bluuebunny/crossref_metadata_2025 huggingface dataset:
NCOG-22. SEIZURE OUTCOME ACROSS DISEASE TRAJECTORY IN IDH-MUTANT GRADE 2 GLIOMAS: WHICH IS THE IMPACT OF STANDARD ANTINEOPLASTIC TREATMENTS?
Authors: Bruno Francesco , Pellerino Alessia , Nibali Marco Conti , Pronello Edoardo , Bertero Luca , Garbossa Diego , Bello Lorenzo , Rudà Roberta
Published: November 2023

INTRODUCTION

Most patients with IDH-mutant grade 2 gliomas suffer from seizures. Recently, the INDIGO trial showed that vorasidenib prolonged progression-free-survival (PFS) and time-to-next-intervention in IDH-mutant grade 2 gliomas after surgery. We investigated which factors influence seizure-control in patients with the same characteristics of those of INDIGO. Patients and

METHODS

We retrospectively collected data of non-enhancing IDH-mutant grade 2 glioma patients (as per WHO-2021) who presented with seizures, and evaluated seizure-freedom at 2 months after surgery, 6 months from starting either observation or adjuvant treatments, at recurrence, and 6 months after treatment of recurrence.

RESULTS

Ninety-five patients were included. Oligodendrogliomas IDH-mutant/1p19q-codeleted grade 2 were 69 (72.6%), astrocytomas IDH-mutant grade 2 were 26 (27.4%). Thirty-five (36.8%) received gross-total resection (GTR). After surgery, 49 (51.6%) achieved seizure-freedom, more frequently after GTR vs non-GTR (57.9% vs 35.1%, p=0.048). Sixty-eight (71.6%) low-risk patients underwent observation, while 27 (28.4%) high-risk patients received adjuvant radiotherapy (RT) and/or chemotherapy (CT). Among the latter, 17/27 (63.0%) had persistent seizures before treatment initiation and, after 6 months, all of them displayed seizure-reduction, with 2/17 (7.4%) seizure-free. In a multivariable analysis on PFS, ≥ 50% seizure-reduction (vs < 50%) after 6 months of adjuvant treatment reduced the risk of progression (HR 0.048, 0.004-0.585, p=0.017). Eighty-six (90.5%) patients recurred, and 51/86 (59.3%) displayed seizures. After 6 months of treatment of recurrence, 50/51 (98.0%) achieved seizure-reduction, with 10/51 (19.6%) seizure-free. In a multivariable analysis, either CT or RT increased the probability of seizure-freedom at 6 months after recurrence (HR 5.316, 1.582-17.869, p=0.007).

CONCLUSION

We defined the entity of seizure-control after standard treatments throughout the disease course. Two findings are noteworthy: the prognostic importance of seizure-reduction after adjuvant treatments; the possibility to achieve seizure-control also with treatment of recurrence. This study could serve as a benchmark for future evaluation of seizure-control with IDH inhibitors.
NCOG-24. RISK-ADAPTED TREATMENT STRATEGIES WITH PRE-IRRADIATION CHEMOTHERAPY IN PEDIATRIC MEDULLOBLASTOMA: OUTCOMES FROM THE POLISH PEDIATRIC NEURO-ONCOLOGY GROUP
Authors: Cochrane Anne , Perek-Polnik Marta , Wang Jinli , Chojnacka M , Drogosiewicz M , Filipek I , Swieszkowska E , Tarasinska M , Kowalczyk P , Abdelbaki Mohamed S , Dembowska-Bagińska Bożenna
Published: November 2023

Craniospinal irradiation (CSI) has been a major component of the standard of care treatment backbone of childhood medulloblastoma. However, chemotherapy regimens have varied based on protocol, patient age, and molecular subtyping. In one of the largest studies to date, we analyze treatment outcomes in children with newly-diagnosed medulloblastoma treated with pre-irradiation chemotherapy followed by risk-adapted radiotherapy and maintenance chemotherapy. A total of 153 patients from the Polish Pediatric Neuro-oncology Group were included in the analysis. Median age at diagnosis was 8.0 years. Sixty-seven patients were classified as standard risk and 86 as high risk. Overall survival (OS) and event-free survival (EFS) for standard-risk patients at 5 years (± standard error) were 87 ± 4.3% and 84 ± 4.6% respectively, while 5-year OS and EFS for high-risk patients were 81 ± 4.3% and 79 ± 4.5% respectively. This study demonstrates promising survival outcomes in patients treated with pre-irradiation chemotherapy followed by risk-adapted CSI and adjuvant chemotherapy. Such an approach may be useful in cases where initiation of radiotherapy may need to be delayed, a common occurrence in many institutions globally.
NCOG-27. LONG-TERM OUTCOMES OF GAMMA KNIFE RADIOSURGERY FOR GROWING MENINGIOMA
Authors: Kim Yeong Jin
Published: November 2023

Gamma knife radiosurgery (GKRS) has become an effective treatment modality for intracranial meningioma. However, the role of GKRS in managing growing meinigoma during follow-up remains uncertain. This study aims to investigate the long-term outcome after GKRS treatment on meningioma for growing meningioma at follow-up. A retrospective analysis was conducted on patients who underwent GKRS as primary treatment for growing meingiomas between 2004 and 2021. Growing meningioma was defined as a >10% increase in volume compared to the previous imaging. Fifty-nine patients who received GKRS as initial treatment were included in this study with minimum follow-up period of 12 months. Patient clinical-radiological data, tumor characteristics and procedural details were analyzed. Tumor progression and regression were defined as a >10% increase or decrease in volume, respectively, compared to pre-GKRS image. Tumor volumes within ±10% of pre-GKRS volume were considered stable. At a median follow-up of 41 months (range 15-197 months), tumor volume was unchanged in 16 patients (27.1%), decreased in 41 patients (69.5%), and increased in 2 patients (3.4%). In multivariate analysis, growth rate was significantly associated with tumor progression (hazard ratio [HR]=2.059, 95% confidence interval [CI]=1.028-4.123, p=0.042). Eleven patients (18.6%) experienced new or worsening symptoms. In multivariate analysis, factors predicting new or worsening neurological function were preexisting symptoms (HR=7.159, 95% CI=1.468-34.911, p=0.015) and tumor calcification (HR=11.921, 95% CI=2.400-59.202), p=0.002), and pre-existing peritumoral edema (HR=9.751, 95% CI=1.666-57.058, p=0.012). GKRS demonstrates a high tumor control rate as well as an acceptable complication rate in growing meningioma. Effective tumor control is more likely in patients with slow-growing tumor.
NCOG-28. RECURRENCE OF PLEOMORPHIC XANTHOASTROCYTOMA PRESENTING WITH DIFFUSE LEPTOMENINGEAL SPREAD
Authors: White Jessica , Grigsby-Rocca Giovanna , Bermudez Camilo , Neth Bryan , Uhm Joon , Mustafa Rafid
Published: November 2023

