bluuebunny/crossref_metadata_2025 huggingface dataset:
EPCO-52. SUBTYPES AND SURVIVAL ANALYSIS OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA WITH RADIOMICS FEATURES
Authors: Barillot Noemie , Alentorn Agusti , Hernandez Isaias , Mokhtari Karima , Hoang-Xuan Khe , Mathon Bertrand
Published: November 2023

Primary Central Nervous System Lymphoma (PCNSL) is a rare and heterogeneous disease with dismal prognosis. Recently, four molecular clusters with clinical relevance have been identified with different potential therapeutic targets in each group. Nevertheless, multi-omics data collection and analysis are expensive and not adapted for clinical practice. Therefore, the identification of surrogate markers to identify PCNSL subtypes from routine data is required, like using hematoxylin and eosin slides from brain biopsies. We used a cohort of 108 patients and we selected the 5000 nuclei for each patient among roughly 1,500,000 nuclei. Once hematoxylin and eosin slides have been digitized, tessellated, normalized and the nuclei have been segmented and filtered with the computation of a solidity score, the PyRadiomics package provides us with more than 800 features for each nuclei. Firstly, we were interested in survival analysis. In a second time, we also used these features for training classification models. We used a partial least squared Cox model, which is a classic Cox model applied to latent components constructed by using linear combinations of the original variables. RESULTS: for our first cohort are promising (C-index of 0.87, std 0.01), with a significant increase compared to the clinical features model (C-index of 0.68, std 0.03). We are now challenging these results with three other cohorts of brain and systemic lymphoma. This study paves the way for a stratification of the clinical evolution based on the machine learning analysis of digital pathology in PCNSL that could be easily translated to a broad range of diseases or other brain tumors.
DISP-12. BRAIN CANCER CANADA FUNDS CRITICALLY NEEDED RESEARCH AND ADVOCATES FOR PATIENTS, WITH THE AIM TO IMPROVE OUTCOMES FOR CANADIANS DIAGNOSED WITH PRIMARY MALIGNANT BRAIN TUMOURS
Authors: Soares Jessica , Angelini Anita , Ladak Ali , Devan Kaviya , Loebenberg Lia , de Arujo Elvin , Power Jason , Leong Russell , Ayyadhury Shamini , Hoang Yung , Peeters Marc , Scalisi Angela , Canada Brain Cancer
Published: November 2023

Brain Cancer Canada (BCC) is a national, volunteer-driven charity supporting paediatric and adult primary malignant brain tumour research and patient advocacy. To achieve these goals BCC 1) awards grants to Canadian doctors and scientists advancing brain cancer research, and 2) advocates for equitable pharmacare for brain cancer patients. BCC is committed to funding innovative research projects, with the aim to improve treatment options for patients. Led by its Scientific Advisory Committee, submissions are reviewed, screened, and undergo a systematic evaluation by the panel. Recommendations on successful proposals are provided to the board for approval. This May, the charity awarded 5 research grants, totaling $380,000 CAD. These projects include supporting the acquisition of a next-generation DNA Sequencer, advancing FET-PET/MRI imaging, pioneering a novel approach to combat Diffuse Intrinsic Pontine Glioma (DIPG), developing a novel dual-hit therapeutic approach for glioblastoma, and other projects focusing on precision medicine. BCC has taken a deliberate and firm stand in highlighting the drug coverage disparities that exist for patients afflicted with brain cancer BCC’s Pharmacare Advocacy Committee has found that disparities exist owing to the lack of a national drug program, and a patchwork of alternative schemes varying by province/territory. These findings are well documented by others. For example, our research shows that temozolomide (TMZ), the global standard of care for treating gliomas, is not covered in 4 provinces. Our pharmacare research on TMZ and 5 other drugs further confirm the disparity in coverage that hinders patient welfare and imposes a confusing and detrimental strain on the healthcare system. With, the dependence on take-home medication increasing, it is critical we take immediate action in supporting this marginalized group. With the support of The Society for Neuro-Oncology, Brain Cancer Canada will be better positioned to reach its goals and support people affected by primary malignant brain tumours.
IMMU-07. THE CXCL16/CXCR6 AXIS REGULATES CD8+ T-CELL RECRUITMENT AND FUNCTION IN GLIOBLASTOMA
Authors: Chia Tzu-Yi , Billingham Leah , Boland Lauren , Wan Hanxiao , Wang Si , Katz Joshua , Hou David , Cervantes Gustavo Ignacio Vazquez , Han Yu , Lopez-Rosas Aurora , Zhang Peng , Lee-Chang Catalina , Miska Jason
Published: November 2023

INTRODUCTION

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a poor prognosis and no curative treatment. Immunotherapy, revolutionizing oncology, is currently ineffective for GBM due to the immunosuppressive tumor microenvironment. A critical driver is tumor-associated macrophages (TAMs) infiltration, which is correlated to T-cell deficiency and tumor progression. While the interactions between TAMs and T-cells are known to inhibit the antitumor functions, the mechanisms driving these interactions in GBM are still not established. Our data shows that the CXCL16/CXCR6 axis is likely the predominant chemokine-receptor interaction among TAMs and CD8+ T-cells population in GBM. Understanding the role of this axis is crucial in modulating antitumor immune functions in GBM.

METHODS

We designed several migration and adhesion assays to determine how the CXCL16/CXCR6 axis influences: CD8+ T-cell migration, TAM: CD8+ T-cell interactions, and CD8+ T-cell dysfunction in GBM. In addition, long-term survival with immune checkpoint treatment was done to understand the influence of the axis on murine tumor growth.

RESULTS

While CXCR6 deficiency prevented T-cell infiltration into tumors, the CD8+ T-cells cells within the tumors expressed more markers associated with cytotoxicity and exhaustion. Furthermore, CXCR6 deficient CD8+ T cells were less adherent to immunosuppressive TAMs. Importantly, CXCR6 deficiency worked in concert with anti-PD1 to promote tumor rejection in the CT2A tumor-bearing model of GBM.

