tbuckley/cabot-search huggingface dataset:
IMMU-31. DAMAGE RESPONSE FROM SYSTEMIC RNA VACCINATION RESTORES HUMORAL IMMUNITY IN GLIOBLASTOMA
Authors: Rachel Moor, Mahya Aghaee, Sheila Carrera-Justiz, Sadeem Qdaisat, Chao Xie, Dhruvkumar Soni, Christina von Roemeling, Anna DeVries, Brandon Wummer, Frances Weidert, Jonathan Chardon-Robles, John Ligon, Paul Castillo, Natalie Silver, Cassie Kline, Michael Prados, Sabine Mueller, Eugene Hwang, Maryam Rahman, Ashley Ghiaseddin, Duane Mitchell, Nathan Seligson, Hector Mendez-Gomez, Helen Moore, Elias Sayour
Journal: Neuro-Oncology (2024)

Abstract Therapies against glioblastoma (GBM) remain stymied by poor penetration across the blood-brain barrier (BBB) and systemic immunotolerance. These outcomes necessitate development of therapies simultaneously targeted to tumors while engineering peripheral immunity to co-localize for synergistic responses. We developed RNA loaded lipid particles (LPs) to simultaneously function as inducers of cytotoxic responses in the GBM tumor microenvironment (TME) and as systemic activators of peripheral immunity. RNA-LP mediated response was studied in mice bearing KR158b tumors and in canines and humans with spontaneous glioma and glioblastoma respectively. We found that RNA-LPs could localize to the brain TME of animals bearing murine gliomas and rapidly upregulate damage associated signaling pathways including p53-CDKN2A. This correlates with increased gene signatures for complement and proteosome processing. Simultaneously, in the periphery, RNA-LPs increase integrin expression on activated T cells and ICAM expression in brain tumors helping steer T cell translocation across the BBB. In canines with malignant gliomas, response to RNA-LPs correlated with increasing tumor size suggesting pseudoprogression. Similar to murine glioma, canine gliomas harvested within 48h of vaccine administration demonstrated rapid increases in complement and p53 pathway activation. In one human patient treated with RNA-LPs per NCT04573140 (PNOC020 trial), we demonstrate biopsy confirmed pseudoprogression with increases in p53 pathway signaling and complement activation. In post-treatment tumor biopsy samples, there was increased hyperexpanded post-infusion intratumoral IgH clones. Systemic administration of RNA-LP elicits damage response in the TME that predisposes complement activation and humoral immunity. Coupled with peripheral recruitment of T cells that can translocate across the BBB, RNA-LPs elicit potent bi-directional adaptive immunotherapy against GBM.
SURG-42. THE T1/T2 RATIO IS ASSOCIATED WITH RESECTABILITY IN PATIENTS WITH IDH-MUTANT ASTROCYTOMAS CNS WHO GRADES 2 AND 3
Authors: Jonathan Weller, Eddie de Dios, Sophie Katzendobler, Alba Corell, Anna Dénes, Michael Schmutzer-Sondergeld, Niloufar Javanmardi, Niklas Thon, Joerg-Christian Tonn, Asgeir Store Jakola
Journal: Neuro-Oncology (2024)

Abstract PURPOSE IDH-mutant astrocytomas CNS WHO grade 2 and 3 show heterogenous appearance on magnetic resonance imaging (MRI). In the pre-molecular era, the discrepancy between T1 hypointense and T2 hyperintense tumor volume in absolute values has been proposed as a marker for diffuse tumor growth. We set out to investigate if a ratio of T1 to T2 tumor volume (T1/T2 ratio) is associated with resectability and overall survival in patients with IDH-mutant astrocytomas. METHODS Patient data from two centers (Center A: Sahlgrenska University Hospital, Gothenburg, Sweden; Center B: LMU University Hospital, Munich, Germany) were collected retrospectively. Inclusion criteria were as follows: pre- and postoperative MRI scans available for volumetric analysis (I), diagnosis of an IDH-mutant astrocytoma between 2003-2021 (II), and tumor resection at initial diagnosis (III). Tumor volumes were manually segmented. The T1/T2 ratio was calculated and correlated with extent of resection, residual T2 tumor volume, and overall survival. RESULTS The study comprised 134 patients with 65 patients included from Center A and 69 patients from Center B. The median overall survival was 134 months and did not differ between the cohorts (p=0.29). Overall, the median T1/T2 ratio was 0.79 (range 0.15-1.0). Tumors displaying a T1/T2 ratio of 0.33 or lower showed significantly larger residual tumor volumes postoperatively (median 17.9 cm3 versus 4.6 cm3, p=0.03). The median extent of resection in these patients was 65% versus 90% (p=0.03). The ratio itself did not correlate with overall survival. In multivariable analyses, larger postoperative tumor volumes were associated with shorter survival times (HR 1.02, 95% CI 1.01-1.03, p&amp;lt;0.01). CONCLUSION The T1/T2 ratio might be a good indicator for diffuse tumor growth on MRI and is associated with resectability in patients with IDH-mutant astrocytoma. This ratio might aid to identify patients in which an oncologically relevant tumor volume reduction cannot be safely achieved.