Pleomorphic xanthoastrocytomas (PXAs) are rare primary brain tumors that mainly affect children and young adults. We report a case of recurrent PXA in an adult and review the literature. To our knowledge, this is the first adult report highlighting clinical, CSF, and imaging findings of recurrent PXA with leptomeningeal spread. A 60-year-old woman presented with a 2-month history of fluctuating mental status, aphasia, low-back pain, progressive paraparesis, and urinary retention. She was previously diagnosed with a left temporal PXA 17 years prior and underwent gross total resection with no evidence of tumor recurrence for the next several years. Approximately 10 months prior to her current presentation, she was found to have radiographic recurrence of the left temporal PXA. She underwent gross total resection, with final pathology revealing anaplastic transformation, WHO grade 3, BRAF V600E mutation positive. She next underwent photon radiotherapy, and chemotherapy with temozolomide. She had good clinical and radiographic response to treatment for 8 months prior to developing her current symptomatology. MRI of the brain and spine showed local recurrence with new diffuse contrast enhancement of the spinal cord and nerve roots. Cerebrospinal fluid (CSF) analysis showed a total nucleated cell count of 10/mcL, protein >1250 mg/dL, glucose < 20 mg/dL, and xanthochromia. CSF cytology was positive for malignant cells consistent with PXA. Although PXA is often associated with a favorable prognosis, recurrence with anaplastic transformation can be associated with dissemination throughout the nervous system and worse outcomes. Despite the rarity of such cases, clinicians should remain vigilant, especially when anaplastic transformation occurs. Early detection of leptomeningeal involvement through thorough CSF analysis and appropriate imaging can facilitate prompt intervention and potentially improve patient outcomes.
NCOG-31. TUMOR TREATING FIELDS: REAL-WORLD SURVIVAL AND QUALITY OF LIFE OUTCOMES ON THE XCELSIOR PLATFORM
Authors: Palmer Joshua , de Rivera Fernando Nino , Awawda Alaa , Williams Sebastian , Irizarry Sabrina , Cole Zachariah , Chavez Gordon
Published: November 2023

OBJECTIVE

xCures operates a direct-to-patient, real-world evidence platform according to the nationwide observational research protocol XCELSIOR (NCT03793088), which aggregates medical data in an FDA-compliant electronic database. We used this platform to analyze advanced registry survival and Quality of Life (QoL) outcomes associated with the use of Tumor Treating Fields (TTFields) for treatment of high grade central nervous system (CNS) tumors.

METHODS

XCELSIOR participants with high grade CNS tumors were invited weekly to complete the EuroQol 5-Dimension (EQ-5D-5L) QoL questionnaire over the course of one year. A EuroQol-endorsed model was used to estimate health state utilities from patients’ EQ-5D responses. The participating patients’ clinical data was accessed from the XCELSIOR platform to enable study of clinical factors and survival outcomes.

RESULTS

225 patients with high grade CNS tumors in total completed at least one EQ-5D questionnaire. 88 patients (39%) had ever used TTFields and 58 of these patients (26%) were currently using TTFields. Patients currently using TTFields had significantly higher average health state utility estimates compared to non-users (p=.00183), with a mean improvement in utility of .14 (SE=.04), indicating significantly higher overall QoL in TTFields users. Mortality events were recorded for 40 participating patients, 14 (35%) of which had used TTFields. From these 40 events the mean/median overall survival (OS) for patients who had used TTFields was 23.39/20.15 months vs 15.77/12.72 months for patients who had not used TTFields, showing significantly higher average OS in patients who had used TTFields (p=.04139).

CONCLUSION

The XCELSIOR platform has enabled the study of real-world clinical and QoL outcomes for patients with CNS tumors. The results show that use of TTFields is associated with improved survival as well as improved overall Quality of Life for patients in a real-world setting, corroborating results seen in trial settings as well as results seen in other real-world studies.
NCOG-32. THE SPECIFIC PSYCHOSOCIAL BURDEN OF CAREGIVERS OF ADULT NEURO-ONCOLOGICAL PATIENTS - A PROSPECTIVE STUDY
Authors: Spieker Mareike , Rapp Marion , Goebel Simone , Karger André , Rieger David , Grosse Lucia , Bombach Paula , Kurz Sylvia , Hippler Melina , Tatagiba Marcos , Sabel Michael , Tabatabai Ghazaleh , Renovanz Mirjam
Published: November 2023

OBJECTIVE

The diagnosis of a brain tumor represents high burden for the patients’ caregivers (CG). Psychosocial screening tools adapted to the burden profile of CG are urgently required but do not exist. The aim was to develop a problem list for neuro-oncological CGs’ unmet needs for an application in combination to the Distress Thermometer scale.

METHODS

CG were prospectively assessed regarding changes in everyday life, relationship, social life, emotional, physical problems, and support needs, either via questionnaire (Center A) or by a qualitative interview (center B). A qualitative content analysis was performed by an inductive/deductive approach using MAXQDA® software.