CONCLUSION

Our data show that while CXCR6 is crucial in trafficking CD8+ T-cells to tumors from the periphery, it promotes immunosuppressive interactions between TAMs/CD8+ T-cells within tumors. Thus, the CXCR6 axis exerts opposing roles in anti-tumor immunity in GBM.
IMMU-16. PUBLIC TUMOR-WIDE NEOANTIGENS DERIVED FROM CLONAL ABERRANT SPLICING EVENTS DRIVE TUMOR-SPECIFIC T-CELL RESPONSES
Authors: Kwok Darwin , Stevers Nicholas , Nejo Takahide , Jung Jangham , Chen Lee , Lakshmanachetty Senthilnath , Etxeberria Inaki , Gallus Marco , Yamamichi Akane , Ramos Emilio , Hong Chibo , Colton Maggie , Chan Gary , Du Aidan , Woo James , Wiita Arun , Klebanoff Christopher , Costello Joseph , Okada Hideho
Published: November 2023

BACKGROUND

Immunotherapy in gliomas is limited by tumor heterogeneity and low mutational burden. We developed a novel comprehensive in silico pipeline for detecting tumor-specific splicing events (neojunctions) across multiple cancer types, and in gliomas, we successfully identified tumor-wide, public, alternatively spliced neoantigens (ASNs) that elicit CD8+ T-cell-mediated immune responses.

METHODS

Our pipeline identified recurring public neojunctions expressed in TCGA RNA-seq (positive sample rate (PSR) > 10%) and not in GTEx normal tissue RNA-seq data (PSR < 1%) across six cancer types. To characterize intratumorally-conserved neojunctions, we utilized multi-site RNA sequencing, and with gliomas, we analyzed approximately 10 maximally-distanced intratumoral sites within 56 patients (n=535). Tumor-wide public neojunction expression was subsequently validated in RNA-sequencing and mass spectrometry (MS) data from patient-derived cell lines (n=68) and samples (n=99). Two independent algorithms then predicted peptide processing likelihood and HLA-binding affinity of ASN candidates. In vitro sensitization (IVS) of healthy donor-derived CD8+ T-cells against high-confidence ASN candidates, followed by 10x VDJ scRNA-seq, was performed to identify ASN-specific TCR sequences. TCRs were transduced into triple-reporter Jurkat76s and co-cultured with ASN and HLA-expressing COS7 cells and glioma cell lines to evaluate TCR functionality.

RESULTS

Our glioma-specific analysis identified 249 public neojunctions with varying intratumoral heterogeneity. 4 ASNs were concurrently identified in transcriptomic and proteomic glioma data and predicted to be presented by HLA-A*02:01 with high confidence. IVS and subsequent 10x VDJ scRNA-seq on expanded CD8+ populations identified TCR clonotypes reactive against neojunctions in RPL22 (n=7) and GNAS (n=1), the latter being highly intratumorally-conserved (detected in > 90% of spatially-mapped biopsies across 17/56 patients (26.78%)). TCR-transduced T-cells demonstrated recognition and immunogenic activation against endogenously processed and presented neoantigens in glioma and transfected COS7 cells.

CONCLUSION

Our unique integrative pipeline identified novel public tumor-wide splice-derived neoantigen candidates and TCRs, offering a promising off-the-shelf immunotherapy approach for gliomas.
IMMU-21. LOW-INTENSITY PULSED ULTRASOUND PROMOTES THE PRESENTATION OF BRAIN-DERIVED ANTIGENS THROUGH ENHANCED TRAFFICKING OF ANTIGEN-PRESENTING CELLS FROM THE BRAIN INTO THE PERIPHERY
Authors: Gallus Marco , Arrieta Victor , Saijo Atsuro , Haegelin Jeffrey , Chuntova Pavlina , Yamamichi Akane , Chen Li , Habashy Karl , Gould Andrew , Amidei Christina , Chang Catalina Lee , Stupp Roger , Canney Michael , Sonabend Adam , Okada Hideho
Published: November 2023

The central nervous system, immunologically unique due to specialized lymphatics and anatomical barriers, often conceals brain neoplasm from the peripheral immune system. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) enables transient opening of the BBB, allowing drug transport and immune cell trafficking into brain tumors. However, it remains unclear whether BBB opening promotes immune cell trafficking from the brain to the periphery. To investigate this, we performed intravital imaging of Colony-stimulating factor receptor 1 (CSFR1) and CX3CR1 reporter mice to visualize antigen-presenting cell locomotion in the brain before and immediately after LIPU/MB using two-photon microscopy. Within one hour after LIPU/MB, we observed the exiting of CSFR1+ and CX3CR1+ immune cells from the brain parenchyma and perivascular space into the bloodstream, a phenomenon we did not observe prior to LIPU/MB treatment. To further evaluate the immunological effects of LIPU/MB on brain antigen presentation, we performed LIPU/MB in novel transgenic mice that express a minigene encoding for 4 immunogenic peptides under the glial fibrillary acidic protein (GFAP) promotor. We observed significant proliferation of naïve antigen-specific CD8 T cells targeting one of the peptides in the cervical lymph nodes one week after LIPU/MB treatment, but not in the animals that received T cells but did not undergo LIPU/MB. These data indicate that LIPU/MB facilitates the presentation of brain-localized antigens to antigen-reactive T cells in the systemic circulation. In 3 out of 5 GBM patients that underwent LIPU/MB plus doxorubicin and anti-PD-1 blocking antibodies, we observed CD11b+CD14+P2YR12+ microglia in blood samples collected after sonication. This increase was present in cycles 3-6 of this treatment. We did not observe the presence of this immune cell population in blood samples from healthy donors. Taken together, our results indicate that LIPU/MB could be a novel approach to enhance brain-antigen presentation in the periphery.
IMMU-22. BLOCKADE OF CD47 RESULTS IN METABOLIC REPROGRAMMING TO ENHANCE IMMUNE CELL-MEDIATED CYTOTOXICITY OF GLIOBLASTOMA
Authors: Tsai Yu-Ting , Lesser Glenn , Soto-Pantoja David R
Published: November 2023

