bluuebunny/crossref_metadata_2025 huggingface dataset:
DDDR-06. ENHANCING GLIOBLASTOMA TREATMENT WITH MOLYBDENUM DISULFIDE(MOS2) NANOMATERIALS AND ULTRASOUND-TRIGGERED TUMOR GROWTH INHIBITION
Authors: Chen Tse-Yu , Yang Meng-Yin
Published: November 2024

INTRODUCTION

Glioblastoma, known for its high mortality rate and limited treatment options, poses a persistent challenge in oncology. Despite advances in surgery, radiation, and chemotherapy, patient outcomes have seen only marginal improvements, with ongoing issues of high recurrence and low survival rates. The advent of nanotechnology, particularly the emergence of Molybdenum disulfide (MoS2) nanoparticles, offers new perspective in semiconductors, energy storage as well as cancer therapies. With its unique physical and chemical properties, MoS2 nanoparticles might be promising in its potential roles in the battle against cancer. We aimed to see whether ultrasound-treated MoS2 nanoparticles can interfere with growth of glioblastoma cells.

METHODS

MoS2 nanoparticles were added to the medium of glioblastoma cells and ultrasound treatments were given. We monitor the cell count as well as cell migration after the treatments.

RESULTS

MoS2 nanoparticles was found to significantly interfere with tumor cell proliferation and boost the production of reactive oxygen species (ROS). These reactive oxygen species were crucial for the apoptosis of brain tumor cells when in the right concentration. Our analysis also demonstrated that MoS2 impedes cell migration and infiltration, effectively halting tumor expansion. Additionally, Comet assay techniques confirmed extensive DNA damage in the treated cells, highlighting MoS2’s potent DNA-altering capabilities which promote programmed cell death.

CONCLUSION

The implications of these findings are significant, establishing a solid scientific basis for employing MoS2 nanoparticles as a targeted anti-cancer agent for brain tumors. While this study underscores the transformative potential of MoS2 nanoparticles in clinical oncology, it also acknowledges limitations such as the need for further clinical trials to evaluate efficacy and safety in humans. Key Words: MoS2 nanoparticles, Ultrasound treatment, Reactive oxygen species, Comet assay, Programmed cell death
DDDR-13. OPTIMIZING BRAIN CANCER THERAPY: BALANCING TUMOR ERADICATION AND NORMAL TISSUE PRESERVATION WITH BPM31510
Authors: Khojasteh Abbas , Kendirli Mustafa Tansel , Narain Niven , Nagpal Seema , Nastke Maria-Dorothea , Gesta Stephane , Recht Lawrence
Published: November 2024

The challenges translating glioblastoma therapies lie in safeguarding normal neuronal and glial tissue. Considering that the central nervous system has the lowest regenerative capacity, the exclusive focus on tumor eradication while neglecting normal tissue response, impedes proper healing. This oversight leads to toxicities ultimately culminating in patient demise with marginal gain in survival. BPM31510 is a nanodispersion encapsulating highly hydrophobic oxidized Coenzyme Q10 (CoQ10), allowing for delivery of supraphysiological CoQ10 concentrations into cancer cells. Initial investigations demonstrated differential responsiveness between cancer and non-cancer cells in vitro, an effect associated with high superoxide levels exclusively in cancer cells. To evaluate this divergence between cancer and non-cancer cells, a competitive co-culture cell-based assay was developed with labeled pairs of glioblastoma and non-cancer cells incubated up to three weeks with various concentrations of BPM31510 to ascertain optimal concentration leading to preferential growth of non-cancer cells. Human astrocyte (HA), mouse fibroblast (NIH 3T3), and rat astrocyte (TNC1) cells were paired with U251 human glioma, mouse GL261 and rat C6 glioma, respectively. Cell growth and spatial extent of the plate containing non-cancer or tumor cells were monitored every other day. Using doxorubicin as control, no dosage was discerned in which non-cancer cells exhibited advantage over tumor cells (i.e., either cultures became all tumor cells or both cell lines were eradicated). Using various concentrations of BPM31510, we identified an optimal dose in which cancer cells diminished while non-cancer cells predominated, reflected by markedly elevated mitochondrial superoxide levels in cancer cells prior to cell death. A co-culture cell-based assay was developed to identify an optimal dose of BPM31510 with selective preservation of non-cancer cells alongside tumor cell death. This approach elucidates developing a “fine tuning” strategy, wherein BPM31510 is titrated over time, thereby promoting normal tissue and healing, and ultimately leading to superior and prolonged functional outcomes.
DDDR-17. A FACILE HIGH THROUGHPUT DRUG SCREENING PLATFORM ENABLES THE CONSTRUCTION OF A PHARMACO-PROTEOGENOMIC INTERACTION LANDSCAPE IN GLIOBLASTOMA
Authors: Zhang Ze-Yan , Ding Yingwen , Ezhilarasan Ravesanker , Graciani Melanie , Modrek Aram , Karp Jerome , Sulman Erik
Published: November 2024

