ATP (eATP) which functions as immunostimulatory signaling molecule. In the TME, eATP is rapidly hydrolyzed into immunosuppressive adenosine by ectoenzymes CD39 and CD73. Using global CD73 knock out (CD73KO) mice or a function-blocking murine antibody, we found that blocking CD73 activity improves oHSV therapy in vivo. Intracranial tumor-bearing CD73KO mice respond significantly better to oHSV therapy than wild type (WT). These long-term survivors also rejected a subsequent tumor challenge, demonstrating development of a memory response. scRNA-seq revealed significantly increased immune cell infiltration in CD73KO mice compared to WT. We evaluated cellular crosstalk using CellChat and uncovered a major CCL-directed signaling pathway in the CD73KO mice. Furthermore, we identified a novel, human CD73 antibody from panning an scFv phage display library derived from human tonsils. This antibody, Ab6, demonstrated functional inhibition of purified CD73 and very high binding affinity for CD73. Co-culture of human GBM cells treated with OV and Ab6 and donor PBMCs resulted in increased tumor cell death. Additionally, human DCs exposed to Ab6 and OV-treated conditioned media were better able to activate T cells. To evaluate in vivo efficacy of this novel antibody, we have generated custom humanized CD73 knock-in mice wherein human CD73 has replaced murine CD73. We are currently evaluating the efficacy of Ab6 and oHSV in these mice against intracranial glioma. These results will support the translation of Ab6 as a potential immune therapeutic to add to the arsenal against brain tumors.
EXTH-70. PRECLINICAL TRIALS OF THE ANTIBODY-DRUG CONJUGATE TISOTUMAB VEDOTIN IN ADULT-TYPE DIFFUSE GLIOMAS
Authors: Sears Thomas , Wang Wenxia , Unruh Dusten , Steffens Alicia , McCord Matthew , Horbinski Craig 
Published: November 2024

Abstract
The gene F3, encoding Tissue Factor (TF), is expressed in many cancers and contributes to their malignancy. Our previous work showed that, among adult-type diffuse gliomas, IDH wild-type (IDHwt) glioblastomas (GBM) express more TF than IDH mutant (IDHmut) gliomas (PMID: 27664011, 30266764, 31222125). Tisotumab vedotin (TisVed), an anti-TF antibody conjugated to monomethyl auristatin E, is a therapeutic designed to target cells expressing TF. We therefore sought to determine the therapeutic potential of TisVed in IDHwt vs. IDHmut gliomas. TisVed was more active against cultured IDHwt GBM cells than IDHmut glioma cells (P&lt;0.0001). This activity was increased by 55% with daily washout of the soluble TF secreted by IDHwt GBM cells. TisVed extended the survival of mice intracranially engrafted with IDHwt GBM by 34% (37.5 days vs. 28 days for IgG control, P=0.006), but not mice with IDHmut glioma (30.5 days, P=0.88). TisVed also reduced the growth of IDHwt GBM flank xenografts by 58% (P=0.045). Unconjugated Tis had no antitumor effect intracranially or in the flank. All 12 flank-engrafted mice treated with Tis, and 9/12 mice treated with TisVed, developed large hematomas in and around the flank xenografts, compared to 0/12 IgG-treated mice (P&lt;0.001). Similarly, a semiquantitative analysis showed that intracerebral hemorrhage was more extensive in Tis/TisVed- treated GBM12 mice than in IgG-treated GBM12 mice (P=0.046). These data indicate that TisVed targets high TF-expressing IDHwt GBM, but not low TF-expressing IDHmut glioma, that its activity is predominately through the vedotin conjugate rather than inhibition of TF signaling, and that it may have some effect against TF-expressing IDHwt GBM, but intracerebral hemorrhage may be a concern.
EXTH-74. COOLING GLIOBLASTOMA WITH A NEURAL IMPLANT
Authors: Enam Syed Faaiz , Barwari Mahabad , Chen Reed , Dobariya Aksharkumar , Patnaik Sourav , Evers Bret , Bellamkonda Ravi , Patel Toral , Patel Ankur 
Published: November 2024