RADT-48. ANALYSIS OF PROTON RADIATION THERAPY INDUCED CONTRAST ENHANCEMENT: A SINGLE INSTITUTION, RETROSPECTIVE STUDY
Authors: Sushant Puri, Ellen Huang, Anne Li, Yurika Tarui, Kristen Redmond, Carmen Kut, Brandi Page, Victoria Croog, John Laterra, Lawrence Kleinberg
Journal: Neuro-Oncology (2024)

Abstract Proton radiotherapy (PRT) has superior physical dose distribution with a lesser integral off target radiation dose exposure compared with standard photon radiotherapy resulting in reduced toxicity of uninvolved normal tissues. However, there may be toxicity in areas targeted for high dose treatment as a result of uncertainty about the relative radiobiologic effect (RBE) of proton radiotherapy compared with photon radiotherapy and the potential for localized high doses at the end of the proton beam range (Bragg peak). This may result in radiation-induced contrast enhancement (RICE) reflecting transient toxicity or permanent injury, particularly when associated with concurrent chemotherapy. We analyzed 150 consecutive adult patients, with a histopathologic diagnosis of CNS malignancy, who underwent only PRT at Johns Hopkins Hospital between 2019 – 2023 with least 1 year of follow-up imaging. RICE was defined as a new post-treatment contrast enhancement on MRI within the radiation field. The determination of disease progression or RICE was confirmed with additional follow-up MRI or pathology. RICE was identified in 14 cases (9.3%). The median age was 48 y (range 19 – 72 years), sex 50% female. Diagnosis was 5 astrocytoma, 3 meningioma, 2 glioblastoma, 1 medulloblastoma, 2 oligodendroglioma, 1 tectal glioma. 4/5 astrocytoma patients were grade 2, 2/3 meningioma was grade 1, 1/3 was grade 2, 2/2 oligodendroglioma was grade 2. The median time since completing PRT to development of RICE was 3.5 months. The median radiation dose was 52.20 Gye (range 23.40 - 60.06). Dexamethasone was used in 11 patients (78 %) and in bevacizumab was used 2. Chemotherapy with temozolomide 7 (50%), PCV 1, and none in 5. 12 (85%) patients were still alive. PRT can also be associated with radiation injury in the target, and more information is needed about the incidence, natural history, and associations with localized dosimetry.
