bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-28. LOW-INTENSITY PULSED ULTRASOUND COMBINED WITH POLY-ICLC AND INTERLEUKIN-2 UNLOCKS THE IMMUNE PRIVILEGE OF THE BRAIN BY PROMOTING EPITOPE SPREADING AND ACTIVATION OF CNS-SPECIFIC NAÏVE T CELLS
Authors: Gallus Marco , Yamamichi Akane , Arrieta Victor Andres , Saijo Atsuro , Chuntova Pavlina , Phyu Su , Phung Lan , Haegelin Jeffrey , Long Haoyu , Lakshmanachetty Senthilnath , Nejo Takahide , Okada Kaori , Chen Li , Habashy Karl , Gould Andrew , Amidei Christina , Chang Catalina Lee , Stupp Roger , Canney Michael , Sonabend Adam M , Okada Hideho
Published: November 2024

Immunotherapies targeting glioma, such as chimeric antigen receptor (CAR) T cell therapies, offer new therapeutic avenues; however, their application has yielded limited success in clinical trials so far. Due to the antigenic heterogeneity of gliomas, targeting a few or several antigens still results in recurrence with “antigen-loss” tumors, indicating the need to engage the endogenous immune system to eliminate these therapy-resistant tumor cells. However, natural anatomical barriers and an immunosuppressive environment allow brain tumors to evade detection by the endogenous immune system. Low-intensity pulsed ultrasound combined with microbubbles (LIPU/MB) has recently been shown to transiently open the blood-brain barrier (BBB), enabling penetration of cells and drugs into the CNS. Using intravital two-photon imaging, two-photon microscopy, multiparametric spectral flow cytometry, and bone marrow chimera mice, alongside blood samples from glioblastoma patients treated with LIPU/MB, we observed that LIPU/MB promotes migration of CNS antigen-presenting cells from the perivascular space into the periphery. To assess the immunological relevance of LIPU/MB-mediated CNS antigen presentation to the peripheral immune system, we have developed new transgenic mice (GFAP-minigene mice) with an intact BBB expressing four immunogenic peptides under the CNS-specific GFAP promoter. In GFAP-minigene mice, LIPU/MB combined with toll-like receptor 3 agonist poly-ICLC and Interleukin-2 promoted priming, activation, and homing of naïve CNS-specific T cells into the brain parenchyma. Cytotoxic T cell activity in the brain was accompanied by MHC-I and MHC-II epitope spreading, mirrored by the occurrence of endogenous T cells in the brain, deep cervical lymph nodes, and spleen harboring other CNS-(minigene) antigen-specific T cell receptors. Collectively, our findings suggest that LIPU/MB combined with poly-ICLC can overcome inherent limitations of immunotherapy by enhancing CNS epitope spreading and activation of naïve CNS-antigen-specific T cells within the context of an intact blood-brain barrier.
IMMU-35. TARGETING THE AHR IMMUNOMETABOLIC HUB DURING VIROIMMUNOTHERAPY OF GLIOMAS
Authors: Lopez-Rivas Andres R , Gillard Andrew G , Parthasarathy Akhila , Shin Dong H , Garcia-Moure Marc , Hampton Lethan A , He Jiasen , Jiang Hong , Fan Xuejun , Wainwright Derek , Quintana Francisco J , Fueyo Juan , Gomez-Manzano Candelaria
Published: November 2024

Glioblastoma (GBM) poses a significant therapeutic challenge in oncology. Recent clinical trials have shown the feasibility of virotherapy to treat patients with GBM. Our laboratory developed an oncolytic adenovirus termed Delta-24-RGD that has been tested in clinical trials for recurrent GBM patients with encouraging results (NCT00805376, NCT02798406). These clinical studies, together with preclinical data, showed that the efficacy of Delta-24-RGD was due to direct tumor cell oncolysis and indirect activation of anti-tumor immune response. To further leverage this immune component, our group generated Delta-24-RGDOX, an armed version of Delta-24-RGD expressing the T-cell activator OX40-L, which exhibits a superior anti-cancer effect. In this project, we aim to further boost the effectiveness of Delta-24-RGDOX by targeting factors that maintain the immunosuppressive characteristic of gliomas. Specifically, we identified the environmental sensor and transcription factor Aryl Hydrocarbon Receptor (AhR) as one of the immunosuppressive factors. We show that AhR is overexpressed in GBM surgical specimens compared to healthy brain tissue, and high AhR expression correlates with poorer survival in glioma patients. Immunofluorescence staining of glioma cells treated with Delta-24-RGDOX demonstrated that AhR translocates to the nucleus, and qPCR showed that translocation resulted in the enhanced transcription of AhR-responsive elements. Additionally, bulk RNA-seq reveals that in vivo glioma models treated with Delta-24-RGDOX exhibit activation of the AhR pathway network. This unexpected and paradoxical activation may be responsible for immune suppression mechanisms, which might hinder the effect of Delta-24-RGDOX. Based on these data, we combined two innovative strategies, the oncolytic virus Delta-24-RGDOX and AhR inhibitors. Survival analysis in immunocompetent models of gliomas treated with this combined therapy showed the greatest therapeutic benefit compared to monotherapy controls. These findings highlight the critical role of AhR activation triggered by Delta-24-RGDOX and position AhR as a potential therapeutic target for enhancing the efficacy of oncolytic adenovirus therapy in GBM.
IMMU-37. PRE-TREATMENT INNATE INFLAMMATION ASSOCIATES WITH SURVIVAL AFTER POLIO VIROTHERAPY AND CAN BE MODULATED TO SENSITIZE GLIOMAS TO IN SITU VACCINATION
Authors: Mazgaeen Lalita , Kornahrens William , Giang Jr Minh-Huy , Howell Georgia , Briley Aaron , Bowie Michelle , Nair Smita , Ashley David , Desjardins Annick , Gromeier Matthias , Brown Michael
Published: November 2024