Abstract
Survival rates for glioblastoma (GBM) patients are low due to the difficulty in eradicating all tumor cells, leading to frequent recurrence. This recurrence is frequently within 2-cm from the original site. Studies indicate that supra-total resection improves survival, and non-destructive local therapies show promise in preventing GBM recurrence. Our research demonstrates that non-freezing, ‘cytostatic’ hypothermia is effective against GBM in rats and can be scaled to pig models. This method, unlike ablative cryogenic hypothermia, safely inhibits GBM growth without damaging healthy tissue. Using in vitro culture models and in vivo rat models via a Peltier device, we tested cytostatic hypothermia. This was followed by finite-element modeling (FEM) to simulate bioheat transfer in human and pig brains. The system consists of a neural implant with a multiprobe array, a Peltier chip, a water block, and an artificial internal circulation system with a piezoelectric pump. In vitro tests identified a cytostatic window of 20–25°C. Miniature Peltier devices were fabricated to achieve this in rats to inhibit GBM growth and extend survival. Rats whose tumors received cytostatic levels of hypothermia survived their full study period. FEM simulations confirmed that multiprobe arrays could cool brain tissue to 25°C without significantly raising skin temperature. Portable systems were successfully fabricated and tested in pigs, achieving safe target temperatures with minimal EEG and OCTA changes. Our findings suggest that cytostatic hypothermia can be scaled to larger animals and made implantable and portable, offering a promising non-destructive approach to halting GBM growth and prolonging survival, moving closer to becoming a viable treatment option for patients with GBM.
EXTH-76. REDIRECTING STROMAL CELLS TO IGNITE ANTI-TUMOR IMMUNITY AGAINST GLIOBLASTOMA
Authors: DeVries Anna , von Roemeling Christina , Moor Rachel , Wummer Brandon , Weidert Frances , Chardon-Robles Jonathan , Ligon John , Castillo Paul , Mendez-Gomez Hector , Sayour Elias 
Published: November 2024

Abstract

BACKGROUND
The dismal prognosis of high-grade gliomas demands novel treatment approaches. Through the development of a novel mRNA lipid particle aggregate (RNA-LPA) vaccine, our lab has shown anti-tumor efficacy in preclinical murine studies and promising immunological responses in canine glioma models and human studies (Cell. 2024 May 9;187(10):2521-2535.e21). The translational potential necessitates further investigating the immune activation mechanism to allow greater applicability of this therapy in the future.

OBJECTIVE
We sought to unravel mechanistic cross-talk for immune initiation following intravenous administration of RNA-LPAs.

METHODS
We used Ai14 reporter mice to determine RNA-LPA transfected cellular subsets and dual reporter mice to assess cellular infiltration into murine glioma models. Murine gliomas were generated via implantation of K2 or KR158b-luc cell lines.

RESULTS
Following intravenous administration, we found fibroblastic reticular cells in secondary lymphoid organs take up RNA-LPAs. We show that FRCs have direct contact with antigen presenting cells and mediate release of full-length proteins following RNA-LPA transfection. Similar to the periphery, there is transfection of stromal cells in the brain tumor microenvironment (TME) and recruitment of infiltrating leukocytes. In response to RNA-LPAs, transfected stromal cells release type I interferon (IFN-I), which is requisite for anti-tumor efficacy. IFN-I mediates upregulation of CD69 on lymphocytes leading to sequestration following co-localization with RNA-LPAs. IFN-I is necessary for LFA-I expression on T cells, which is important for T cell trafficking across the blood-brain barrier. In preclinical models to track antigen specific immunity, we find systemic RNA administration elicits an increase in tumor reactive T cells with decreased S1P1 expression suggestive of a ‘locked-in’ response within the TME.

CONCLUSION
While stromal cells are regulatory niches in glioblastoma ecosystems, we show they can be leveraged for immunologic cross-talk that facilitates T cell recruitment, trafficking and sequestration in the TME critical for immunologic reprogramming and long-lasting immunotherapy.
EXTH-77. INFANT-TYPE HEMISPHERIC GLIOMAS WITH INITIAL RESPONSE FOLLOWED BY RESISTANCE ON TARGETED AGENTS
Authors: Wilson David , Ocal Eylem , Tanaka Tomoko , Parker Lora , Jayappa Sateesh , Gokden Murat , Bielamowicz Kevin 
Published: November 2024