Despite decades of intensive research, the number of treatment options for glioblastoma (GBM), a devastating disease, remains very limited. The vast tumor heterogeneity of GBM and the blood-brain barrier (BBB) represent major hurdles to developing effective therapeutics. Here, we present CARPOOL, a high-throughput therapeutic screening approach designed to facilitate accurate and parallel interrogation of numerous patient-derived GBM spheroid cultures (GSCs), capturing the disease’s heterogeneity. We validated CARPOOL in vitro and in vivo and then applied it for drug screening using a library of over 700 BBB-penetrating compounds across 23 omics-profiled GSCs. This screening identified numerous potential anti-GBM compounds, including previously non-oncology drugs. Clustering analysis provided insights into the mechanisms of action of some of the compounds. Coupling these results with omics data of the GSCs enabled the identification of genetic, subtype, and gene expression-based predictors of drug sensitivity. Our study presents a new approach for advancing drug screening and in vivo preclinical therapy evaluation for precision oncology. Furthermore, our construction of a pharmaco-proteogenomic interaction landscape offers a valuable resource for both basic and translational glioblastoma research.
DDDR-49. REPURPOSING OF THE ANTI-VIRAL DRUG RIBAVIRIN AS A POTENTIAL MENINGIOMA THERAPEUTIC
Authors: Casaos Joshua , Perryman Travis , Harary Maya , Vitte Jeremie , Shah Shilp , Na Brian , Giovannini Marco , Everson Richard
Published: November 2024

INTRODUCTION

High grade meningiomas provide significant challenges to treatment. Recent works have demonstrated meningiomas to express higher levels of the epigenetic regulator enhancer of zeste homolog 2 (EZH2), as well as the protein eIF4E, a key player in translation. These two molecules are demonstrated targets of the well tolerated antiviral drug, ribavirin, which has recently shown promise as an anti-neoplastic agent. Based on these findings we sought to investigate the effect of ribavirin on meningioma tumorigenesis utilizing in vitro and in vivo meningioma models.

METHODS

Several immortalized human meningioma cell lines, three immortalized mouse meningioma cell lines, and a panel of human primary cell cultures were assessed. Cell proliferation, cell colony formation, clonogenic assay, and cell death were assessed. Furthermore, we tested ribavirin efficacy in vivo utilizing two aggressive high grade syngeneic orthotopic allograft meningioma models in FVB WT mice.

RESULTS

We provide evidence that ribavirin significantly impairs meningioma cell growth and proliferation, and induces cell death in vitro. Most importantly, we demonstrate that ribavirin alone significantly improves the survival of mice orthotopically implanted with MGS2 cells. Ribavirin-treated animals exhibited a significantly increased median survival (67 days) compared to controls (41 days; p=0.0009;) in an orthotopic convexity meningioma xenograft model. Furthermore, ribavirin treatment resulted in increased survival in an orthotopic skull base meningioma xenograft model.

CONCLUSION

Our work establishes that ribavirin is effective against meningioma in vitro and in vivo. Ribavirin treatment reduced proliferation in all cell lines tested, in both high and low grade models, induced cell death, and prolonged survival in two aggressive in vivo models, potentially via modulation of the EZH2 and eIF4E pathways. Given the lack of medical therapy for high grade meningiomas, these findings provide a framework for further investigation into ribavirin’s effects on meningioma tumorigenesis, and demonstrate ribavirin as a potential new therapeutic option in the treatment of meningioma.
EOLP-01. PROPOSED FRAMEWORK FOR A PILOT MULTIDISCIPLINARY BEREAVEMENT FOLLOW-UP AND BRAIN AUTOPSY REVIEW FOR BEREAVED CAREGIVERS IN PEDIATRIC NEURO-ONCOLOGY
Authors: Wright-Nadkarni Mariah , Schaefer Megan , Moscato Emily , Stanek Joseph , Gerhardt Cynthia , Fouladi Maryam , Patel Priyal , Lazow Margot
Published: November 2024

INTRODUCTION

Brain tumors remain the leading cause of cancer-related death in children. The death of a child is distressing for caregivers and often associated with negative psychosocial outcomes. Bereaved caregivers frequently desire ongoing support after their child’s death. At our institution, brain autopsies with the option for tissue donation to research are offered to all families after the death of a child. Specific follow-up conducted to date and review of autopsy results have varied widely. We propose a pilot study to (1) evaluate feasibility of a comprehensive, multidisciplinary bereavement follow-up meeting with autopsy results review and grief supports for bereaved caregivers in pediatric neuro-oncology at Nationwide Children’s Hospital and (2) assess caregiver and provider perceptions regarding this follow-up meeting using mixed-methods design.

METHODS/DESIGN

Bereaved caregivers of children with a brain tumor who died and underwent brain autopsy through our institutional tissue donation protocol will be offered a follow-up meeting after their child’s death. The follow-up meeting will test an established PICU bereavement framework in the pediatric neuro-oncology setting with the addition of brain autopsy results review. Meetings will include caregivers and providers from neuro-oncology, palliative care, and psychosocial team (e.g., psychologist, social worker, chaplain). Caregivers will complete a Likert-scale questionnaire followed by a semi-structured interview via telephone. The goal is to conduct 7-10 meetings. Providers will participate in a focus group to provide feedback. Interviews and the focus group will be recorded, transcribed, and analyzed qualitatively. Concepts to be explored include perceived need for follow up; overall experience; satisfaction with structure, modality, and content; and perceived benefit and meaning of autopsy review.

LONG-TERM GOAL

To develop, evaluate, and formalize a comprehensive multidisciplinary bereavement follow-up meeting, guided by caregiver and provider feedback, that can be expanded to other institutions and become a “standard of care” for bereaved caregivers in pediatric neuro-oncology.
EPID-08. PATTERN OF EPIDEMIOLOGICAL DISTRIBUTION OF INTRACRANIAL NEOPLASMS IN NIGERIA FROM 1960: A SYSTEMATIC REVIEW AND POOLED ANALYSIS
Authors: Alare Kehinde , Alare Samson , Adetunji Busayo , Chukwumaeze Chukwunonso , Oluwumi Emmanuel , Periola Abdulazeez , Omoniyo Taiwo , Odesanya Okikioluwa , Adedokun Precious , Adedokun Stephen , Bakwa Nenkimun
Published: November 2024

BACKGROUND

Intracranial neoplasms, encompassing a range of benign and malignant tumors, pose significant health challenges worldwide. This study systematically reviews the epidemiological patterns of intracranial neoplasms in Nigeria from 1960 to the present, providing a comprehensive analysis of their distribution, demographic characteristics, and temporal trends.