RESULTS

A total of 50 caregivers were assessed (25 in center A via questionnaire, 25 in center B via interviews) during outpatient visits. Most frequently reported need was the need for psychological support (29/50, 58%). This was true after initial diagnosis (26/50, 52%) as well as in case of clinical deterioration of their loved-one (30/50, 60%). The results leaded to problem categories, congruent to the NCCN distress thermometer categories for cancer patients (practical, social, emotional, physical, and spiritual/existential problems). We detected new topics including “constraints/organization of (medical) appointments” (25/50, 50%) or “constant availability required for partner” (21/50, 42%). Also, 70% (35/50) put their own interests last or adapted their leisure activities. In the qualitative interviews (Center B), further items were identified, e.g., “dealing with psychological problems of the patient” (3/25, 12%), “different coping strategies among patient/caregiver” (4/25, 16%). We defined additional problem categories specifically adapted to CG of neurooncological patients, e.g., “problems due to neurocognitive/neuropsychological symptoms of the loved-one” and “problems with role as a caregiver”.

CONCLUSION

The interviews reflected the unmet needs of brain tumor caregivers. Our problem list developed for CG of neurooncological patients might allow for the targeted assessment and optimization of care.
NCOG-34. BRAIN PET IMAGING OF PAIRED HELICAL FILAMENT TAU IN OLDER ADULTS WITH CANCER: PILOT STUDY TO IDENTIFY MECHANISMS OF COGNITIVE IMPAIRMENT AFTER CANCER THERAPY
Authors: Parsons Michael , Von Imhof Liesel , Eckbo Ryan , Katsumi Yuta , Touroutoglou Alexandra , Arrillaga-Romany Isabel , Dickerson Bradford , Dietrich Jorg
Published: November 2023

BACKGROUND

Cancer-related cognitive impairment (CRCI) occurs in up to 75% of patients treated with chemotherapy for systemic cancer, and older patients treated for CNS cancer receiving brain radiation therapy (RT) and chemotherapy are particularly at risk. The mechanisms of injury and CRCI remain unknown. In neurodegenerative disorders, deposition of paired helical filament tau (PHFTau) is correlated with nature and extent of cognitive symptoms. The role of PHFTau in CRCI has not been elucidated. We conducted a pilot study to determine whether CRCI is associated with PHFTau.

METHODS

Patients (age >60) diagnosed with mild cognitive impairment (MCI) or dementia after chemotherapy and/or brain RT underwent Tau PET imaging using [F18]Flourtaucipir. Cortical [F18]Flourtaucipir binding was quantified by standard uptake value ratio (SUVR) in 68 regions of interest (ROIs) and compared to a control group (n=22). SUVR in each ROI for each subject was considered significantly elevated when it was >2SD above the control group (p< 0.05). Neuropsychological test scores were correlated with PHFTau distribution.

RESULTS

Five patients with MCI/Dementia following cancer therapy participated. Two patients with prior chemo-RT for CNS cancer and prominent executive dysfunction had no significant F[18]T807 uptake. However, three patients treated with systemic chemotherapy for non-CNS cancer and neuropsychological profiles dominated by episodic memory impairment showed F[18]T807 uptake in patterns typical of AD dementia in temporal, parietal and cingulate ROI’s (n=2), or uptake in the entorhinal and inferior temporal ROIs (n=1).

DISCUSSION

In this pilot study, [F18]Flourtaucipir imaging of patients with cancer and MCI/Dementia showed that executive dysfunction after RT was not associated with abnormal PHFTau whereas amnestic declines after chemotherapy were associated with PHFTau in medial temporal lobes and beyond. Given the cross-sectional study, timing of tau accumulation in relation to cancer/treatment is unknown. Prospective studies are needed to understand the relevance of PHFTau in CRCI.
EXTH-03. A VEGF+ SUBPOPULATION OF SCHWANN CELLS DRIVES VESTIBULAR SCHWANNOMA TUMORIGENESIS
Authors: Asuzu David , Stoica Stefan , Laraba Liyam , Arhin Martin , Gandhi Jasleen , Mullaney Dustin , Mandal Debjani , Parkinson David , Chittiboina Prashant
Published: November 2023

INTRODUCTION

Up to 95% of vestibular schwannomas (VS) are sporadic, however their molecular underpinnings remain obscure.

OBJECTIVE

To perform transcriptomic profiling of VS and investigate novel tumorigenic mechanisms.

METHODS

We analyzed 19 VS samples (7 sporadic, 12 NF2), and performed single-cell RNA sequencing (scRNAseq, n = 4) or single-nucleus (snRNAseq, n = 15), assays for transposase-accessible chromatin (snATACseq, n = 15) and bulk DNA methylation (n = 14). CellChat was used to predict cell-cell interactions. We characterized transcription factor binding using ChIPseq. We validated our key findings at the mRNA and protein levels using RNAscope (n = 5) and multiplex immunocytochemistry (mIHC; n = 5). Mechanistic studies were conducted using NF2-null Periostin-Cre+ mice versus their Cre- control littermates.

RESULTS

We profiled the VS transcriptome and identified markers for Schwann cells, macrophages, T cells and endothelial cells. We identified eight Schwann cell subclusters which were enriched for known markers for myelinating, immature, repair and non-myelinating subtypes. We also unexpectedly identified a subset of VS Schwann cells with high expression of VEFGA, and these cells were enriched for signaling via laminin, NCAM, NRXN and NEGR pathways. Using RNAscope and mIHC, we verified VEGFA expression in S100B+ Schwann cells. snRNAseq and snATACseq demonstrated increased TEAD1 expression in Schwann cells, as well as increased chromatin accessibility for TEAD family transcription factor motifs. We used ChIPseq to confirm increased TEAD1 binding at the promoters of 714 genes including VEGFA. NF2-null Periostin-Cre+ mice developed spontaneous schwannomas within their dorsal root ganglia which showed increased vegfa expression, and this was partly reversible using a novel pharmacological TEAD inhibitor in-vivo.