RADT-13. REAL-WORLD DATA ON NEWLY DIAGNOSED WHO 4 GLIOMAS UNDERGOING TTFIELDS: SURVIVAL ANALYSIS AND RELAPSE PATTERNS FROM A SINGLE CENTER
Authors: Jing Zhang, Yanwei Liu, Xiaoguang Qiu, Wei Zhang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tumor treating fields (TTFields) therapy is more and more widely used to treat patients with glioblastoma due to its effectiveness and low toxicity. In the 2023 V1 NCCN guidelines, TMZ combined with TTFields is the only preferred Class 1 recommended standard treatment for ndGBM patients aged ≤70 years. METHOD A total of 37 patients who were newly diagnosed as WHO 4 Gliomas in Tian Tan Hospital from 2020.8 to 2023.10 with TTFields were included in this retrospective analysis, and the median follow-up time was 449 days. RESULT The median age of the 37 patients was 50 years old, and 17 of them were male. Total resection was performed in 18 patients (48.6 %) and nearly total resection was performed in 14 patients (37.8%). The median time from diagnosis to first wearing of TTFields was 83 days(2.76 months). The median wearing time of TTFields was 9 months, and the median wearing compliance was 90%.The median PFS from diagnosis was 494 days (16.5 months). The 18 months OS rate was 86.7% from diagnosis to time of death after wearing TTFields. Among 37 patients receiving TTFields, 6 (16.2%) were found to have radiation damage. A total of 3 patients had non-radiological area and distal contralateral recurrence, and PFS were 7.2 months, 16.1 months, and 22.8 months, respectively. CONCLUSION PFS is associated with high total resection rate, early wearing of TTFields (median 2.76 months), and long wearing (median 9 months) with high compliance (median 90%). The recurrence pattern of patients with long-term wearing TTFields needs to be further explored. Currently, we are integrating clinical information and exploring the imaging characteristics of patients with distant metastases based on multimodality radiomics platform.
EXTH-14. IRREVERSIBLE TARGETING OF THE C-MYC/TOPOISOMERASE I AXIS IN GLIOBLASTOMA: DUAL INHIBITION USING A NOVEL INDENOISOQUINOLINE INHIBITOR
Authors: Erin Walker, Sabrina Nusraty, Miyeon Jung, Yesh Banasavadi Siddegowda, Masahiro Oishi, Aimee Dowling, Ashish Chowdhury, David Barnes, Desmond Brown
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma–the most common primary CNS malignancy–is notorious for its cellular and molecular complexity and uniform fatality. Overexpression of the c-MYC and TOPOISOMERASE 1 (TOP1) oncogenes is implicated in more than 50% of human cancers. They are involved in the pathogenesis of glioblastomas with overexpression correlating with decreased overall median survival in glioblastoma patients. LMP744 is a non-camptothecin indenoisoquinoline small molecule inhibitor designed to target the C-MYC/TOP1 axis. The compound is inherently stable, has high brain penetrance, and irreversibly binds to its target providing several advantages over the camptothecin class of drugs. Human glioblastoma cells treated with LMP744 show a dose-dependent decrease in viability with LD50 ranging between 50 and 100 nM compared to 100-200µM following treatment with temozolomide in the same cell lines. Treatment results in a pro-apoptotic effect in exposed cells as well as S-phase arrest. Protein arrays and confirmatory western blots demonstrate increased CHK2 and decreased p53 and GSK-a/ß in treated cells. Orthotopic xenotransplantation via stereotactic injection of human glioblastoma cells (7×105 cells/4 µL) in nude mice showed exquisite sensitivity to LMP744 without adverse events. Administration of 20 mg/kg of LMP744 via tail vein injection resulted in total eradication of tumor signal on bioluminescent imaging. These preliminary findings suggest that LMP744–and perhaps the class of non-camptothecin indenoisoquinolones–is a promising novel candidate for glioblastoma pharmacotherapy.