METHODS

A systematic review was conducted following PRISMA guidelines, encompassing studies published from 1960 onwards. Databases including PubMed, Google Scholar, and African Journals Online were searched using relevant keywords. Eligible studies were those that reported on the incidence, prevalence, or demographic details of intracranial neoplasms in Nigeria.

RESULTS

A total of 45 studies met the inclusion criteria, encompassing 3,517 cases of intracranial neoplasms. The pooled analysis revealed a significant increase in the incidence of intracranial neoplasms over the study period. The pooled prevalence between the year 1960 to presences is 3.22 (95% CI: 1.66 – 5.22), while the pooled 10-yearly incidence was 3.66(95% CI: 1.67 – 6.32), the incidence rose from 2.18% in 1960-1969 to 4.08% in 2000-2009, and eventually to 4.84% in 2010 – 2019. The most common types of intracranial neoplasms identified were gliomas, meningioma pituitary adenomas; meningioma was the leading type found in adults followed by glioma and pituitary adenoma, while in pediatric age group glioma was leading followed by medulloblastoma, and craniopharyngioma. The demographic analysis indicated a higher prevalence in males compared to females with male-to-female ratio of 1.17:1, with the majority of cases occurring in the fourth to sixth decades of life. Geographic distribution showed higher incidence rates in southern Nigeria especially south east and south west compared to Northern Nigeria, potentially reflecting disparities in diagnostic facilities and healthcare access.

CONCLUSION

This review highlights an increasing trend in the incidence of intracranial neoplasms in Nigeria, with distinct demographic and geographic patterns. The findings underscore the need for improved diagnostic capabilities, enhanced public health strategies, and targeted interventions to address the burden of intracranial neoplasms in Nigeria.
DISP-01. FACTORS AFFECTING POST-ABLATION OUTCOMES AND TRIAL ENROLLMENT IN DIVERSE PATIENTS UNDERGOING LASER INTERSTITIAL THERMAL THERAPY
Authors: Haskell-Mendoza Aden , Gonzalez Ariel , Reason Ellery , Jackson Joshua , Seas Andreas , Zaidi Saif , Mohan Aditya , Lerner Emily , Srinivasan Ethan , Bradbury Claire , II James Herndon , Goodwin C Rory , Fecci Peter
Published: November 2024

BACKGROUND

Laser interstitial thermal therapy (LITT) is a surgical treatment for progressive brain metastases (BM) following stereotactic radiosurgery (SRS). Although LITT has been increasingly accepted, little is known regarding factors influencing presentation and outcomes of patients with diverse backgrounds.

METHODS

Retrospective review of all patients receiving their index LITT treatment for BM at a single center from 2015 – 2023. Patient demographics and geospatial data was used to compare differences in receipt of LITT by race or ethnicity, survival outcomes, and clinical trial enrollment.

RESULTS

From 2015-2023, 137 patients presented for LITT to 146 intracranial lesions. One hundred and six patients (77.3%) were non-Hispanic White (NHW), while among Hispanic or non-White (HNW) patients, 25 (18.2%) were Black or African American, 5 (3.6%) were Asian American, and 1 (0.7%) was Hispanic/Latino. Among HNW patients, women more frequently received LITT (p = 0.022), with skin cancers being a more frequent indication among NHW patients (P = 0.019). NHW patients traveled a median of 62.0 (6.2 – 1045.9) miles to receive LITT vs 25.9 (1.31 – 238.3) miles for HNW patients (p = 0.001). Length of stay, discharge location, or readmission rates did not differ between groups. In multivariate analyses, probability of clinical trial enrollment was less among those of female sex (P = 0.049), HNW race/ethnicity (P = 0.041), or external referral status (P = 0.035), while post-LITT overall survival was predicted by pre-LITT KPS (P = 0.0007) and recurrent tumor on biopsy (P = 0.0002).

CONCLUSIONS

Differences in presentation for LITT by race or ethnicity may be influenced by underlying patient factors, including sex, systemic disease histology, and distance from a treating center, which do not influence post-LITT procedural outcomes or survival. Accordingly, clinical trial enrollment should be prioritized for vulnerable patient populations to realize the full benefits of laser ablation.
DISP-15. FOLIC ACID SUPPLEMENTATION IN WOMEN OF REPRODUCTIVE AGE WITH HISTORY OF INTRACRANIAL TUMOR AND SEIZURES
Authors: Farrukh Alexandra
Published: November 2024

BACKGROUND

Meningiomas and gliomas are the most common intracranial brain tumors. The most common gliomas can be further classified as oligodendroglioma, astrocytoma, ependymoma and glioblastoma. These tumors often cause epilepsy and necessitate the use of anti-seizure medications, posing risks to reproductive-age women due to potential teratogenic effects. The most preferred anti-seizure medications used in pregnancy are levetiracetam and lamotrigine. The American Academy of Neurology advocates folic acid supplementation for women taking anti-seizure medications (ASMs) regardless of type to mitigate these risks.

OBJECTIVE

This retrospective chart review aims to assess the utilization of folic acid supplementation in women of reproductive age with a history of intracranial tumors and seizures.