CONCLUSIONS

We performed detailed epigenetic and transcriptomic profiling of sporadic and NF2-associated VS and uncovered TEAD1-mediated overexpression of VEGFA in a subset of VS Schwann cells. TEAD inhibition may constitute a novel therapeutic target for VS.
EXTH-06. GLIOBLASTOMA PATIENT SPECIFIC TRANSCRIPTOME REMODELING IN RESPONSE TO MDM2 ANTAGONIST TREATMENT OF WILD-TYPE P53 CANCER STEM CELLS IS ASSOCIATED WITH SENSITIVITY AND STRATEGIES FOR COMBINATION THERAPY
Authors: Meng Yuling , Mughal Nouman , Datta Indrani , Nuga Oluwademilade , Irtenkauf Susan , Hasselbach Laura , Quenneville Kristyn , Brown Stephen , deCarvalho Ana
Published: November 2023

Over 70% of glioblastomas are p53 wild-type and these patients could benefit from p53 reactivation treatment. Here we determined the sensitivity of a glioblastoma patient-derived cancer stem cells (CSCs) panel to three MDM2 antagonists (MDM2a) to test to what extent transcriptional reprogramming is affected by genomic background and correlates to response to acute treatment with MDM2 antagonists. IC50 concentrations and area above the curve (AAC) were measured from dose response curves obtained from 4 and 7-day treatment. The inhibitors were specific to wt-p53 CSCs, but these presented a wide range of sensitivity. Seven wt-p53 CSCs were treated RG7112 IC50 concentrations or DMSO control for 24h (n=4). RNA was isolated for Illumina Truseq stranded mRNA libraries sequenced at 30M depth. Quantified raw counts were processed using NOISeq R package to determine differentially expressed genes (DEG) between control and treated samples. In addition to the expected high representation of upregulated p53 targets in all cell lines, we observed significan cell specific transcriptome alterations, including enrichment of survival pathways, such as mTOR, ERK and NFkB in the less sensitive CSC lines, which did not readily correlate with the individual genomic landscapes. E2F targets, G2-M cell cycle check point and DNA-repair pathways were highly enriched in the downregulated genes. Combination of MDM2a with radiation treatment (RT) was synergistic to a subset of CSCs. As validation we found that MDM2a treatment was effective in sensitizing a resistant orthotopic mouse glioblastoma PDX to fractionated RT, with maximum efficacy when treatment started 24h prior to RT vs simultaneously (Log-rank Mantel-Cox test: p=0.0006 vs 0.0277). The integration of the treatment-mediated transcriptional patterns with differential sensibility to MDM2 antagonists and genomic landscape of the CSC panel provides a platform to identify targets for combination therapies, which is the most promising clinical application of the reactivation of wt-p53 in GBMs.
EXTH-07. NEOADJUVANT PD1 BLOCKADE ALTERS THE TUMOR MICROENVIRONMENT POST-SURGERY IN A PRECLINICAL MODEL OF RECURRENT GLIOBLASTOMA
Authors: Hoang-Minh Lan , Mitchell Duane , Klippel Kelena , Yang Changlin , Trivedi Vrunda , Doonan Bently , Von Roemeling Christina , Yegorov Oleg , Sriharan Akshayaa , Francis Connor , Shin David , Karachi Aida , Sarkisian Matthew
Published: November 2023

SIGNIFICANCE

Clinical trials investigating neoadjuvant immunotherapy in recurrent glioblastoma patients have shown promising results. In this study, we aimed to assess the impact of neoadjuvant PD1 blockade on the tumor microenvironment after surgery using a relevant murine model of recurrent glioblastoma.

OBJECTIVE

Our objective was to investigate the effects of neoadjuvant PD1 inhibition on mouse survival and analyze the transcriptome and spatial genomic changes within the intratumoral immune populations following surgery. We compared these changes with those observed in adjuvant anti-PD1 treatment.

RESULTS

Through our established murine resection model of recurrent KR158 glioblastoma, we demonstrated that neoadjuvant PD1 inhibition prior to tumor debulking significantly improved mouse survival compared to adjuvant treatment. Transcriptome and spatial genomic analyses revealed notable alterations in immune exhaustion and activation pathway genes after neoadjuvant anti-PD1 treatment, distinguishing it from adjuvant anti-PD1 treatment. RNA and protein analyses indicated upregulation of various pathways, including PI3K/AKT, NOTCH, NK cell, MAPK, NF-kB, type II interferon, and TNF, in the neoadjuvant treatment group compared to the adjuvant anti-PD1 treatment group. Single-cell RNA sequencing analyses further revealed an increased proportion of CD8 T, NKT, and NK cells, accompanied by a decreased percentage of CD4 T cells in the neoadjuvant group. Importantly, we observed a significant enhancement in the interaction strength between CD8 T cells and all other immune cells in the neoadjuvant group compared to the adjuvant treatment group.

CONCLUSIONS

Our findings demonstrate distinct differences in immune cell populations and gene expression profiles between neoadjuvant and adjuvant anti-PD1 therapies in our murine recurrent glioblastoma resection model. These insights provide valuable understanding of the potential mechanisms underlying the divergent efficacy of neoadjuvant and adjuvant anti-PD1 therapies.
EXTH-11. ADOPTIVE CELLULAR THERAPY OVERCOMES GLIOMA IMMUNE ESCAPE BY DISRUPTING MDSC PROLIFERATION AND RECRUITMENT
Authors: Figg John , Francis Connor , Jin Dan , Dean Bayli DiVita , Font Laura Falceto , Reid Alexandra , McDonald Brianna , Hilferty David , Long-James Kaytora , Flores Catherine
Published: November 2023

INTRODUCTION

Our group has previously shown that adoptive cellular therapy (ACT) significantly extends survival in models of medulloblastoma, brain stem glioma, and glioblastoma. Further, ACT significantly decreases myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME), suggesting that ACT may ameliorate glioma-mediated immunosuppression. We hypothesize that ACT-mediated reduction of MDSCs is driven by cell proliferation and recruitment mechanisms, but these mechanisms have not been defined. In this study, we quantified the proportions and cell cycle states of MDSCs in the TME and peripheral lymphoid tissues as well as chemokines in serum to determine how ACT affects MDSC recruitment.