CTNI-66. IDH-MUTANT GLIOMA PATIENTS TREATED WITH VORASIDENIB: ONGOING DATA FROM THE VORASIDENIB EXPANDED ACCESS PROGRAM
Authors: Timothy Cloughesy, Katherine Peters, Howard Colman, Jennie Taylor, Ingo Mellinghoff, Helen Shih, Christelle Chacar, Jonathan Dewey, Patrick Wen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Vorasidenib (VOR) is an oral, brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase 1/2 (mIDH1/2) demonstrating clinical efficacy and safety in patients with mIDH1/2 glioma in the phase 3 INDIGO study (NCT04164901). Servier launched an expanded access program (EAP, NCT05592743) in November 2022 designed to provide access to VOR for patients with mIDH1/2 glioma. Early clinical outcomes of patients treated in this EAP are presented. METHODS Eligible participants were aged ≥12 years with mIDH1/2 glioma and, in the opinion of the treating oncologist, would potentially benefit from treatment with VOR. Safety assessments occur every two weeks for the first two 28-day cycles, then monthly for the duration of treatment. RESULTS As of the March 31, 2024 data cutoff, 71 participants have initiated treatment with VOR. Mean (SD) age was 42.7 (14.8) years; 39 (55%) were male; and 34 (48%) with astrocytoma. mIDH mutation status was 46 (65%) mIDH1. One participant had separate tumors with either mIDH1 or mIDH2 identified. The majority of participants had grade 2 gliomas (n=51 [72%]) and non-contrast–enhancing disease (n=49 [69%]). As of the data cutoff, 62 (87%) participants remain on treatment, with the majority initiating treatment within the past 6 months (n=49 [69%]). Nine (13%) participants have discontinued treatment due to: radiographic progressive disease (n=3); clinical progressive disease (n=4); adverse event (AE) unrelated to treatment (n=1); or other reason (n=1). Three participants have died (disease progression [n=2], unrelated infection [n=1]). At least one AE of any grade was seen in 35 (49%) participants, with 4 (6%) experiencing unrelated serious AEs. Eight (11%) patients had AEs of special interest (defined as grade 2 or higher ALT/AST elevations). Ten (14%) patients had AEs that led to dose interruption and one (1%) patient had dose reduction. Additional treatment duration and various subgroup analyses will be presented.
NIMG-88. EVALUATION OF DIFFUSION AND PERFUSION MRI FEATURES FOR DIFFERENTIATING RECURRENT BRAIN METASTASES AND RADIATION NECROSIS
Authors: Guowen Shao, Francesco Sanvito, Won Kim, Benjamin Ellingson, Jingwen Yao
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BM) are a frequent and serious complication of cancer. Differentiating between BM and radiation-induced necrosis (RN) after radiotherapy remains challenging. Diffusion-weighted imaging (DWI) derived apparent diffusion coefficient (ADC) maps and perfusion-weighted imaging (PWI) derived relative cerebral blood volume (rCBV) have the potential to distinguish between BM and RN. Despite the potential of these imaging modalities, previous studies have been limited by the absence of histopathological confirmation. In this study, we utilized a patient cohort that underwent stereotactic biopsy as part of their Laser Interstitial Thermal Therapy (LITT) following suspicious radiographic progression. This allowed us to evaluate the efficacy of ADC and rCBV imaging features with histopathological validation. METHODS In this study, 29 patients underwent MRI scans (3 with 1.5T, 26 with 3T) prior to LITT. Pathology confirmed 11 patients with BM and 18 with RN. Regions of interest (ROIs) in the contrast-enhanced lesion and T2 hyperintensity lesion were identified using post-contrast T1-weighted images and fluid-attenuated inversion recovery (FLAIR) images. Mean values and histogram-based features (standard deviation, 10%, 90%) of lesion volume, ADC, and rCBV within tumor ROIs were compared between the BM and RN using the Wilcoxon rank-sum test. RESULTS Our findings indicated that the mean values of ADC in the enhancing and non-enhancing lesion ROIs did not significantly differ between BM and RN patients. However, in the contrast-enhanced lesion regions, we observed a significant difference in the standard deviation of rCBV (p&amp;lt;0.05), and the 90th percentile value of rCBV also suggested potential differences between BM and RN (p=0.069). In the T2 hyperintensity lesion regions, lesion volume (p&amp;lt;0.05) and the mean of rCBV (p&amp;lt;0.05) show significant differences between BM and RN. CONCLUSION This study demonstrates the potential of using rCBV to aid in the clinical diagnosis of BM. Additionally, our findings indicate that T2 hyperintensity regions, beyond just contrast-enhancing lesions, may provide valuable information for differential diagnosis.