METHODS

Data were extracted from The Ohio State University Wexner Medical Center’s Epic Electronic Medical Record database using Epic’s “Slicer Dicer” program, spanning a five-year period from March 2019 to March 2024. Inclusion criteria comprised women aged 18-50 years of age with a history of meningioma, oligodendroglioma, astrocytoma, ependymoma, or glioblastoma and a documented history of seizures. Diagnoses were obtained using Systemized Nomenclature of Medicine – Clinical Terms (SNOMED CT). Variables included demographics, tumor type, and anti-seizure medication usage, and folic acid supplementation. Anti-seizure medications included levetiracetam and lamotrigine.

RESULTS

Preliminary analysis of 182 patient charts revealed that less approximately 60% of these patients were prescribed anti-seizure medications. Of these, 3 patients received concurrent folic acid supplementation, despite recommendations from the American Academy of Neurology.

CONCLUSION

Our findings suggest a suboptimal utilization of folic acid supplementation in women of reproductive age with a history of primary brain tumor and seizures with ASM use, highlighting the need for improved adherence to clinical guidelines. Further research is warranted to explore barriers to implementation and strategies to optimize folic acid supplementation in this population.
DISP-19. ETHNIC DISPARITIES IN METASTASIS PATTERNS AND TREATMENT UTILIZATION AMONG METASTATIC BREAST CANCER PATIENTS WITH BRAIN METASTASIS: A RETROSPECTIVE ANALYSIS OF US HEALTH SYSTEMS DATA (2019-2023)
Authors: Podder Vivek , Ranjan Tulika , Bardhan Mainak , Jayram Diya , Mahtani Reshma , Ahluwalia Manmeet Singh
Published: November 2024

INTRODUCTION

The treatment landscape for metastatic breast cancer (MBC) with brain metastasis (BM) has evolved due to novel therapies. However, outcomes remain poor and vary among groups. This study investigated ethnic disparities in metastasis (mets) patterns and treatment use among MBCBM patients (pts).

METHODS

We analyzed deidentified data from seven US health systems in the Guardian Research Network from December 2019 to December 2023. Pts with MBC were categorized by IHC scores: hormone receptor+/HER2-, HER2-low (IHC 1+ or 2+ with negative FISH), HER2 positive, and Triple Negative (TNBC). We used descriptive and comparative statistical analysis.

RESULTS

Of 421 MBC pts, 200 (47.5%) had HER2+, 167 (39.7%) had HR+/HER2-, and 54 (12.8%) had TNBC. 159 (37.7%) were reclassified as HER2-low, primarily from HR+/HER2- (127; 76.0%) and TNBC (32; 59.3%). Bone mets developed in 29.6% of pts, more prevalent in HER2+ (39.5%), TNBC (25.9%), and HR+/HER2- (19.1%) groups. Non-Hispanics showed higher BM prevalence (74.4% vs. 25.6%). HR+/HER2- BM pts had higher bone mets (71.88%) than HER2+ BM (65.82%). TNBC BM pts had the highest rate of liver mets (57.1%). HER2-low BM pts showed mets across liver (40%), lung (34.29%), and bone (68.57%). In the HER2+ BM group, non-Hispanics had higher liver (40.13% vs. 32.35%) and bone mets (69.08% vs. 52.94%) than Hispanics. In TNBC BM group, Hispanics had higher liver mets (66.67% vs. 35%), while non-Hispanics had higher lung mets (32.5% vs. 11.11%). Both ethnic groups in HR+/HER2- category had high bone mets (78.95% vs. 73.33%). There were disparities in the use of CDK4/6 inhibitors, ICIs, and mTOR inhibitors, with Hispanics frequently using them.

CONCLUSION

HR+/HER2- BM pts were most affected by bone mets, followed by HER2+ BM. TNBC BM pts predominantly had liver mets. Non-Hispanics had higher BM prevalence. Hispanics frequently used ICIs, CDK4/6 and mTOR inhibitors, which were more frequently used by Hispanics. Further research should explore these disparities in mets patterns, treatment choices, and responses.
IMMU-02. INTRACRANIAL PROGRESSION IS LESS COMMON IN PATIENTS WITH ADVANCED NSCLC RECEIVING CANCER IMMUNOTHERAPY
Authors: Kemmotsu Naoya , Ninomiya Kiichiro , Otani Yoshihiro , Michiue Hiroyuki , Tanaka Shota , Togashi Yosuke
Published: November 2024

BACKGROUND

Intracranial metastases are common in patients with non-small cell lung cancer (NSCLC) and their prognosis is very poor. Furthermore, intracranial progression is common during systemic therapy due to the inability to cross the blood brain barrier, but the impact of cancer immunotherapy on intracranial progression remains unclear.

METHODS

We analyzed clinical data to evaluate the frequency of intracranial progression in patients with advanced NSCLC treated with PD-1 blockade therapies compared to patients not treated with PD-1 blockade therapies (Approval number: 2201-022). We also evaluated durable responses to PD-1 blockade and analyzed tumor-infiltrating lymphocytes using tumor-rechallenging murine models.

RESULTS

The clinical data analysis showed that the frequency of intracranial progression was significantly lower in patients with advanced NSCLC treated with PD-1 blockade than in patients treated with cytotoxic chemotherapy. In murine models, intracranial rechallenged tumors after initial rejection by PD-1 blockade therapy were suppressed, as observed for subcutaneous tumors. Accordingly, PD-1 blockade increased long-lived memory precursor effector T cells and antigen-specific T cells in intracranial lesions. In contrast, intracranial rechallenged different tumors were not suppressed.