METHODS

ACT was performed in C57BL/6J mice bearing a syngeneic high-grade glioma derived from KR158B-luciferase cell line. The treatment platform included total body irradiation, hematopoietic stem cell rescue, total tumor ribonucleic acid (ttRNA) electroporated dendritic cells, and tumor-reactive T cells. Following ACT completion, we evaluated the proportions and cell cycle states of MDSCs using flow cytometry. Bromodeoxyuridine (BRDU) and 7-aminoactinomycin (7-AAD) defined cell cycle phases. Serum chemokines were measured using a membrane-based sandwich immunoassay.

RESULTS

We replicated our previous findings that ACT reduces the level of MDSCs in the TME. Additionally, ACT significantly decreased the proportion of MDSCs in S-phase in the TME. Conversely, levels of MDSCs in peripheral lymphoid tissue were significantly increased in mice treated with ACT, with a significant increase of MDSCs in S-phase. Analysis of serum chemokines revealed significant decreases in multiple chemokines implicated in MDSC recruitment such as CXCL13 and CXCL16.

CONCLUSION

These findings suggest that ACT decreases proliferation and chemotactic recruitment of MDSCs to the TME, which may also explain MDSC accumulation peripheral lymphoid tissue in ACT-treated mice. These immune mechanisms likely contribute to ACT’s efficacy against brain cancer, preventing tumor immune escape, and offer new therapeutic targets for optimizing cellular immunotherapies.
EXTH-12. CYTOCHROME C OXIDASE SUBUNIT 4 ISOFORM 1 MEDIATES ONCOLYTIC HERPES SIMPLEX VIRUS-1 EFFICACY IN HIGH-GRADE GLIOMA
Authors: Gary Sam , Laufer Vincent , Tuy Kaysaw , Kang Kyung-Don , Oliva Claudia , Griguer Corinne , Hjelmeland Anita , Friedman Gregory
Published: November 2023

RATIONALE

Outcomes for patients with high-grade glioma (HGG) are dismal despite standard of care surgical resection, radiation, and temozolomide (TMZ) chemotherapy.

RESULTS

from our Phase I trial of pediatric patients with recurrent HGG suggest oncolytic herpes simplex virus-1 (oHSV) is safe with promising efficacy. However, optimization of oHSV therapy is needed to achieve more durable responses. Based on our prior work with matched pair HGG cell lines and patient-derived xenografts (PDXs) with and without acquired TMZ resistance, oHSV efficacy is enhanced in TMZ-resistant cells with no difference in oHSV entry receptor (CD111) expression. Microarray transcriptomic data of four PDXs with and without TMZ resistance revealed downregulation of interferon (IFN) responses. Cytochrome c oxidase subunit 4 isoform 1 (COX4I1) is expressed in recurrent HGG samples and cell lines. While COX4I1 positively regulates influenza virus replication, no study has investigated the role of COX4I1 in mediating oncolytic virotherapy efficacy.

HYPOTHESIS

We hypothesized that COX4I1 expression mediates HGG sensitivity to oHSV through suppression of IFN signaling.

METHODS

Using previously published models, oHSV cytotoxicity was assessed in vitro using Alamar Blue and CellTiter-Glo assays. oHSV infectivity and CD111 protein expression was assessed by flow cytometry. COX4I1 protein expression was measured by immunoblot. mRNA expression of IFN-stimulated genes was assessed by qPCR.

RESULTS

COX4I1 overexpression increased oHSV cytotoxicity and infectivity compared to empty vector controls. Short hairpin RNA knockdown of COX4I1 decreased oHSV cytotoxicity and infectivity in TMZ-resistant cells compared to pLKO controls. IFN-stimulated genes IFNB1, TMEM173, DDX58, IFIH1, and OAS1 were all significantly decreased in COX4I1 overexpressing cells and TMZ-resistant cells compared to parental lines.

CONCLUSIONS

Overexpression of COX4I1 sensitizes HGG cells to oHSV, and COX4I1 knockdown de-sensitizes TMZ-resistant HGG cells to oHSV, suggesting a novel role of COX4I1 in mediating HGG sensitivity to oHSV.
EXTH-15. A NOVEL IMMUNE-BASED TREATMENT STRATEGY FOR COMBATTING PROTEIN TUMOR HETEROGENEITY
Authors: Wilkinson Daniel , Srinivasan Ethan , Lerner Emily , Fecci Peter
Published: November 2023

Cell-based immunotherapy has revolutionized the treatment of many hematological malignancies but has mostly fail against solid tumors, including glioblastoma (GBM). The reason for this failure is multi-fold, but one of the most significant barriers is the extensive intratumoral heterogeneity that characterizes these tumors. Unfortunately, this problem has not been eliminated by personalized medicine strategies aimed at sequencing individual tumors and targeting the uncovered neoantigens. Thinking “outside the box” led us to examine other types of tumor-specific alterations that might more ubiquitously characterize tumor cells, while still being targetable by an immune-based platform. Our investigations led us to the phospholipid phosphatidylserine (PS). PS is typically present on the cytoplasm-facing side of the plasma membrane, where it remains out of view to the immune system. Cellular stresses can lead to dysregulation of processes that keep PS facing internally and instead promote PS exposure on the cell surface. We show here that tumor cells frequently lose the capacity to regulate their plasma membrane and exhibit detectable levels of PS on their surface. Moreover, inducing cell stress through radiation and chemotherapy of tumor cells further enhanced PS exposure. In this study, we aimed to target PS with an immune-based therapy. To this end, we engineered a bi-specific T cell engager (BiTE) consisting of the natural high-affinity PS receptor TIM4 linked to an anti-CD3scFv. This TIM4 BiTE is hypothesized to redirect all T cells to PS, resulting in T cell-mediated killing of tumor cells with exposed PS. Indeed, TIM4 BiTE facilitated potent killing of multiple human tumor cell lines in vitro, including in models of protein heterogeneous tumors. When TIM4 BiTE was delivered intratumorally to a heterogeneous glioma-bearing mouse, survival was significantly extended. These data provide evidence that targeting PS with an immune-based platform represents a potential novel treatment strategy for combatting tumor heterogeneity.
EXTH-16. DEVELOPMENT OF INTRATHECAL (IT) DRUG DELIVERY PLATFORM TO CURE BREAST CANCER (BC) LEPTOMENINGEAL DISEASE (LMD) BY PEPTIDE-PULSED TYPE 1 CONVENTIONAL DENDRITIC CELL (CDC1) VACCINE IN PRECLINICAL MODEL
Authors: Law Vincent , Snyder Colin , Macaisa Lauren , Garg Saurabh , Czerniecki Brian , Forsyth Peter
Published: November 2023