IMMU-17. ADENOSINE DEAMINASE ACTING ON RNA (ADAR) SILENCES TUMOR-INTRINSIC INTERFERON RESPONSE IN DIFFUSE MIDLINE GLIOMA
Authors: Christian Ramsoomair, Jesus Castro, Deepa Seetharam, Ashish Shah, Danny Reinberg
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children and is currently incurable. Clinical trials using immune checkpoint blockade (ICB) therapy have failed to show efficacy due to multifactorial mechanisms including limited lymphocyte infiltration, low immune checkpoint (IC) expression, and a low mutational burden. Adenosine deaminase acting on RNA (ADAR) is an RNA editor, which limits anti-tumor immunity by editing/preventing the sensing of endogenous double-stranded RNA (dsRNA). We have found that ADAR protein levels are significantly elevated in DMG patients, suggesting that ADAR’s immune-silencing function is relevant to DMG immune suppression. The onco-histone driver H3K27M promotes epigenetic dysregulation in DMGs, de-suppressing retroelement transcription, a major source of endogenous dsRNA. By inhibiting ADAR, we expect that the increased levels of dsRNA will stimulate intracellular type-1 interferon (IFN) responses, induce chemokine secretion, and promote antitumor CD8+ cytotoxicity. METHODS Human DMG cells and patient-derived glioma spheres were treated with silencing RNA to transiently knockdown (KD) ADAR levels for assays involving in vitro viability and proliferation. Affected pathways were identified using immunoblotting and quantitative PCR. RESULTS Our data shows that ADAR protein levels are elevated in DMG patient proteomic datasets and cell lines. ADAR-depleted patient-derived DMG cell lines exhibit significantly less proliferation compared to control siRNA and ADAR-depleted hTERT-astrocytes (Mann-Whitney test, P-value &amp;lt;0.0001, ****). CONCLUSION Our results demonstrate that DMG tumor cells have an ADAR selective dependency in vitro. In ongoing studies, we aim to determine if ADAR-depletion improves in-vivo survival in both immunodeficient and immunocompetent models in combination with immunotherapies against DMG.
EXTH-03. CAR T-CELLS TARGETED TO B7-H3 OR HER2 FUNCTION INDEPENDENTLY OF ANTIGEN DENSITY IN XENOGRAFT MODELS OF EPENDYMOMA
Authors: Sanya Mehta, Jorge Ibanez, Haley Houke, Siri Ippagunta, Erik Emanus, Stephen Mack, Giedre Krenciute
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Targeted treatment options are desperately needed for ependymomas (EPN). Chimeric antigen receptor (CAR) T-cells have immense potential to positively transform treatment outcomes; however, little is known regarding antitumor efficacy of CAR T-cells against EPNs. Specifically, antigen density has emerged as a major influencer of CAR T-cell potency. However, the specific high and low antigen density thresholds governing CAR T-cell efficacy for EPN are unknown. The goal of this project is to determine the role of antigen density in CAR T-cell potency against EPN. METHODS Using quantitative flow cytometry, we determined antigen density of B7-H3 and HER2 (the two CAR targets currently in pediatric EPN clinical trials), on EPN patient derived cell lines (1425, ST1, CPITT, ST2, EPI, L46SJ). We generated B7-H3 and HER2-CAR T-cells with CD28z signaling domain and compared long-term cytolytic activity, expansion, and cytokine production against EPNs. RESULTS We found that all EPN cell lines express remarkably high yet variable density of B7-H3 (62,700 – 335,440 molecules/ cell). In contrast, surface density of HER2 was consistently and significantly lower (860 – 24,488 molecules/ cell). In repeated-stimulation assays, B7-H3-CAR T-cells killed 7-10 times and expanded up to 325,360-fold when cultured against EPN. However, we observed no significant difference in total expansion or correlation with antigen density against EPNs. Surprisingly, expansion of HER2-CAR T-cells against EPNs was drastically higher and greatly exceeded that of B7-H3-CAR-T cells against the same EPN cells despite much lower antigen density. CONCLUSIONS Our work shows that both B7-H3 and HER2 are good targets against EPN, despite drastic differences in antigen density. Results suggest that lower antigen density of HER2 may be superior for CAR T-cell activity. Future work will validate whether HER-CAR T-cells have superior antitumor efficacy in vivo to further delineate role of antigen density thresholds in CAR T-cell potency.