CONCLUSIONS

The CNS has been considered a site in which cancer patients tend to experience progression during systemic therapies, however our results indicate that cancer immunotherapies can prevent intracranial progression, maintaining long-term effects intracranially as well as systemically. (Kemmotsu N. et. al., Int J Cancer, 2024)
IMMU-15. CD74/MIF SIGNALING AXIS DISRUPTION IN BONE MARROW-DERIVED MYELOID CELLS DELAYS MALIGNANT PROGRESSION IN A PRECLINICAL MODEL OF GLIOMA
Authors: Canella Alessandro , Rajendran Sakthi , Nazzaro Matthew , Schmitt Claire , Kreatsoulas Daniel , Wang Wesley , Rajappa Prajwal
Published: November 2024

INTRODUCTION

CD74, a chaperone associated with the major histocompatibility complex class II (MHC-II), plays a crucial role in assembling and transporting MHC-II molecules on the cellular surface. Beyond its physiological function in antigen presentation, CD74 is a negative regulator of inflammation, and its dysregulation is associated with inflammatory disorders and cancer. Notably, tumor stem cells release macrophage migration inhibitory factor (MIF) to trigger CD74 immunosuppressive signaling in tumor-infiltrating immune cells, thereby abrogating CD8+ T cell activation and promoting angiogenesis. While CD74 expression is known in dendritic cells, macrophages and B cells, our recent findings reveal its upregulation in immunosuppressive macrophages within the low-grade glioma (LGG) tumor microenvironment, and its negative correlation with the survival of adolescent and young adult patients with LGG. HYPOTHESIS. We hypothesize that inhibiting CD74/MIF in immunosuppressive myeloid cells may affect tumor progression and prevent malignant transformation (MT) to high-grade glioma (HGG).

METHODS

To test our hypothesis, we isolated bone marrow cells from immunocompetent RCAS n/tv-a LGG bearing animals, differentiated them into bone marrow-derived myeloid cells (BMDMs), silenced CD74 expression, and co-cultured them with primary CD8+T cells. Moreover, we inhibited CD74/MIF signaling in vivo. RESULTS. Deconvolution analysis of tumor-infiltrating immune cells revealed upregulation of CD74 and its network in myeloid cells during LGG compared to HGG. Silencing CD74 in LGG BMDMs in vitro resulted in the downregulation of genes associated with migration, proliferation, and immunosuppression. The co-culture of LGG CD74KD-BMDMs with CD8+ T cells increased the expression of T cell activation genes. In vivo treatment of LGG mice with MIF inhibitors significantly decreased myeloid cell infiltration in the tumor microenvironment (TME) and prolonged survival.

CONCLUSIONS

These preclinical studies highlight a role for the CD74/MIF signaling axis in glioma and present a novel immunotherapeutic target to modulate the activity of immunosuppressive myeloid cells in order to delay MT.
IMMU-19. PRECLINICAL THERAPEUTIC ACTIVITY AND PET IMAGING OF STING AGONIST 8803 IN GLIOBLASTOMA
Authors: Najem Hinda , Lea Spencer T , Tripathi Shashwat , Hurley Lisa , Chen Chao-Hsien , Sooreshjani Moloud , Bowie Michelle L , Hartley Genevieve , Pacheco Sebastian , Dmello Crismita , Lee-Chang Catalina , Procissi Daniel , Lukas Rimas V , Lesniak Maciej S , Ashley David M , Curran Michael A , Balyasnikova Irina , Heimberger Amy B
Published: November 2024

STING (stimulator of interferon genes) activation triggers interferon (IFN) release within the tumor microenvironment from myeloid cells and other cell types, inducing proinflammatory anti-tumor immune responses. The small molecule STING agonist, 8803, elicits long-term survival in 56% (QPP4; p=0.0003) to 100% (QPP8; p<0.0001) of mice with orthotopically implanted immune checkpoint-resistant glioblastoma models after 2-3 doses. In humanized mice, in which glioblastoma-cell STING is epigenetically silenced, 8803 therapeutic activity is maintained. The combination therapy of 8803 with anti-PD-1 relatively further enhances survival in immune checkpoint-resistant models. Ex vivo flow cytometry and proteomic sequential multiplex profiling during the therapeutic window demonstrate global immunological reprogramming, specific tumor-antigen immune responses, increased tumor immune effector trafficking, and release of IFN. It has been shown that IFN signaling augments intracellular nucleotide metabolism and increases [18F]-FLT uptake in pancreatic cancer. We evaluated the longitudinal [18F]-FLT uptake in CT-2A-bearing mice using MRI/PET/CT at days 0, 2, and 4 after intratumoral 8803 delivery. Brain images were acquired before and after [18F]-FLT tracer and 8803 administrations. The CT was used for PET attenuation/correction, and the MRI was used for tumor segmentation. Regional analysis of PET-derived [18F]-FLT SUV maps used advanced image processing approaches as a function of time to enhance the voxel-by-voxel interpretation of the acquired images. [18F]-FLT uptake increased from baseline in all mice treated with 8803 compared to control mice with a peak at 48-96 hours. Concordant sequential multiplex immunofluorescence demonstrated that the STING expression was prominent along the tumor vasculature, myeloid, and tumor cells. p-IRF-3 expression, reflective of STING pathway activation, showed a diffuse pattern after treatment. Based on the preclinical data, PET imaging at 48-96 hours post-treatment represents the appropriate imaging modality and timepoint to maximize the ability to detect STING-dependent changes for a therapeutic strategy that reprograms the glioblastoma microenvironment and improves survival across multiple preclinical models of glioblastoma.
IMMU-22. TWIST1-MEDIATED ENDOTHELIAL PLASTICITY DRIVES GLIOBLASTOMA RESISTANCE TO CAR T IMMUNOTHERAPY
Authors: Yang Fan , Akhtar Md Naushad , Gong Yanqing , Fan Yi
Published: November 2024