BACKGROUND

LMD is a rare form of metastasis in the meninges. Approximately 5% of advanced stage BC will develop LMD and currently there is no cure. One of the major hurdles is drug penetration due to the blood brain barrier (BBB) and blood-cerebral spinal fluid (CSF)-barrier. While the Ommaya reservoir is used clinically to overcome this challenge, there has not been an optimized preclinical model that allows researchers to adequately test novel therapies in the CSF space.

METHODS

The Forsyth lab have recently developed an MRI-compatible device called the “murine Ommaya” which mimics the Ommaya reservoir and allows repeated IT administration of drugs in minute 3-7 μL directly into CSF, bypassing BBB. In a joint effort with Dr. Czerniecki, whose lab have developed a pipeline for screening immunogenic MHC class II peptides from tumor-associated oncodrivers and subsequently generating tumor-targeting cDC1s, we have created a platform to IT deliver peptide-pulsed cDC1 immunotherapy directly targeting BC-LMD.

RESULTS

Currently, we have tested the efficacy of treatment in HER2+ LMD and triple negative breast cancer (TNBC) LMD models and found a very favorable response; LMD mice that received IT cDC1 therapy showed tumor regression and their survival were significantly prolonged. About 70% of mice from HER2+ LMD and 30% from TNBC LMD were eventually disease-free. Cured mice also exhibited resistance against LMD recurrence.

CONCLUSIONS

Our preliminary data suggest IT cDC1 vaccine is effective against the incurable BC-LMD. We are currently investigating the mechanism(s) by which IT cDC1-initiated CD4 Th1 adaptive immune response against LMD. By using single-cell RNA-sequencing technique, we are analyzing the immune landscape in CSF tumor microenvironment in response to IT cDC1. FDA-approved phase 1 clinical trial has been funded by the DOD. Future approach includes employing our IT cDC1 immunotherapy platform in other cancer types, such as LMD from melanoma.
EXTH-21. FKBP38 REGULATES SELF-RENEWAL AND SURVIVAL OF GBM NEUROSPHERES
Authors: Dowling Aimee , Walbridge Stuart , Ertekin Celine , Bryant Jean-Paul , Kohut Eric , Chowdhury Ashis , Brown Desmond , Heiss John , Banasavadi-Siddegowda Yeshavanth Kumar
Published: November 2023

Glioblastoma (GBM) is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection followed by radiation and chemotherapy. The quest for novel therapeutic targets to treat GBM is underway. FKBP38, a member of the immunophilin family of proteins, is a multidomain protein that plays an important role in the regulation of cellular functions including apoptosis and autophagy. In this study, we tested the role of FKBP38 in GBM tumor biology. Expression of FKBP38 is upregulated in the patient-derived primary GBM neurospheres (GBMNS) compared to normal human astrocytes. Attenuation of FKBP38 expression decreased the viability of GBMNS and increased the caspase 3/7 activity indicating that FKBP38 is required for the survival of GBMNS. Further, the depletion of FKBP38 significantly reduced the number of neurospheres that were formed implying that FKBP38 regulates the self-renewal of GBMNS. Also, the transient knockdown of FKBP38 increased the LC3-II/I ratio suggesting the induction of autophagy with the depletion of FKBP38. Further investigation showed that the negative regulation of autophagy by FKBP38 in GBMNS is mediated through the JNK/C-Jun-PTEN-AKT pathway. In vivo, FKBP38 depletion significantly extended the survival of tumor-bearing mice. Overall, our results suggest targeting FKBP38 imparts an anti-GBM effect by inducing apoptosis and autophagy and thus can be a potential therapeutic target for GBM therapy.
EXTH-22. AN IND-ENABLED STUDY USING A NOVEL CHECKPOINT BLOCKADE OF LAIR1 FOR GLIOBLASTOMA THERAPY
Authors: Tao Haipeng , Chen Dongjiang , Yang Changlin , Nguyen Duy , Pepe Alfonso , Pedro Diego , Jin Linchun , Liu Ruixuan , Liu Tianyi , Von Roemeling Christina , Abbas Muhammad , Hou Alicia Y , Petit Nicole , Abboud Georges , Mendez-Gomez Hector , Weidert Frances , Jin Dan , Long-James Kaytora , Sayour Elias , Deleyrolle Loic , Gregory Sawyer W , Mitchell Duane , Huang Jianping
Published: November 2023

BACKGROUND

Our research study focuses on the recently discovered immune checkpoint known as Leukocyte-Associated Immunoglobulin-like Receptor 1 (LAIR1), which is found to be overexpressed on tumor-associated myeloid cells (MAMC), including Tumor-associated macrophages (TAM) and Myeloid-derived suppressive cells (MDSC), in GBM and other solid cancers. The overexpression of LAIR1 in gliomas is associated with poor survival, which has prompted investigations into the potential of LAIR1 blockade (aLAIR1) as a therapeutic strategy. In preclinical mouse models, Objective: A) To investigate the mechanism of LAIR1, a new class of immune checkpoint. B) To develop strategies for blocking LAIR1 signaling as a means of cancer therapeutics, thereby enabling novel mono and combinatorial treatments for GBM.