CNSC-57. THE ROLE OF NEURON-TO-GLIOMA SYNAPTIC COMMUNICATION IN THERAPEUTIC RESISTANCE
Authors: Svenja K Tetzlaff, Ekin Reyhan, C Peter Bengtson, Nikolas Layer, Anton J Faymonville, Alina Heuer, Varun Venkataramani
Journal: Neuro-Oncology (2024)

Abstract Glioblastomas, primary brain tumors known for their extensive brain colonization and high therapeutic resistance, pose significant treatment challenges. Recent research has revealed that glioblastoma cells can form functional multicellular networks both with themselves, surrounding astrocytes and neurons. However, the investigation of the glioblastoma neuronal connectome has been limited by a lack of suitable methodologies. In this study, we utilized an adapted rabies-based retrograde tracing approach to characterize tumor-connected neurons and examine the neuronal connectome of the tumor in the context of therapy resistance. Our initial findings demonstrated that radiotherapy induces hyperexcitability in tumor-connected neurons, as shown by patch-clamp electrophysiology. This hyperexcitability was associated with an increase in neuron-tumor connectivity post-irradiation. To mitigate this increased neuronal input to therapy-resistant glioblastoma cells, we combined radiotherapy with the anti-epileptic drug perampanel. This combination therapy, which inhibits overall neuronal activity while delivering tumor cell-toxic photon irradiation, proved significantly more effective in reducing the number of therapy-resistant tumor cells. In summary, we employed a novel methodology to investigate the role of the neuronal tumor connectome in therapeutic resistance, identifying tumor-connected neurons as a potential target for improving glioblastoma treatment.
PATH-16. MOLECULAR ALTERATIONS IN IDH-MUTANT ASTROCYTOMA: A MULTI-INSTITUTIONAL RETROSPECTIVE STUDY
Authors: Keng Lam, Hanim Ozkizilkaya, ái Den Milton, Antonio Dono, Vinodh Kumar, Jason Johnson, Yoshua Esquenazi, Chirag Patel, Leomar Ballester
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Many molecular alterations are being identified for diagnosis and prognosis in patients with isocitrate dehydrogenase (IDH)-mutant astrocytoma. However, contemporary survival data for these tumors with respect to their molecular alterations are lacking. Moreover, the prognostic value of histologic grading in IDH-mutant astrocytomas remains controversial. METHODS This was a retrospective study of adult IDH-mutant diffuse astrocytoma patients in whom clinical and molecular alteration data were collected. Overall survival (OS) was estimated using the Kaplan-Meier method. Group differences in OS were assessed by the log-rank test and associations between OS and measures of interest were evaluated using Cox proportional hazards regression models. RESULTS We identified 241 eligible patients with median age of 33 years (range, 16-73 years). The most frequent mutations were in IDH1 (98%), TP53 (91%), ATRX (70%), ARID1A (8%), BRCA2 (6%), TSC2 (6%), CDKN2A (6%), and CREBBP (6%). IDH2 mutations were identified in 2% of cases. By univariate analysis, age &amp;gt;40 years (hazard ratio [HR], 2.02; 95% CI, 1.19-3.43; P =.009) was associated with worse OS. BRCA2 wild-type status compared with mutated BRCA2 (HR, 0.42; 95% CI, 0.20-0.90; P =.024) and histology-based grade 2 compared with grade 3 astrocytoma (HR, 0.41; 95% CI, 0.23-0.74; P =.003) were associated with improved OS. In multivariable analysis, age&amp;gt;40 years (HR, 2.14; 95% CI, 1.22-3.75; P =.008) was associated with worse OS. Patients with WHO grade 2 astrocytoma remained associated with improved OS compared to those with grade 3 disease (HR, 0.45; 95% CI, 0.24-0.84; P =.013). CONCLUSIONS Age and histological grade remain essentials for risk stratification among IDH-mutant astrocytoma patients. Further studies are warranted to determine the role of BRCA2 mutation in prognosis.