Glioblastoma (GBM) is the most common and most aggressive malignant primary brain tumor in adults. Among the most lethal human malignancies, GBM is highly resistant to cytotoxic treatments and molecularly targeted therapies, and also generally refractory to T cell–based immunotherapies, largely due to their immunologically cold nature, i.e., characterized by a paucity of tumor T cell infiltrates that result from the immunosuppressive microenvironment. Here, we identify a distinct mechanism driven by spatiotemporal interaction of leukocytes with tumor stromal cells, namely, mesenchymal-like population of endothelial cells (ECs) form an immunosuppressive vascular niche that regulates macrophage polarization and induces GBM resistance to CAR T immunotherapy. Our single-cell transcriptome analyses of human and mouse GBM tumors identify a subpopulation of ECs acquire robust immunosuppressive phonotypes to drive alternative macrophage polarization. These ECs are spatially localized proximately to immunosuppressive macrophages and selectively express Twist1. Furthermore, we reveal a Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which Twist1+ tumor ECs produce osteopontin to locally promote immunosuppressive macrophage phenotypes. Genetic or pharmacological ablation of Twist1 reverses macrophage-mediated immunosuppression and enhances T cell infiltration and activation, leading to reduced GBM growth and extended mouse survival. Importantly, pharmacological inhibition and lipid nanoparticle-mediated targeted inactivation of Twist1 overcome GBM resistance to Egfrviii CAR T cell immunotherapy. Thus, these findings uncover a spatially restricted mechanism controlling vasculature-mediated tumor immunity and suggest that targeting endothelial Twist1 may offer exciting opportunities for GBM immunotherapy.
IMMU-26. TARGETING CHK2-YBX1/3 INTERACTION TO OVERCOME IMMUNOSUPPRESSION IN GLIOMAS
Authors: Chen Li , Harish Mahalakshmi , Kalas Vasilios , Habashy Karl , Arrieta Victor A , Kim Kwang-Soo , Yeeravalli Ragini , Tiek Deanna M , Song Xiao , Mishra Snehasis , Wang Lu , Lee-Chang Catalina , Ahmed Atique U , Venkatraman Prasanna , Rocklin Gabriel J , Sonabend Adam M , Dmello Crismita
Published: November 2024

Whereas the contribution of tumor microenvironment to the profound immune suppression of glioblastoma (GBM) is clear, tumor-cell intrinsic mechanisms that regulate resistance to CD8 T cells are less studied. We performed an in vivo CRISPR screen to identify glioma intrinsic kinases that contribute to evasion of tumor cells from CD8 T cells. The screen revealed a DNA damage response gene-checkpoint kinase 2 (Chek2) to be the most important kinase contributing to escape from CD8 T-cell recognition. Genetic depletion or pharmacological inhibition of Chek2 with blood-brain-barrier permeable drugs that are in the clinical trials, in combination with PD-1/PD-L1 blockade, led to survival benefit in preclinical glioma models. Analysis of human GBMs demonstrated that Chek2 expression is inversely associated with antigen presentation and T-cell activation. However, the mechanism underlying the immunosuppressive function of Chek2 in gliomas is unknown. Here, we identified that glioma tumor cell intrinsic Chek2 interacts with Y-Box Binding Protein 1 and 3 (Ybx1&3) in ex vivo gliomas using immunoprecipitation followed by mass spectrometry. Independently, YBX3 was also identified as one of the most significantly phosphorylated protein upon Chek2 knockout using phosphoproteomics analysis. The YBX1&3 are DNA/RNA binding proteins implicated in transcriptional regulation of immune-modulatory genes. In silico docking using Alphafold and PIPER tool in Schrodinger revealed that the YBX1 cold-shock domain interacted near the ATP/ADP binding site in CHK2. This interface was also part of the CHK2-CHK2 dimer interface. Consistent with our model, disruption of CHK2 dimerization using prexasertib led to increased colocalization of CHK2-YBX1 in human GBM patient derived xenograft cells. Further, targeting of CHK2-YBX1 interaction with YBX1 inhibitor SU056 reversed the repression of IFNγ response genes in glioma cells. Together this study unveils a kinase independent (non-catalytic) function of CHK2, providing insight into the non-canonical immunosuppressive role of CHK2 in gliomas.
IMMU-56. THE TIGIT/CD155 AXIS PLAYS A CRITICAL ROLE IN EXTRACELLULAR VESICLE-MEDIATED PROGRAMMING OF THE GLIOBLASTOMA MICROENVIRONMENT
Authors: Asad Mohamad , Inocencio Julio , Mitrasinovic Stefan , Aoiki Minori , Parney Ian , Crisman Celina , Lasala Patrick , Eskandar Emad , Himes Benjamin
Published: November 2024

Glioblastoma (GBM), the most common and deadly primary brain tumor, exerts profound local and systemic immunosuppressive effects through a variety of mechanisms. Tumor-derived extracellular vesicles (EVs) are increasingly appreciated as critical mediators of these effects. In surveying the tumor-immune microenvironment in samples of ultrasonic aspirate collected during surgical resection of GBM (n=13), we identified several key immunomodulatory markers expressed across a range of myeloid cell populations. Particularly, we found TIGIT, classically understood as a T cell inhibitory protein, expressed across a range of myeloid cell populations in patient samples, including in myeloid-derived suppressor cells (MDSCs, 46.84±16.78% of total monocytic MDSCs). Using EVs collected from patient-derived cell lines, we were able to recapitulate these effects upon co-culture with monocytes derived from the peripheral blood of healthy donors (n=7). Furthermore, Induced MDSCs significantly inhibit T cells proliferation (70.97±8.454%, compared to control 19.4±5.71; p<0.03), concomitant with a surge in Th2 immune responses via TIGIT/CD155 axis. This effect was reversed after TIGIT silencing, indicating a TIGIT-dependent immune suppression in the GBM microenvironment. Our study indicates EV-induced TIGIT upregulation in myeloid cells as a crucial immunosuppressive mechanism in glioblastoma, with potential therapeutic applications.
IMMU-61. THE LAST OF US: A FUNGI BASED DENDRITIC CELL VACCINE
Authors: Artiga Kevin , Valenzuela Alex , Hsu Mitchell , Wang Herui , Ye Juan , Zhuang Zhengping
Published: November 2024

BACKGROUND

Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults. The current standard treatment for newly diagnosed GBM involves maximal surgical resection followed by radiotherapy and temozolomide. Despite these interventions, the median overall survival for GBM patients remains approximately 15 months, highlighting the critical need for innovative therapeutic approaches.