Glioblastoma (GBM) is the most aggressive and malignant brain tumor. There is growing interest in using immunotherapy to treat GBM, however, clinical trials with immune checkpoints have shown little efficacy, likely due to significant GBM-associated systemic and intra-tumoral immunosuppression. The expression of the transmembrane protein CD47 contributes significantly to immunosuppression limiting innate and adaptive anti-tumor responses. Our new data shows that patient biopsies showed strong immunoreactivity to CD47 in GBM compared to normal adjacent tissue. Furthermore, high CD47 expression in GBM patients resulted in poor survival, indicating that CD47 may be a potential target for GBM treatment. Beyond the “don’t eat me signal”, CD47 facilitates its intracellular signaling through PLIC1 and it still unknown how CD47-related can influence metabolic reprogramming in the tumor microenvironment. Previous studies that upregulated fatty acid oxidation (FAO) provide GBM cells with metabolic plasticity to accommodate its dynamic nutrient microenvironment. Respirometry data revealed that blocking CD47 in murine cell line (CT2A) reduces mitochondrial function and ATP production by over 40-50% respectively (p*< 0.02). The reduction in mitochondrial respiration is linked to an over 50% reduction in FAO (*p< 0.004). This was associated with significant decreases in CPT1a, FASN, ATGL, and CD36 indicating a reduction in FA metabolism mediators. On the other hand, blocking CD47 on murine microglia (SIMA9), showed an opposite result from cancer cells, with increasing mitochondrial respiration and FAO. Initial shows differential responses may be due to the engagement of PLIC1 to CD47. Furthermore, blocking CD47 on microglia increased three-fold of the immune cell-mediated GBM cell cytotoxicity (*p< 0.005), suggesting that metabolic reprogramming associated with CD47 blockade could result in the improvement of immune adaptive responses in the GBM microenvironment. Taken together, our data indicated that CD47 blockade may be a prospective treatment to reduce GBM metabolic plasticity and increase microglia-mediated GBM killing.
IMMU-26. MRNA CAR T CELL TRAFFICKING FOLLOWING INTRA-VENTRICULAR ADMINISTRATION IN PRECLINICAL MODELS OF DIFFUSE MIDLINE GLIOMA
Authors: Al-atrache Zein , Mcmanus Olivia , Harvey Kyra , Dickson Conor , Patterson Luke , Beaubien Ezra , Wilson Cullen , Hajeebu Sreehita , Keil Samantha , Braun Molly , Meechan Michael , Vitanza Nicholas , Iliff Jeffrey , Madsen Peter , Foster Jessica
Published: November 2023

BACKGROUND

GD2-directed chimeric antigen receptor (CAR) T cells have shown promise as a potential therapeutic for diffuse midline glioma. We have previously shown intra-tumoral infusions of mRNA CAR T cells result in tumor regression with improved safety and toxicity profile in murine models. For human trials, the optimal route of CAR T cell administration into the central nervous system should maximize in vivo potency while minimizing procedural morbidity. Prior mRNA CAR T literature has reported decreased solid tumor infiltration with systemic delivery, so we sought to determine mRNA CAR T cell trafficking into pontine tumors from the cerebral spinal fluid to inform clinical translation of this therapy.

METHODS

Mice engrafted with SU-DIPG13P* tumor cells in the pons were treated with 5x106 mRNA CAR T cells into the lateral ventricle (LV) and brains were harvested 24 hours later. Tumor and T cells were analyzed using confocal microscopy to determine the migration of CAR T cells.

RESULTS

LV injection of GD2-directed CAR T cells resulted in T cell trafficking to the subarachnoid spaces, tumor site, and surrounding parenchyma. The highest concentration of T cells was in the subarachnoid space directly adjacent to the tumor (p< 0.0001) and decreased on a gradient to subcortical tumor. Even at 24 hours after injection, T cells were identified within the center of the tumor mass. CD19-directed control CAR T cells showed similar distribution within the subarachnoid with significantly decreased T cells at the tumor site.

CONCLUSION

Ventricular infusions of mRNA CAR T cells showed effective migration to pontine tumors within 24 hours. While CAR T cells did not fully penetrate the parenchyma within that timeframe, GD2-directed mRNA CAR T cells were detected within the center of the tumor mass, indicating ventricular administration may be sufficient for clinical delivery. Additional routes are being explored in ongoing work.
IMMU-35. G-AMINOBUTYRIC ACID DRIVES GLIOBLASTOMA IN FEMALES BY ACTIVATING THE COMPLEMENT SYSTEM
Authors: Bayik Defne , Pathak Asmita , Chin Diana , Lin Feng , Iavarone Antonio , Lathia Justin
Published: November 2023