Abstract
Pediatric-type Diffuse High Grade Gliomas (pHGG) are a rare brain tumor with high mortality and need for more effective treatment options. pHGG’s make up only about 10% of CNS tumors but are responsible for a majority of the deaths. Infant-type Hemispheric Gliomas are a subtype of pHGG with tyrosine kinase alterations in genes such as ROS1, ALK, MET, and NTRK1-3. Despite advances in categorization and targeted therapies, the natural history of patients with infant HGG treated with targeted therapy over time needs to be better characterized, including the durability of objective responses. We present a retrospective case series involving two patients diagnosed with Infant-type Hemispheric Gliomas at Arkansas Children’s Hospital from 2022-2024. Each diagnosis was determined based on histology, targeted tumor sequencing, and methylation profiling. Both patients were initially treated with primary surgical resection and systemic chemotherapy. Each patient experienced disease progression. Actionable pathogenic mutations were identified in both patients (a MET alteration in patient 1 who was then started on Cabozantinib, an ALK fusion in patient 2 subsequently treated with Lorlatinib) with an objective disease response in both patients. In both cases, further relapse occurred while on targeted inhibition. Relapse specimen was not available for patient 1, but for patient 2, recurrent tumor sequencing revealed similar genetics from the diagnostic specimen except for a MET copy number gain suggesting the mechanism of resistance in this patient. Infant-type Hemispheric Gliomas with targetable alterations can show meaningful responses to pathway inhibition. Relapse after initial response may warrant additional surgical sample to identify new alterations which can lead to changes in therapy. Larger prospective cohorts are needed to study targeted agents in this population, and early integration during radiation or after initial diagnosis may be needed.
EXTH-79. BREAKING THE BARRIER: ADOPTIVE CELLULAR THERAPY HALTS GLIOMA IMMUNOSUPPRESSION BY TARGETING MYELOID-DERIVED SUPPRESSOR CELL MIGRATION AND CELL CYCLE MECHANISMS
Authors: Figg John , Francis Connor , Jin Dan , Reid Alexandra , Font Laura Falceto , Dean Bayli DiVita , Love Caitland , Hilferty David , McDonald Brianna , Flores Catherine 
Published: November 2024

Abstract

INTRODUCTION
Our group previously demonstrated that adoptive cellular therapy (ACT) significantly increased overall survival in mice across several brain cancer models. ACT remodels the tumor microenvironment (TME) in a pleiotropic manner, and specifically depletes immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) which are a significant barrier to efficacious immunotherapy responses. This led us to hypothesize that ACT depletes MDSCs from the glioma microenvironment by inhibiting MDSC proliferation and migration, thereby overcoming glioma immunosuppression.

METHODS
We quantified MDSC cell cycle, apoptosis, and localization in the TME and peripheral lymphoid tissues using flow cytometry as well as chemokines in the TME from glioma-bearing mice treated with ACT. C57BL/6J mice intracranially received KR158b-luciferase glioma and were treated with ACT. After treatment, MDSC cell cycle was quantified using bromodeoxyuridine and 7-aminoactinomycin to define cell cycle phases. MDSC apoptosis and cell death states were quantified by measuring annexin-V and propidium iodide. Anatomic localization of MDSCs was measured by comparing host (CD45.2) and transferred HSC-derived cell markers (CD45.1) in the TME and spleen. A multiplex array was performed using tumor lysates to quantify cytokine and chemokine levels within the TME.

RESULTS
We observed that MDSCs in the TME were significantly less proliferative and exhibited significantly increased levels of apoptosis and cell death after ACT. HSC-derived MDSCs were significantly enriched in the spleen of ACT-treated mice, but both transferred HSC-derived MDSCs and host MDSCs were depleted in the TME. Finally, ACT significantly decreased several chemokines in the TME, including interleukin-16 and monocyte chemoattractant protein-5.

CONCLUSION
These results indicate that ACT shifts MDSC cell cycle states away from proliferation towards cell death, and inhibits peripheral recruitment to the TME. Our investigation revealed novel, myeloproliferative chemokines that are decreased by ACT, representing a novel mechanism underlying disrupted MDSC migration to the glioma microenvironment and ultimately to overcoming glioma-mediated immunosuppression.
EXTH-80. A NOVEL BISAMINOQUINOLINE DERIVATIVE NANOPARTICLE (BAQ13-NP) FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Bloch Orin , Min Dullei , Lin Tzu-Yin , Li Yuanpei 
Published: November 2024