OBJECTIVE

Our laboratory has previously developed a subcutaneous autologous tumor vaccine incorporating irradiated (IR) tumor cells with phagocytosis-stimulating ligands (Mannan-BAM), toll-like receptor (TLR) agonists, and an immunostimulant anti-CD40 antibody (collectively termed MBT). This combination has shown efficacy in mouse models of colon carcinoma, breast cancer, melanoma, and, more recently, gliomas. Our study aimed to create a dendritic cell (DC) vaccine using this strategy.

METHODS

To evaluate whether MBT could induce the maturation of DCs in vitro, we harvested BMDCs from mice and co-cultured them in the presence of MBT-tagged irradiated tumor cells. We then analyzed the maturation markers using flow cytometry and assessed cytokine production via ELISA. To test the efficacy of this approach in vivo, we utilized two different murine glioma models (SB28 and GL261).

RESULTS

Using flow cytometry, we observed a significant upregulation of important co-stimulatory molecules. Additionally, ELISA analysis demonstrated that MBT-treated DCs significantly increased the secretion of Type 1 cytokines while limiting the secretion of the regulatory cytokine IL-10. MBT-primed DCs combined with immune checkpoint inhibitor PD-1 increased mouse survival in a glioma model compared to WT mice. However, mice eventually succumbed to cerebral edema. Histology demonstrated significant treatment effects.

CONCLUSION

Our results demonstrate that MBT effectively matures DCs ex-vivo. Further research is required to immunophenotype the response to vaccination in glioma models and explore ways to overcome resistance.
IMMU-69. THERAPEUTIC WINDOW ENABLING ERADICATION OF RESIDUAL GLIOMA STEM CELLS BY INTRACRANIAL NK CELL THERAPY FOLLOWING TEMOZOLOMIDE-INDUCED TUMOUR DEPOPULATION – A POSSIBLE ROLE OF CYTOTOXIC EXTRACELLULAR VESICLES
Authors: Meehan Brian , Adnani Lata , Zhu Xianbing , Tawil Nadim , Garnier Delphine , Nakano Ichiro , Huang Sidong , Rak Janusz
Published: November 2024

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. Efficient NK cell-mediated killing of GBM cells occurs at high effector to target ratios precluding effective eradication of large tumour remnants, 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. Notably, while TMZ caused near complete regression of intracranial GSC xenografts this was followed by inevitable recurrence of drug-resistant lesions. 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 intracranially, and upon tumour formation were treated with a sequence of TMZ (systemically), at 2, 7, 14, and 21 days later with irradiated NK92MI cells. Remarkably, this combined therapy completely obliterated recurrent disease at 2 and 7 days but not beyond 14 days. 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-12. CUTANEOUS TOXICITIES OF MITOGEN-ACTIVATED PROTEIN KINASE INHIBITORS IN CHILDREN AND YOUNG ADULTS WITH NEUROFIBROMATOSIS-1
Authors: Sadighi Zsila , Tripathy Sanjna , Peacock Brianna , Patel Anisha
Published: November 2024

BACKGROUND

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. Cutaneous adverse events (CAEs) are common and may hinder patients’ abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1.

METHODS

We reviewed institutional medical records of patients under 30 years with a diagnosis of “NF1,” “NF2,” or “other neurofibromatoses” on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response.

RESULTS

The median age of 40 patients with NF1 was 14 years old. Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%) (Table 1). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%) (Figure 1). Twenty-three out of the 28 cases of acneiform eruption were in post-pubertal patients (82.1%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi (Table 2). There was no significant association between CAE presence and tumor response (p=0.39).

CONCLUSIONS

MEK inhibitors have been demonstrated as a valuable treatment, but CAEs complicate the ability to stay on the treatment. Most patients in our cohort developed a CAE, demonstrating its prevalence in this population. Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.
INNV-32. LASER INTERSTITIAL THERMAL THERAPY FOLLOWED BY CONSOLIDATION STEREOTACTIC RADIOSURGERY (LITT-CSRS) IN PATIENTS WITH NEWLY DIAGNOSED BRAIN METASTASIS
Authors: Dharnipragada Rajiv , Shah Rena , Reynolds Margaret , Dusenbery Kathryn , Chen Clark
Published: November 2024

INTRODUCTION

The efficacy and safety of laser interstitial thermal therapy followed by consolidation radiosurgery (LITT-cSRS) was previously studied in brain metastasis that recurs locally after initial radiosurgery (BMRS). Here, we characterize the clinical outcome of LITT-cSRS in patients with newly diagnosed brain metastasis.

METHODS

Between 2017 and 2023, ten consecutive cancer patients with newly diagnosed brain mass of unclear etiology who underwent stereotactic needle biopsy (SNB) and LITT in the same setting followed by consolidation SRS (cSRS) with > 6 months follow-up were identified retrospectively. Clinical and imaging outcomes were collected.