Interaction between tumor and neural cells drives the progression of glioblastoma (GBM), which is characterized by enhanced immunosuppressive myeloid cell accumulation. Our previous results revealed that myeloid-derived suppressor cell subsets (MDSCs) play a central role in tumorigenesis in a sex-specific manner, with monocytic MDSCs (mMDSCs) accumulating in male tumors and granulocytic MDSCs (gMDSCs) correlating with a worse outcome in females. However, host factors governing sex differences in MDSC subset activity remained unknown. Here, we report that g-aminobutyric acid (GABA) receptor expression by gMDSCs informs their sex-specific behavior. We observed that only female gMDSCs but not male gMDSCs or mMDSCs from either sex respond to GABA by upregulating the antiviral innate immune pathway. As part of this signature, GABA-stimulated female gMDSCs had higher complement 1qa (C1qa) expression. To test the potential role of the GABA pathway on GBM outcome, we tested the GABA analogue pregabalin in preclinical models. Female mice treated with pregabalin succumbed to disease earlier, consistent with our previous observation that gMDSCs have a central role in GBM progression in females. In contrast, pregabalin treatment had no effect in male mice with tumors or immunocompromised female mice. To further evaluate whether C1q is a relevant physiological target, we performed single-cell sequencing of tumor-infiltrating versus circulating MDSC subsets and detected high levels of C1q expression in gMDSCs from tumors. C1q KO transgenic female mice had significantly better outcomes compared to wild-type littermates upon implantation with syngeneic mouse GBM lines, while C1q expression status did not impact the outcome in males. Correspondingly, only in female patients C1q expression correlated with poor prognosis. Collectively, these results identify a neuron-immune-cancer communication axis and indicate that GABA and C1q alter anti-tumor immune responses in a sex-specific manner. These results support the future assessment of the GABA pathway and complement inhibitors as potential immunotherapy agents.
IMMU-39. EFFICACY OF IMMUNE CHECKPOINT INHIBITORS IN GLIOBLASTOMA FROM REAL-WORLD DATA ANALYSIS
Authors: Stuhlmiller Timothy , Quinn Jameson , Awawda Alaa , Blondin Nicolas , Iwamoto Fabio , Nabors Burt , Redfern Charles , Wasserman Asher , Cole Zachariah , Shapiro Mark , Kesari Santosh
Published: November 2023

Immune checkpoint inhibitors (ICIs) failed to show efficacy in a randomized trial in glioblastoma (GBM). We utilized the patient-led XCELSIOR platform (NCT03793088) to evaluate ICIs in real-world GBM treatment. XCELSIOR centralizes EMR data from all care sites, creating longitudinal, source-verified data. Identity verification permits accurate overall survival (OS) calculations. As of 6/8/2023, 726 GBM patients were enrolled in XCELSIOR. Median diagnosis date was 1/13/2021 and median age was 56. Seventy-five patients (10%) received ICIs: 53 received pembrolizumab (71%) and 26 received nivolumab (35%) including 12 with ipilimumab (16%). Median days from diagnosis to ICI initiation was 263 days with 22 patients treated at 1st line, 39 at 2nd line, and 14 at 3rd line or later. Data was annotated for 71 patients treated with ICIs and 394 patients not treated with ICIs (no-ICI). Median OS (mOS) from diagnosis for all ICI patients vs. no-ICI was 4.95 years (95% CI 2.18-NR) vs. 1.75 years (1.56-2.03, p < 0.0001). Key features in the ICI cohort were 46% methylated MGMT, 47% gross total resection, 61% exposed to non-SOC agents besides ICI. Creating a propensity score matched cohort for these features, ICI vs. no-ICI had a numerically increased but non-significant mOS of 2.58 years (1.78-NR, n=62) vs. 2.05 years (1.76-2.61, n=113) but a 5-year survival rate of 44% for ICI vs. 16% for no-ICI. Optune use was similar, 39% ICI and 29% no-ICI. Common non-SOC agents used in the ICI cohort were everolimus (11%), osimertinib (8%), lenvatinib (7%), abemaciclib (7%), and neoantigen peptide vaccines (7%). Among unmethylated MGMT patients, mOS was 1.78 years for ICI vs. 1.8 years for no-ICI. These data suggest activity of ICIs for a subset of GBM patients, but do not support use in patients with unmethylated MGMT. Next steps will focus on discrete combination regimens in this evolving data.
IMMU-40. DECITABINE PRIMES GLIOBLASTOMA TO NY-ESO-1 SPECIFIC T-CELL CYTOLYSIS VIA DNA DEMETHYLATION OF NY-ESO-1, CANCER-TESTIS ANTIGENS, AND PRO-INFLAMMATORY SIGNATURES
Authors: Lai Thomas , Sun Lu , Treger Janet , Li Tie , Li Kevin , Prins Terry , Lai Albert , Prins Robert , Everson Richard
Published: November 2023

INTRODUCTION

Previous work has shown that the DNA hypomethylating agent, Decitabine (DAC), can improve the immunogenicity of Glioblastoma (GBM) for immuno-therapeutic targeting through the upregulation of cancer testis antigens (CTA). Specifically, our group has published preclinical proof of principle that DAC upregulates NY-ESO-1, a well-studied and highly immunogenic CTA, in GBM for targeting by systemic adoptive T-cell therapy. However, the exact mechanisms by which this DAC-induced immunogenic enhancement occurs in GBM remains to be elucidated. We hypothesize that hypomethylating agents like DAC enable targeted immune therapy to overcome low immunogenicity in GBM cells via CpG demethylation of antigens and subsequent upregulation of inflammatory and antigen presentation gene signatures.

METHODS

We induced NY-ESO-1 expression in vitro in immortalized GBM lines and primary gliomaspheres using DAC and investigated the response of DAC-treatment using targeted bisulfite sequencing and quantitative real-time PCR. To functionally assess for specific immune killing of DAC treated GBM cells, we co-cultured DAC-treated cell lines with T-cells transduced to express a NY-ESO-1 specific T-cell receptor. Lastly, we performed probe-based methylation array and bulk RNA sequencing to interrogate global transcriptomic and epigenomic changes resulting from DAC treatment.

RESULTS

Sustained exposure to low dose (0.5 uM – 1 uM) DAC in immortalized and primary cell lines resulted in time-dependent demethylation of the CpG island of NY-ESO-1 and the subsequent robust increase in mRNA expression. Upregulation of NY-ESO-1 rendered specific T cell recognition and lysis of immortalized and primary cell lines. DAC upregulated other pro-inflammatory and immuno-modulatory signatures via CpG demethylation to enhance T-cell mediated targeted cytolysis of GBM.