Abstract
Aminoquinolines, such as hydroxycholoquine, are known to inhibit autophagy and slow cancer cell growth, improving survival in preclinical models of glioblastoma. Unfortunately, they failed to demonstrate benefit in clinical trials due to a lack of sufficient potency and BBB penetration. We have developed a novel bisaminoquinoline derivative packaged in a nanoparticle (BAQ13-NP) with improved potency and intratumoral accumulation after systemic administration, confirmed by distribution and toxicity studies in animals. In this study, we evaluated the impact of BAQ13-NP on tumor cell autophagy and survival using patient-derived glioma cell lines and murine models. GBM patient-derived cell lines (n=4) and murine glioma cells (GL261, CT-2A) were treated with BAQ13-NP (1-4 µM) in culture, demonstrating growth restriction to less than 50% of control at 5-7 days (p&lt;0.01) by MTT assay. Cells treated with BAQ13-NP also demonstrated reduced autophagy with significant increases in accumulation of LC3B and p62 (p&lt;0.01) and reduced IL-6 dependent STAT3 phosphorylation in tumor cells, T cells, and myeloid cells (p&lt;0.01). In addition, treatment of tumor cells with BAQ13-NP reduced IL-6 production over 50% (p&lt;0.01). Mice with orthotopic GL261 or CT2A tumors were treated with BAQ13-NP by tail vein injection (25 mg/kg q2 days) starting 7 days post implantation. Significantly increased survival was observed in BAQ13-NP treated GL261 (HR 0.75, p=0.030) and CT2A (HR 0.78, p=0.033) bearing mice compared to vehicle control treated animals. Reduced tumor size at specific intervals was also observed with BAQ13-NP treatment, corelating with improved survival. BAQ13-NP can inhibit autophagy and slow glioma tumor growth, improving survival in preclinical models. Given the excellent distribution and low toxicity of this novel agent when delivered intravenously, we believe it has great potential to improve outcomes for GBM patients. Our drug has recently received IND approval and will soon be tested in a phase I clinical trial.
EXTH-84. A DURABLE RECURRENT INTRACEREBROVENTRICULAR INFUSION METHOD IN MICE FOR PRECLINICAL ASSESSMENT OF CELLULAR THERAPEUTICS
Authors: Chen Chao-Hsien , Curran Michael 
Published: November 2024

Abstract

BACKGROUND
Significant advancement in cellular treatments for glioblastoma has been made in recent years. The administration route has shifted from intravenous access to local delivery, namely intracerebroventricular (ICV) delivery, in order to prevent the injected cellular products from becoming trapped in peripheral organs such as liver and spleen. There is currently no reliable preclinical system available to accurately examine new cellular treatments that involve long-term recurrent infusion into the cerebral ventricles.

METHOD
We optimized the surgical device and technique by modifying a commercially available ICV device with a predetermined needle length, eliminating the requirement for spacers hence relieving the tension of the surgical wounds. To avoid skin puncture, we substituted the tunneled catheter with a silicon catheter. The surgical incisions were secured with autoclips in replacement of sutures. We administered periodic infusions of engineered monocytes on a weekly basis using the tunneled catheter for a duration of 8 weeks. The rate of wound dehiscence was monitored.

RESULTS
The delivery of the engineered monocytes to the cerebral ventricle via the ICV device has been confirmed using a bioluminescence-based imaging. The device and the tunneled catheter demonstrate a long-lasting durability for a minimum of 8 weeks. The optimized device and method effectively reduce the occurrence of post-operative wound dehiscence. Using a silicon catheter minimizes skin punctures.

CONCLUSION
Our optimized ICV device, material, and surgical approach offer a dependable preclinical instrument for the long-term and recurrent delivery of cellular therapies that reflect patients’ clinical treatment schedules and provide a more accurate evaluation of their translational potential.
QLTI-04. UPDATE ON HIGH-GRADE GLIOMA PATIENTS TREATED WITH TTFIELDS FROM NANFANG HOSPITAL IN CHINA
Authors: Zheng Haojie , Que Tianshi , Yi Guozhong , Li Zhiyong , Qu Shanqiang , Zhang Peidong , Yuan Xi , Wang Yajuan , Liu Junlu , Nan Jing , Liu Ting , Xu Haiyan , Qi Songtao , Huang Guanglong 
Published: November 2024

Abstract

OBJECTIVE
Tumour-treating fields (TTFields) have changed the first-line clinical practice of glioblastoma worldwide due to their promising therapeutic efficacy. The aim of this study was to investigate the clinical efficacy of TTFields therapy for HGG in Nanfang Hospital, China. In 2023 ASNO we reported PFS.Now we reporte update about OS from our single center study.

METHODS
From January 2019 to December 2022, a total of 25 patients with newly diagnosed HGG (ndHGG) treated with TTFields were retrospectively included in our study. Among these patients, 9 patients received concurrent radiochemotherapy in combination with TTFields and 16 patients received non-concurrent chemoradiotherapy in combination with TTFields. The primary endpoint of the study was mPFS and mOS (Kaplan-Meier method used to estimate PFS and OS survival curves). Secondary endpoint was the influences about KPS score in PFS and OS.