RESULTS

The histology of the BM were: breast cancer (n=3), melanoma (n=3), non-cell cell lung cancer (n=3), colon (n=1). There were no wound or procedural complications. All patients were discharged home, with a median one-day hospital stay (range: 1-2 days). All patients were off corticosteroid therapy by the one-month follow-up. cSRS were carried out 12-27 days (median of 19 days) after SNB+LITT. There were no subsequent emergency room presentation, 30-day or 90-day re-admission. The Karnofsky Performance Score (KPS) remains stable or improved at the 3 months-follow-up. With a median follow-up of 416 days (13.8 mo; range: 199-1,096 days), there was one local recurrence at 384 days (12.8 mo) post-LITT-cSRS. Of note, this is the only patient who underwent incomplete ablation with LITT and the location of the recurrence corresponded to the residual tumor that was not treated with LITT. With exception of this patient with local recurrence, all patients showed decreased FLAIR volume surrounding the LITT-cSRS treated BMRS by the six-month follow-up.

CONCLUSIONS

To our awareness, this case series represent the first to describe LITT-cSRS in the setting of newly diagnosed BM. The results presented here provide pilot data to support the safety and efficacy of LITT-cSRS and lay the foundation for future studies.
INNV-34. APPLICATION OF 200 KHZ TUMOR TREATING FIELDS (TTFIELDS) IN PATIENTS WITH INFRATENTORIAL HIGH-GRADE GLIOMA: CASE SERIES
Authors: Kamiya-Matsuoka Carlos , Patel Chirag , Battiste James
Published: November 2024

BACKGROUND

200 kHz Tumor Treating Fields (TTFields) therapy is FDA-approved for supratentorial newly-diagnosed and recurrent glioblastoma. However, reports of its application in patients with infratentorial high-grade glioma (HGG) are rare. Based on computational modeling, the therapeutic field strength (~1 V/cm peak-to-peak) is thought to be achievable for infratentorial HGG.

METHODS

Two patients with infratentorial HGG received off-label 200 kHz TTFields therapy with the Optune® device (Novocure, Ltd.). To reduce impaired range of motion of the neck, the electrode transducer arrays were “skeletonized” by cutting a portion of the adhesive material surrounding them. Application of the electrode arrays was performed with the neck in flexion, to further promote neck range of motion. Cloth tape was used for reinforcement as necessary. Electrode arrays were changed every 2-3 days. We report the results of patient survival and adverse events.

RESULTS

Patient 1: 22-year-old man with high-grade diffuse pontine glioma with recurrences and prior treatments (including radiation, temozolomide, lomustine, and dopamine receptor D2 [DRD2] antagonist), tolerated TTFields combined with systemic treatment (initially with a bi-functional DNA alkylating agent; subsequently with temozolomide and bevacizumab) for 5 months with stable disease for 4 months. He experienced grade 1 rash of the neck. Patient 2: 58-year-old woman with diffuse glioma of the brainstem (H3K27M-mutated) with multiple recurrences and prior treatments (including concurrent radiation and temozolomide, and DRD2 antagonist), tolerated TTFields combined with systemic treatment (lomustine and bevacizumab). The TTFields infratentorial layout was iteratively modified with respect to placement of the electrode transducer arrays, for improved tolerability. With the TTFields+systemic combination therapy, the patient was stable for 8 months with no local TTFields-related side effects.

CONCLUSIONS

We provide initial post-marketing evidence that off-label use of 200 kHz TTFields in infratentorial HGG is safe and feasible. Prospective studies are necessary to validate the efficacy of this approach.
PATH-03. SPATIAL-RESOLVED METABOLOMICS ANALYSIS IN HISTOLOGICAL AND MOLECULAR GLIOBLASTOMAS USING A MOF/MXENE-ASSISTED LDI-MSI PLATFORM
Authors: Guo Xiaopeng , Liang Weiqiang , Ma Chunxia , Zhao Yuanli , Wang Yu , Ma Wenbin
Published: November 2024

Glioblastoma (GBM) is a highly aggressive primary brain tumor encompassing both histological and molecular subtypes. Metabolites within the tumor microenvironment play critical roles in regulating tumor behavior and response to therapy. Understanding their spatial distribution provides valuable insights for diagnosis and treatment. We investigated metabolite patterns of histological GBMs (hist-GBMs) and molecular GBMs (mol-GBMs) by developing a novel MOF/MXene platform for enhanced surface-assisted laser desorption/ionization mass spectrometry. Utilizing this platform, we analyzed the metabolomes of three hist-GBMs and three mol-GBMs. Our platform exhibited exceptional sensitivity, repeatability, and stability in detecting metabolite molecules. Analysis of the metabolomes revealed distinct spatial distributions and concentrations of various metabolites, including carbohydrates, amino acids, organic acids, nucleotides, and their precursors. Notably, certain metabolites such as TG(15:0/20:3n6/20:5(5Z,8Z,11Z,14Z,17Z)), PG(20:3(6,8,11)-OH(5)/i-21:0), and SM(d20:1/20:3(6,8,11)-OH(5)) were significantly enriched in hist-GBMs compared to mol-GBMs, while others, including lithocholic acid glycine conjugate, PE(P-16:0/14:1(9Z)), and CE(11:1D5), exhibited higher peak intensity in mol-GBMs. Overall, our findings underscore the existence of unique metabolomic signatures distinguishing hist-GBMs from mol-GBMs. In conclusion, heterogeneous metabolite distributions among hist-GBMs and mol-GBMs were revealed by our novel MOF/MXene assisted LDI-MSI platform, and unique metabolic signatures were identified. Advanced metabolomics analysis holds promise for precise biomedical diagnostics and individualized therapeutic strategies in GBMs.