CONCLUSION

Hypomethylating agents like DAC upregulate immunogenic signatures in primary and immortalized GBM cells, rendering them susceptible to antigen specific T-cell targeting. These pleiotropic effects demonstrate strong preclinical rationale for use of DAC to sensitize GBM for targeting by immune therapies.
IMMU-41. IMMUNOLOGICAL TARGETING OF SLOW-CYCLING CELLS TO PREVENT RECURRENCE IN GBM
Authors: Chakraborty Avirup , Conforti Cole , Sobanjo Olusegun , Hodge Ethan , Engelbart Mia , Castillo Paul , Flores Catherine , Huang Jianping , Mitchell Duane , Deleyrolle Loic
Published: November 2023

Glioblastoma (GBM) is the most common primary malignancy of the central nervous system (CNS) and is typically fatal due to recurrence despite aggressive treatment. Targeting residual cells after surgical tumor removal is challenging due to the infiltrative nature of GBM. It is crucial to develop effective adjuvant therapies that can combat the drivers of disease recurrence. Traditional anticancer treatments tend to eliminate rapidly dividing cells while sparing dormant or infrequently dividing populations. Numerous studies have identified slow-cycling cells (SCCs) in various cancers, including high-grade glioma, which are resistant to therapies. Our laboratory has discovered SCCs in high-grade glioma, which are highly infiltrative and treatment-resistant cells responsible for driving recurrence. It is imperative to develop an effective strategy to specifically eliminate this cell population in order to reduce recurrence and improve survival rates. Importantly, these cells have a defined cellular niche that contains potentially immunogenic neoantigens, making them suitable targets for immune-based therapies. Our primary objective is to utilize SCC antigens in the form of RNA or peptides to stimulate the immune system and enable it to identify and target treatment-resistant clones. By focusing on these crucial drivers of recurrence, our aim is to achieve strong and effective tumor control. Our research findings indicate that our approach effectively primes T cells to identify and target treatment-resistant cells in glioma. Our results demonstrated that T cells specific to slow-cycling cells (SCC-T cells) showed greater activation when exposed to treatment-resistant tumor cells, as evidenced by increased differentiation of CD8 cells and enhanced development of effector and memory cells. Furthermore, SCC-T cells exhibited the highest level of anti-tumor activity, resulting in a significant reduction in tumor cell proliferation and an increase in apoptosis. Taken together, these results highlight the effectiveness and superiority of our SCC-based immunotherapy platform in targeting treatment-resistant glioblastoma cells.
IMMU-45. REVERSIBLE PARKINSONISM AFTER BCMA-DIRECTED CAR T CELL ADMINISTRATION
Authors: Gewirtz Alexandra , Mailankody Sham , Usmani Saad , Santomasso Bianca
Published: November 2023

B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR)T cell therapy has revolutionized the treatment of patients with relapsed or refractory multiple myeloma (MM), resulting in FDA-approval of two products, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). In addition to immune effector cell associated neurotoxicity syndrome (ICANS), a novel hypokinetic movement disorder resembling parkinsonism has been reported with BCMA-targeting CAR. Cases reported to date have been irreversible or fatal, and guidance on how to manage this complication is limited. Here we describe a patient with MM who developed features of parkinsonism on day 24 post ide-cel infusion which were apparently reversible with supportive care and dexamethasone. A 77 year-old man with MM received standard lymphodepletion followed by ide-cel. He developed grade 1 cytokine release syndrome (CRS) for which he received tociluzumab, followed by transient expressive aphasia (grade 2 ICANS) on day 23. Brain MRI showed no structural abnormality. On day 24 he developed new tremor and gait impairment. Neurologic examination revealed cogwheeling in bilateral wrists, hypomimia, soft speech, and slowed gait. Lumbar puncture and electroencephalogram were unremarkable. FDG-PET brain did not show basal ganglia hypometabolism or abnormal avidity. Lymphocyte percentage was elevated and correlated with a high level of circulating CAR+ T cells. He was started on dexamethasone 10 mg q day, receiving a total of 17 days of steroids with improvement in symptoms. At day 60, ambulation was improved and cogwheeling and hypomimia resolved. By day 90, all neurological symptoms had resolved. Improvement remained sustained as of last follow up day 120. To our knowledge, this is the first case report of steroid responsive parkinsonism after BCMA-CAR therapy. Our report supports close neurological monitoring of patients beyond 30 days after BCMA-CAR and suggests that intervening early in the setting of hypokinetic movement disorders may lead to sustained reversal of symptoms.
IMMU-52. LOW-INTENSITY PULSED ULTRASOUND CONDUCTS ANTIGEN-INDEPENDENT T CELL HOMING INTO THE BRAIN PARENCHYMA WITH THE INTACT BLOOD-BRAIN BARRIER
Authors: Gallus Marco , Saijo Atsuro , Haegelin Jeffrey , Chuntova Pavlina , Yamamichi Akane , Lakshmanachetty Senthilnath , Okada Hideho
Published: November 2023