METHODS

1) Conduct coculture experiments using human TAMs and autologous CAR T cells in a 3D microgel bio-printing system, which allows us to recreate TME using patient-derived immune cells and a heterogeneous glioma model. By monitoring this coculture system, we aim to gain insights into the inhibitory effects of TAMs on T cells mediated by LAIR1. 2) Utilize tumor-burden wild-type and LAIR1 knockout mice to compare the intratumoral immune cell infiltration between WT and KO mice. 3) Employ sc-RNA-seq to identify key molecules involved in the TAM-T cell interaction. 4) Perform pathway analysis to identify signaling pathways that are influenced by this interaction.

RESULTS

aLAIR1 shifted macrophage polarization from M1 to M2 and increased memory CD8+ T cells intratumorally. It reversed MDSC- or M2- macrophage-mediated T-cell suppression, resulting in enhanced antitumor response as a standalone treatment and when used in combination with CAR T cell therapy in PD-1-resistant tumor models.

CONCLUSIONS

LAIR1 is a newly identified innate immune checkpoint that is highly expressed on TAMC in solid tumors, contributing to tumor progression and drug resistance. Blocking the LAIR1 signaling pathway shows promise as an effective approach for cancer therapy.
EXTH-27. ASSESING THE EFFECT OF ELECTRIC FIELD THERAPY ON PATIENT DERIVED GLIOMA STEM CELL LINES AND GLIOMA INFILTRATING CEREBRAL ORGANOIDS
Authors: Narayanan Ashwin , Zhao Jinwei , Olukoga Tomisin , Bullock Christopher , Fu Richard
Published: November 2023

Glioblastoma (GBM) is the most aggressive primary brain tumour in adults. Electric field therapy (EFT) is a new cancer treatment applied after safe maximal tumour resection that interferes with cancer cell division, slowing tumour recurrence and prolonging life. In GBM patients, this therapeutic modality has demonstrated an increase in median survival from ~16 to ~21 months. This study aimed to assess and decipher the effectiveness of EFT on patient-derived glioblastoma stem cell lines (GSC) as well as on advanced Glioma infiltrating cerebral organoid models (GLICOs). To achieve the project goals, we used a novel In-vitro EFT stimulation apparatus to test stimulation parameters on multiple patient-derived GSC lines as well as GLICO models derived from them. We used advanced microscopy and transcriptomic sequencing to visualize and decipher the causal effect of our stimulation regime on the in-vitro models. We observe a strong effect of our EFT regime on multiple GSC lines as well as on GLICOs when compared to their controls. Transcriptomic analysis showed multitude of differentially expressed mRNAs between the treated and control samples with multiple pathways being dysregulated from nuclear proteins, cell mitosis-related events and activation of non-apoptotic mediated programmed cell death pathways indicating a novel mechanism of action. Advanced causal inference studies using the data also provided novel insights on combinatorial therapies that could enhance the efficacy of the treatment. This study provides novel understanding of the mechanism of EFT with potential for optimised treatment regimens for GBM patients.
EXTH-30. GOLD NANOSTARS OBVIATE LIMITATIONS TO LASER INTERSTITIAL THERMAL THERAPY (LITT) AND ENHANCE THE POST-LITT IMMUNE RESPONSE
Authors: Srinivasan Ethan , Liu Yang , Odion Ren , Chongsathidkiet Pakawat , Wachsmuth Lucas , Haskell-Mendoza Aden , Edwards Ryan , Canning Aidan , Willoughby Gavin , Hinton Joseph , Norton Stephen , Lascola Christopher , Maccarini Paolo , Mariani Christopher , Vo-Dinh Tuan , Fecci Peter
Published: November 2023

Laser interstitial thermal therapy (LITT) is a minimally-invasive technique for the treatment of intracranial tumors that uses a stereotactically-guided laser and real-time magnetic resonance imaging (MRI) to monitor ablation progress. Previous applications of gold nanostars (GNS) in laser ablation of tumors have studied extracranial tumors only and utilized externally administered near infrared radiation that cannot penetrate the cranial compartment. Herein, we present a novel platform for employing GNS in intracranial tumors. We developed non-toxic GNS that exhibit maximum photothermal effects at the 1064 nm laser wavelength used in the FDA-approved clinical Neuroblate® LITT system. Monte Carlo simulations demonstrate that our GNS can accelerate and focus thermal energy distributions. Using ex vivo tumor phantom models, we found that GNS-infused phantoms demonstrate more rapid heating and improved spatial conformation of thermal energy, with neighboring material exposed to lower temperatures than controls. In our intracranial CT-2A glioma model, we quantified accumulation of radiolabeled GNS in tumor tissue via PET/CT. As further validation of tumor-selective GNS accumulation, we used two-photon luminescence to show that GNS selectively accumulate and are retained in intracranial tumors at 24 and 72 hours post-injection. We then utilized our in vivo heterotopic CT-2A model to assess the capacity of systemically-delivered GNS to augment laser ablation; we were able to achieve higher ablation temperatures and more efficient temperature ramping with LITT+GNS. Finally, we explored the potential of LITT+GNS to synergize with immunotherapy to further enhance the post-ablation immune response and found that combination therapy resulted in improved tumor control and immunologic memory that was protective against tumor rechallenge. These results support the ability of GNS to optimize LITT for the treatment of intracranial tumors by improving efficiency and safety, and illustrate the potential of this platform to synergize with immunotherapy.
EXTH-33. RAGE INHIBITOR (TTP488) AS AN ALTERNATIVE TO DEXAMETHASONE FOR MANAGING CEREBRAL EDEMA FOLLOWING BRAIN TUMOR SURGERY
Authors: Dayyani Mojtaba , Filippov Aleksandr , Zhang Ian , Georges Joseph , Saeed Zaan , Turunen Jillyn , Zhang Larry , Maus Rachel , Portnow Jana , Badie Behnam
Published: November 2023

BACKGROUND

Cerebral edema (CE) commonly occurs after neurosurgical procedures and contributes to patient morbidity and neurological deterioration. Corticosteroids alleviate brain edema during the perioperative period, but they impose several undesirable side effects and interfere with immunotherapies in patients with malignant brain tumors.

OBJECTIVE

To assess the anti-inflammatory effects of TTP488 (inhibitor of receptor for advanced glycation end products) on CE formation following tumor resection in glioma models.