RESULTS
The 25 ndHGG patients treated with TTFields included nine males and sixteen females with a mean age of 47.1 years (12-68). Gross total resection (GTR) was performed in eighteen patients. Twenty-one patients were IDH wild type, eleven patients showed methylation of the MGMT promoter. Followed up until January 2024, the median PFS was 13.3 months [95% CI: 11.33-15.2] with TTFields combined and 4.0 months (95% CI, 3.8-4.4) without TTFields treatment in EF-14.Median OS was 26.53 months [95% CI:19.47-33.57] with TTFields and 16.0 months (95% CI, 3.8-4.4) control in EF-14. In the KPS stratification, OS was 27.5 months (95% CI: 22.95-32.1) vs 4.3 months (95% CI: 0-11.2), p=0.0001. The OS of patients with concurrent chemoradiotherapy combined with TTFields vs. without concurrent chemoradiotherapy combined with TTFields was 26.5 months (95% CI: 24.33-28.7) vs 21.2 (95% CI: 3.1-39.3) months, p=0.59.

CONCLUSIONS
TTFields therapy is an effective treatment for HGG. In this study the addition of TTFields resulted in a statistically significant improvement in PFS and OS.
QLTI-10. IMPACT OF A NEURO-ONCOLOGY HOSPITALIST MODEL ON INPATIENT CANCER CARE DELIVERY AT A SINGLE INSTITUTION
Authors: Barden Mary 
Published: November 2024

Abstract
Patients with brain tumors are often admitted to the hospital at critical stages of their disease course: initial diagnosis, relapse, end-of-life, and for management of serious complications. Patients who develop neurologic complications from systemic cancers and their treatments also frequently require management in the hospital setting. Most neuro-oncologists have busy outpatient practices and limited inpatient responsibilities. Their experience with hospital workflows, bandwidth to see inpatients, and comfort level managing certain diagnoses such as immunotherapy neurotoxicities may be variable, even within a single institution. Recent literature supports the beneficial role of the Oncology Hospitalist, a physician who specializes in the care of hospitalized patients with cancer. Oncology Hospitalist care improves length of stay, cost effectiveness, and the patient and oncologist experience. To our knowledge, the role of a hospitalist who specializes in the care of patients with neuro-oncologic issues has not yet been investigated. Here we describe the responsibilities and examine the impact of a Neuro-Oncology Hospitalist at a single institution over a 2-year period, with a focus on metrics of quality and efficiency of care. Patients and cancer care systems benefit from the dedicated inpatient presence of a neuro-oncologist, supporting the development of a Neuro-Oncology Hospitalist model.
QLTI-11. PREDICTORS OF PROLONGED LENGTH OF STAY IN LASER INTERSTITIAL THERMAL THERAPY FOR INTRACRANIAL PATHOLOGIES: A SINGLE CENTER EXPERIENCE
Authors: Berke Chandler , Knott Maxon , Khalafallah Adham , Shah Ashish , Ivan Michael , Komotar Ricardo 
Published: November 2024

Abstract

INTRODUCTION
Laser interstitial thermal therapy (LITT) offers a minimally invasive approach for treating intracranial pathologies, often with shorter hospital stays than traditional craniotomies. Yet, some patients still face prolonged length of stay (PLOS), highlighting the need to identify contributing factors and improve post-LITT outcomes.

OBJECTIVE
To evaluate factors contributing to PLOS following LITT for intracranial pathologies.

METHODS
A retrospective review was conducted between 2013-2023 for patients undergoing LITT for intracranial pathology at a tertiary care center. PLOS was defined as discharge &gt;2 days. Multivariate logistic regression analyzed variables as contributors to PLOS including ICU LOS (hours), preoperative maximum tumor diameter (cm), lesion location, lesion pathology (high grade glioma (HGG)/glioblastoma (GBM) vs. other), and mFI-11 score (binary ≥ or &lt; 75th percentile).

RESULTS
The cohort consisted of 288 patients, with 29% (83/288) and 71% (205/288) having PLOS and non-PLOS, respectively. Mean age was similar between the PLOS (63-years) and non-PLOS (60-years) groups (p=0.09). The PLOS group had a 55% male predominance compared to 57% female in the non-PLOS group. Greater mFI-11 scores showed increased risk of PLOS [4.01, (2.11, 7.60), p&lt;0.000]. Lesions having a subcortical location [3.43 (1.70, 6.95), p=0.001] or diagnosis of HGG or GBM [2.87 (1.54, 5.34), p=0.001] had increased risk of PLOS. Importantly, maximum pre-operative diameter did not significantly alter risk of PLOS [1.05 (0.98, 1.13), p=0.151].

CONCLUSION
For the first time, we show that patient comorbidities, subcortical lesion location, HGG/GBM pathology, and greater time spent in the ICU portend increased risk of PLOS following LITT. Future work should validate our model with the goal of optimizing post-operative patient management and resource allocation.