The blood-brain barrier (BBB) protects the brain parenchyma from excessive inflammation but also leads to poor immune cell homing, hampering the success of immunotherapies, such as ones for low-grade glioma, where the BBB is intact. Low-intensity pulsed ultrasound (LIPU) combined with the application of microbubbles allows the non-invasive, transient opening of the BBB and recent studies have observed immune cell infiltration into malignant gliomas following LIPU. While these data warrant mechanistic investigations on the effects of LIPU in preclinical settings, most mouse models of malignant glioma already display BBB disruption. Therefore, to study whether LIPU affects antigen-specific immune cell trafficking through the BBB, we created a novel immunocompetent mouse model of non-tumor bearing mice that display an intact BBB and express a minigene cassette encoding for four immunogenic peptides in glia cells under the glial fibrillary acidic protein (GFAP) promotor. These peptides are either presented by major histocompatibility complex (MHC) class I: human melanoma antigen glycoprotein (gp) 100 and lymphocytic choriomeningitis virus (LCMV)gp31) or class II: LCMV gp66 and tyrosinase-related protein 1. Minigene expression in astrocytes induced antigen-specific T cell proliferation and Interferon-γ release in vitro. Intravenous adoptive T cell transfer of naïve or respectively CD3/CD28-coactivated antigen-specific CD 8 T cells targeting gp100 peptide followed by immediate LIPU treatment induced T cell homing into the CNS parenchyma, and astrocyte-T cell interaction was confirmed by ex-vivo two-photon imaging. Furthermore, some animals that underwent immediate LIPU treatment after transfer of preactivated antigen-specific T cells developed neurological deficits such as ataxia, while no deficits were observed in those animals that underwent LIPU but did not receive T cells or received activated T cells but did not undergo LIFU treatment. In conclusion, LIPU might be a novel effective tool to support antigen-independent immune cell homing with the intact BBB.
IMMU-55. THERAPEUTIC WINDOW ENABLING ERADICATION OF RESIDUAL GLIOMA STEM CELLS BY INTRACRANIAL NK CELL AND EXTRACELLULAR VESICLE-MEDIATED THERAPY FOLLOWING TEMOZOLOMIDE-INDUCED TUMOUR DEPOPULATION
Authors: Meehan Brian , Adnani Lata , Zhu Xianbing , Tawil Nadim , Garnier Delphine , Nakano Ichiro , Huang Sidong , Rak Janusz
Published: November 2023

Glioblastoma (GBM) is an incurable brain cancer, where dismal outcomes result from disease recurrence driven by tumour-initiating glioma stem cells (GSCs). GSCs survive and expand in the brain after surgery, radiation and temozolomide (TMZ) amidst weak immune and natural killer (NK) cell surveillance. NK cell-mediated killing of GBM cells occurs at effector to target rations precluding effective eradication as enforced by clinical trials with autologous NK cells in an adjuvant setting. Here we explore in a human GSC xenograft model whether tumor depopulation using high dose Temozolomide (TMZ) could create a window of curative opportunity for endogenous or exogenous NK cells. We observed that while subcutaneous (sc) xenografts of patient derived GSCs are infiltrated by endogenous functional (NCR1+) NK cells in SCID mice, the corresponding intracranial (ic) tumours remained NK cell depleted. In NK-deficient NSG mice, neither site contained functional NK cells. Notably, while TMZ caused near complete regression of GSC xenografts in both strains of mice and both locations (sc and ic), this was followed by recurrence of drug resistant lesions in all cases except NK-infiltrated sc SCID xenografts. This effect was obliterated by anti-sialo GM1 treatment. To explore whether direct delivery of NK cells into depopulated intracranial tumours would change the lethal course of the disease, mice were injected with GSCs ic, and upon tumour formation were treated with a sequence of TMZ (systemically), and two days later with irradiated NK92MI. Remarkably, this combined therapy completely obliterated recurrent disease. To assess whether NK92MI cells could be replaced by their derived extracellular vesicles (NK-EVs), the latter were injected i.c. post TMZ in GSC xenograft bearing mice. A single injection of NK-EVs resulted in tumour eradication in some but not all mice. Thus, chemotherapy-dependent tumour depopulation may create a unique window of opportunity for curative NK-mediated immunotherapy in GBM.
INNV-04. RAPID CLINICAL AND RADIOLOGICAL RESPONSE TO BEVACIZUMAB IN A PATIENT WITH SCHWANNOMATOSIS
Authors: Yankelevich Maxim , Kaiser Kaydee , Zakalik Karol , Krishnan Anant , Fullmer Joseph
Published: November 2023

Limited evidence exists for optimal management of schwannomatosis, the least common neurofibromatosis syndrome characterized by multiple schwannomas and intractable pain in the absence of vestibular schwannomas and germline NF2 mutation. We present a case of a 32-year-old man with a family history of schwannomas who had been dealing with multiple paraspinal schwannomas throughout entire spine, neurological deficits and chronic severe pain since high school. He had multiple laminectomies with resection of schwannomas. By the time neurooncologist saw the patient he had been on daily narcotics for more than 10 years, was not ambulatory due to paraparesis and was dependent on chronic Foley catheter for urination. He was found to have SMARCB1 c.93G >A germline mutation that has not been reported before. Total spine MRI demonstrated further progression of multiple spinal schwannomas with cord compression. The patient started on bevacizumab 10 mg/kg IV every 4 weeks (the first dose 5 mg/kg) but had to have an 8-week interval between his second and third cycle because of slowly healing pressure ulcers over bilateral upper buttocks. The patient started to show improvement in leg movements and strength after 2 cycles, his urinary catheter was discontinued, and he started urinating on his own after 3 cycles of bevacizumab. MRI obtained after 3 cycles demonstrated decreasing size and enhancement of multiple schwannomas. The patient continued bevacizumab every 4 – 6 weeks and continued with clinical improvement of strength and mobility. He started to stand with support for several minutes after 6 cycles of bevacizumab and reported better control of pain. He started outpatient physical therapy sessions. The plan is to continue bevacizumab therapy long term. This case demonstrated efficacy of bevacizumab as an alternative treatment option to improve quality of life and avoid surgeries in patients with this rare debilitating condition.
INNV-11. USE OF IVOSIDENIB IN THE TREATMENT OF LOW GRADE GLIOMAS
Authors: Ribeiro Anatevka , Ney Douglas
Published: November 2023