METHODS

Mice harboring orthotopic CT-2A gliomas were randomly assigned to three groups and underwent tumor resection. TTP488, dexamethasone, and vehicle were administered perioperatively (day -4 pre-op to day 7 post-op) and post-operative neurological function was examined. CE was assessed on serial brain MRIs over a 7-day period, and using manual segmentation techniques, tumor-related volumes were calculated. In a separate survival experiment, the effect of each drug on anti-PD-1 immunotherapy response was measured.

RESULTS

In each group, CE peaked on post-operative day 2 and gradually diminished by day 7. On post-operative day one, mice treated with TTP488 showed a marked reduction in CE compared to those treated with either dexamethasone or vehicle with mean CE volumes of 1.75±1.08%, 2.69±0.77%, and 3.87±1.07%, respectively (P=0.02, TTP488 vs vehicle). Furthermore, the TTP488 group had better functional recovery scores (P=0.04) and wound healing (dehiscence, P=0.00003) compared to the vehicle group. Interestingly, unlike dexamethasone, TTP488 did not abrogate the efficacy of immunotherapy in the CT-2A glioma model.

CONCLUSION

TTP488 was as effective as dexamethasone in alleviating CE caused by tumor resection and did not interfere with the efficacy of immunotherapy. TTP488 could potentially be an alternative to dexamethasone in the perioperative management of patients undergoing tumor resection or other neurosurgical interventions.
EXTH-34. LOCAL DELIVERY OF AN IL-15 SUPERAGONIST USING A REPLICATING RETROVIRUS SYNGERIZES WITH TEMOZOLOMIDE TO INCREASE LYMPHOCYTE INFILTRATION AND SURVIVAL IN TWO POORLY IMMUNOGENIC GLIOBLASTOMA MOUSE MODELS
Authors: Haddad Alexander F , Spatz Jordan , Saha Atul , Montoya Megan , Collins Sara , Gill Sabraj , Wang Elaina , Chuntova Pavlina , Salha Diana , Young Jacob , Kasahara Noriyuki , Aghi Manish
Published: November 2023

Glioblastoma (GBM) leads to systemic and local immunosuppression and immunotherapies have had limited clinical success. We evaluated the treatment efficacy of RLI (receptor-linker-IL-15), a superagonist of T-cell activator IL-15, delivered to tumor cells using a tumor-selective retroviral replicating vector (RRV) in the syngeneic murine SB28 and Tu2449 GBM models, which are poorly immunogenic with low-mutational burden and known resistance to immunotherapy, similar to human GBM. RRV-RLI replicated and spread in cultured SB28 murine GBM cells with robust production of functional RLI (165.4 ± 5.3 ng/mL). Stereotactic injection of RRV-RLI into pre-established intracerebral Tu2449 tumors led to complete eradication of intracerebral tumors with long term survival (median not reached) in > 85% of treated mice vs. median survival of 12.5 days in control mice (p=0.001). Treated mice demonstrated significantly increased CD8 T cell infiltration. These mice also demonstrated immunologic memory to intracranial rechallenge. In SB28, RRV-RLI delivery into intracerebral tumors reduced tumor growth on bioluminescence imaging, and increased median survival compared to controls (55 vs. 19 days, p=0.002), with long-term survival in 12% of treated mice. Combining RRV-RLI treatment with systemically administered temozolomide (TMZ) in the SB28 model provided long term survival (median not reached) in >60% of treated mice. Immunologic analysis of treated tumors revealed a significant increase in CD8 T cell (2.1% to 20.5% of CD45 cells) and Natural Killer cell (1.4% to 9.6% of CD45 cells )infiltration in RLI-RRV+TMZ mice vs. PBS+TMZ mice. RLI was not detected in the blood of treated mice, and tumor-localized RRV-RLI gene delivery showed no adverse systemic immune effects. In summary, RRV-mediated RLI immunotherapy results in immunostimulatory changes that are further potentiated by systemically administered temozolomide. This tumor-localized gene therapy has the potential to synergize with standard of care treatment to reverse the immunosuppressed GBM tumor microenvironment and provide a significant treatment benefit.
EXTH-40. PHOTODYNAMIC ONCOLYTIC VIRUS THERAPY FOR CENTRAL NERVOUS SYSTEM MALIGNANCIES
Authors: Shimizu Kazuhide , Kahramanian Andranik , Maehara Taketoshi , Wakimoto Hiroaki
Published: November 2023

Oncolytic viruses (OVs) have emerged as a clinical therapeutic modality potentially effective to treat cancers that evade conventional therapies, including central nervous system malignancies. Rationally designed combinatorial strategies can augment the efficacy of OVs by boosting tumor-selective cytotoxicity and modulating the tumor microenvironment (TME). Photodynamic therapy (PDT) of cancer not only mediates direct neoplastic cell death but also primes the TME to sensitize the tumor to secondary therapies. This allows for the combination of two potentially synergistic therapies with broader targets. Here, we created G47Δ-KR, clinical oncolytic herpes simplex virus G47Δ that expresses photosensitizer protein KillerRed (KR). Optical properties and cytotoxic effects of G47Δ-KR infection followed by amber LED illumination were examined in human glioblastoma (GBM) and malignant meningioma (MM) models in vitro. G47Δ-KR infection of tumor cells mediated KR expression that was activated by amber LED and produced reactive oxygen species, leading to cell death that was more robust than G47Δ-KR without light. In vivo, we tested G47Δ-KR-based PD-OV therapy employing intratumoral injection of G47Δ-KR followed by amber laser (wavelength: 585 nm) tumor irradiation in GBM and MM xenografts. PD-OV therapy was feasible in GBM and MM xenografts and resulted in potent anti-tumor effects that were superior to G47Δ-KR alone (without laser) or laser alone. RNA sequencing analysis of post-treatment tumor samples revealed PD-OV therapy-induced increases in TME infiltration of variable immune cell types. This study thus demonstrated the proof-of-concept that G47Δ-KR enables PD-OV therapy for neuro-oncological malignancies and warrants further research to advance potential clinical translation.