IDH 1 and IDH 2 are crucial metabolic enzymes which covert isocitrate to alpha-ketoglutarate. During this process, NADP is reduced to NADPH. Mutant IDH produces an oncometabolite, D-2 hydroxyglutarate (2-HG). Elevated 2-HG levels interfere with epigenetic regulation and cellular metabolism leading to oncogenesis and have been postulated to play a role in multiple malignancies. Mutations in IDH1 and IDH2 have been found in AML, cholangiocarcinoma, myeloproliferative, myelodysplastic syndromes, and low-grade gliomas. IDH inhibitors, although not FDA approved for treatment of glioma, have shown promise as a treatment for low-grade gliomas with IDH mutation in clinical trials. Ivosidenib is an orally available inhibitor of IDH1. We examined patients with oligodendroglioma treated off-label with ivosidenib. RANO criteria for low grade glioma was used to determine radiographic response following ivosidenib initiation. Patient ages 28 , 37 , and 37 females with oligodendroglioma, IDH1 mutated, 1p/19q co-deleted, WHO grade 2 were treated with ivosidenib. Treatment was initiated between August 2022 and March 2023. Two patients had two prior recurrences each while the third patient was treated in the neoadjuvant setting following subtotal resection. Two had stable disease as best response at follow-up of 7 and 17 months while the third is awaiting interval follow up. Duration of ivosidenib therapy was 9, 19, and 3 months respectively and is ongoing in all patients. Only grade 1 leukopenia was observed in one patient which resolved without intervention. No seizures since surgery were observed in two patients, while yearly focal seizures occurred in the third patient. Median progression free survival was not able to be determined, however preliminary data reveals stable disease as best response in all three patients without side effects or increased seizure frequency. IDH inhibitors continue to be an area of interest and ongoing research in the treatment of low-grade glioma.
INNV-12. DEMOGRAPHICS, PRESCRIBING PATTERNS, AND SATISFACTION OF HEALTHCARE PROVIDERS WHO PRESCRIBE TUMOR TREATING FIELDS (TTFIELDS) THERAPY TO PATIENTS WITH GLIOBLASTOMA
Authors: Shockley Shermona , Gwyn P Gage , Palmesino Elena , Batzianouli Eleni , Johnson Heather
Published: November 2023

BACKGROUND

TTFields are electric fields that disrupt cellular processes critical for cancer cell survival. TTFields therapy was approved for recurrent and newly diagnosed glioblastoma (GBM) in 2011 and 2015, respectively, and here we report on the demographics, prescribing patterns, and satisfaction of TTFields therapy from healthcare providers (HCPs) throughout the US.

METHODS

In 2022, HCPs completed surveys regarding their satisfaction in prescribing TTFields therapy to patients with GBM, based on their experiences with the device system (NovoTTF-200A; Novocure® GmbH).

RESULTS

Overall, 32 HCPs completed the survey; all respondents had prescribed TTFields therapy in the prior 6 months. Respondents were physicians (66%), nurse practitioners/advanced practice registered nurses (22%), and physician’s assistants (12%); specialties included radiation oncology (50%), neuro-oncology (41%), medical oncology (7%), and neurosurgery (3%). A balance in practice settings was represented: academic/university (34%), cancer specialist center (28%), private practice (22%), and community (16%). Overall, 44% of HCPs reported having ≥37 months experience prescribing TTFields therapy. Most respondents (69%) had prescribed TTFields therapy to 1–5 patients, with 75% reporting no change in volume of treated patients over the past 6 months. Satisfaction was high for patient support services (66% very satisfied; 16% satisfied) and prescription support processes (66% very satisfied; 31% satisfied). There were high overall satisfaction levels with the use of virtual educational resources, certification training, and educational materials for providers and for patients (≥88% very satisfied/satisfied rating each).

RESULTS

were similar for academic and non-academic respondents.

CONCLUSION

These survey data provide insights regarding the demographics and prescribing patterns of HCPs providing TTFields therapy to patients with GBM. These data indicate a high degree of satisfaction with the prescription process and support. Increasing awareness of support programs and resources remains important in overcoming barriers to TTFields therapy initiation to optimize patient experience.
INNV-13. PREDICTION OF MGMT METHYLATION FOR GLIOBLASTOMAS USING AI MODELS. A COST-EFFECTIVE FRAMEWORK FOR LOW AND MIDDLE-INCOME COUNTRIES
Authors: Restini Felipe , Yoshimoto Fernanda Hayashida , de Brito Leticia Hernandes , Vaz Nascimento José Eduardo , Mancini Anselmo , Mendes de Sousa Cecilia Feliz Penido , Starling Maria Thereza Mansur , Hanna Samir Abdallah , Marta Gustavo Nader , Neves Junior Wellington Furtado Pimenta
Published: November 2023

BACKGROUND

MGMT methylation (MGMTmet) is prognostic and predictive for patients with glioblastoma (GBM). However, financial constraints limit access to molecular tests, especially in low and middle-income countries. Artificial intelligence (AI) tools have emerged as a potentially cost-effective solution for identifying MGMTmet. Therefore, we are investigating if an AI model could select those at higher risk to present positive results for molecular confirmation, thus making a better resource allocation.

METHODS

We have selected GBM patients from the public image bank, The Cancer Imaging Archive, and we included all patients with a molecular evaluation of MGMTmet. We defined our volume of interest based on the ESTRO-ACROP 2016 guideline for GBM radiotherapy contouring and then extracted the radiomic features. The collected features underwent structured analysis, and a prediction model for MGMTmet was developed. We used a Random Forest algorithm to identify the most relevant features. Subsequently, the dataset was divided into training and validation sets.

RESULTS

We examined 100 patients with histologically classified high-grade gliomas and wild-type IDH, Sixty-one were unmethylated, and 39 were methylated. In this cohort, over 39,000 features were extracted. To avoid noise and overfitting, the 13 most predictive features were selected. They belong to the following feature classes: demographic, first order, Gray Level Size Zone Matrix, and Gray Level Co-occurrence Matrix. The preliminary model achieved an accuracy of 80% for predicting MGMTmet.

CONCLUSION

our preliminary results show a promising role for AI models in screening patients for molecular testing. This initiative demonstrates the utilization of research to bridge the public health gap. By sharing experiences and fostering collaboration, physicians can work towards mitigating healthcare inequalities in low-middle-income countries. In our future perspectives, we plan to enhance the algorithm's efficacy by incorporating qualitative human-generated features and expanding our sample size.
INNV-15. OPTIMIZING THE ROLE OF THE ADVANCED PRACTICE PROVIDER IN THE MANAGEMENT OF A SINGLE PATIENT INVESTIGATIONAL NEW DRUG (IND)
Authors: Jacobs Susanne D , Johnson Margaret O , Miller Elizabeth S , Patel Mallika , Affronti Mary L
Published: November 2023

BACKGROUND

Single patient Investigational New Drug (IND) applications are a way through which experimental therapies may be accessed by patients with cancer especially if a clinical trial is not available. However, initiating and managing a single patient IND is complex. We will outline our approach used at an academic teaching center to leverage the skills and scope of practice of advanced practice providers (APPs) to facilitate successful initiation and monitoring of individual patients who may be receiving an investigational drug under a single patient IND.

METHODS

We describe a single case of a 52-year-old male with a left thalamic glioblastoma treated with standard of care and monitored off therapy from May 2021 until November 2022. Extended genomic profiling of his tumor at time of biopsy revealed a FGFR3-TACC3 fusion and MGMT promoter methylation, and the decision was made to pursue a single patient IND for anlotinib for use in combination with temozolomide.

RESULTS

Following permission from the US Food and Drug Administration (FDA) to proceed and IRB chair concurrence, the MD and APP conferred with the investigational and clinical pharmacists regarding procurement and dispensing of the drug, in addition to surveillance and associated toxicities. The APP obtained consent, collected data on monitoring parameters and adverse events, checked for drug interactions with the patient’s routine medications, ordered and reviewed all treatment related MRIs, labs, and EKGs, and coordinated with ophthalmology for baseline and monthly eye exams. Performance of initial and follow-up exams, ongoing toxicity review and management, and care coordination with the local oncology team were completed by the APP.

CONCLUSION

As first point of contact for the patient and family, the APP plays a key role in glioma research within the multidisciplinary team by providing ongoing symptom management, education, and monitoring for patients receiving investigational drugs.
INNV-21. EXTENDED SURVIVAL OF RECURRENT ANAPLASTIC OLIGODENDROGLIOMA PATIENT WITH GOOD FUNCTIONAL STATUS ON LONG TERM PEMBROLIZUMAB AND BEVACIZUMAB THERAPY - A CASE REPORT
Authors: Moldenhauer Matthew , Myung Joon , Fu Beverly Dan , Kong Xiao-Tang
Published: November 2023

INTRODUCTION

Anaplastic oligodendroglioma (AO) is a rare high-grade glioma. Standard of care include resection, radiotherapy followed by chemotherapy. However, effective treatment for recurrent AO is limited. Here we report pembrolizumab (Pembro) + bevacizumab (Bev) therapy for recurrent AO.

CASE

A 55-year-old male had a brain mass discovered on MRI in 2012 and received no treatment until resection in 2014. He underwent second tumor resection in late 2016 and pathology demonstrated an AO, WHO grade 3. He received radiation followed by PCV regimen in 2017. Ten months later in March 2018, he had tumor progression on PCV. Temozolomide was started. Two months later, Bev (10 mg/kg) was initiated in May 2018 due to further progression. After 12 months of Bev therapy, in mid-2019, Pembro was added due to new and enlarged lesions on MRI. After 18 months of q-3-week Bev (10mg/kg) + Pembro, Bev was on hold in December 2020 due to multiple TIAs. Single agent Pembro was continued for 6 months until April 2021 when his brain MRI showed increased enhancement. Then q-3-week Bev was resumed at a reduced dose (7.5mg/kg). These dual agents continued for 14 months until June 2022 when Bev dose was further reduced to 5mg/kg due to side effect. Bev was on hold again in December 2022 due to high Urine Protein/Creatinine ratio. Single agent Pembro was continued until May 2023 when lower dose Bev (2.5mg/kg) was resumed after MRI showed one subcentimeter new lesion. The small lesion is stable again on q-3-week 2.5 mg/kg Bev+Pembro. The patient has been clinically functional on Bev+Pembro treatment.

DISCUSSION

Four years of adjuvant pembrolizumab and tailored dose of bevacizumab have resulted in long term repeated stabilization of recurrent AO. The dose and duration of bevacizumab use need to be tailored to minimize adverse effects and to maintain positive effects.
INNV-22. TEMOZOLOMIDE DESENSITIZATION AND CONSIDERATIONS FOR IMPLEMENTATION IN AN ACADEMIC MEDICAL CENTER: A CASE REPORT
Authors: Wojkowski Jenna , Palazis Aphrodite , Ogbogu Princess , Wessell Kathryn Ruda , Roberts Patricia , Newton Herbert
Published: November 2023

Temozolomide is an alkylating agent commonly used in the treatment of central nervous system (CNS) malignancies, including glioblastoma multiforme (GBM). Rashes have been noted to occur in about 19% of patients receiving temozolomide, with severe rashes ( > grade 3) only noted in about 1% of patients. Here we report the case of a 42-year-old female patient diagnosed with GBM who presented with widespread, progressive urticaria on her chest, abdomen, back, legs, and arms during her first adjuvant cycle of temozolomide. With temozolomide being a standard of care in the treatment of GBM, our team decided to attempt a second adjuvant cycle via desensitization prior to exploring alternative treatment options. There is currently no standard for temozolomide desensitization; however, there are a few published case reports. Based on existing literature, a protocol was developed and utilized for a total of four additional cycles. During the second, third, and fourth desensitization cycles, which were completed in the outpatient setting, the patient experienced headache, urticaria, and nausea/vomiting. A steroid taper was prescribed and the patient completed the desensitization protocol and the remainder of each of the aforementioned cycles without further issues. Our case report provides a review of the current literature and discusses operational considerations and limitations related to temozolomide desensitization protocol development and execution. This case illustrates the need for additional data to determine efficacy of desensitization compared to standard dosing regimens.