Early-stage clinical trials in glioblastoma (GBM) have tested various virotherapy strategies, yet only a subset of patients appear to benefit. We previously demonstrated that a recombinant poliovirus (PVSRIPO) functions by inducing MDA5-dependent, type I interferon (IFN) dominant innate inflammation in myeloid cells to provoke durable and functional antitumor T cell responses in mice. Long-term survival after intratumoral PVSRIPO infusion was observed in a subset of patients with recurrent GBM (rGBM) in two clinical trials. Survival after PVSRIPO was associated with higher pre-treatment intratumoral neutrophil density and MHC-class II gene expression, but also higher pre-treatment inflammatory cytokines in blood. Post-treatment induction of type I/III IFNs detected in blood one day after PVSRIPO infusion also associated with survival of patients with rGBM, suggesting that the proficiency of IFN responses to PVSRIPO may dictate therapy outcome. In human ex vivo glioma tissue assays, only a subset of gliomas mounted type I IFN responses to PVSRIPO and STING agonist treatment, in a manner linked with higher pre-treatment IL-1b levels, and lower CXCL10 induction after treatment. Thus, baseline innate inflammation either influences or reflects the capacity of glioma tumors to respond to virotherapy. Strikingly, in glioma bearing mice, peripheral vaccination against tumor irrelevant vaccines in alum adjuvant (i.e., against antigens not expressed by the tumor) induced bone marrow, spleen and intratumoral innate inflammation; rescued the antitumor efficacy of PVSRIPO in an otherwise refractory glioma model; and improved survival after intratumor STING agonist therapy. Notably, peripheral vaccination induced intratumoral neutrophil and CD4+ T cell inflammation, and increased MHC-class II expression on myeloid cells. These data imply a role for pre-treatment systemic innate immune training in the antitumor efficacy of virotherapy and indicate that modulating either systemic innate inflammation and/or the inflammatory status of bone marrow myeloid progenitors may sensitize gliomas to virotherapy.
IMMU-43. GUT MICROBIOTA SHAPE IMMUNE PATTERNS IN NAÏVE AND GLIOMA-BEARING HUMANIZED MICROBIOME MICE
Authors: Cox-Holmes Alexis , Green George , Potier Anna Claire , Wang Yong , McFarland Braden
Published: November 2024

Immunotherapy increases survival in mouse models of glioblastoma, but this is not observed in clinical trials. To address this issue, we employed a humanized microbiome (HuM) mouse model where fecal matter is transplanted from healthy human donors into gnotobiotic mice. Our previous research found that in the GL261 model of glioma, HuM mouse lines could be classified as either responders or nonresponders to anti-PD-1 therapy based solely on the gut microbiota unique to each HuM line. Here, we sought to determine the immune differences between responder and nonresponder HuM lines in both naïve (tumor-free) and glioma conditions. Single-cell RNA-sequencing (scRNA-seq) analysis of naïve colonic CD45+ cells showed that responder colons had higher frequencies of neutrophils and naïve B cells and lower frequencies of plasmablast and plasma cells. Notably, colonic neutrophils in naïve responders upregulated H2-Eb1 and Il1a compared to nonresponders. To validate the scRNA-seq data, flow cytometry was also performed on the naïve lymph nodes (LNs) and brains. The gut-draining LNs of responders had a higher frequency of CD45+ immune cells and CD4+CD8+ T cells and a lower frequency of Tregs than nonresponders. In naïve brains, responders had a higher frequency of CD45+ cells and macrophages than nonresponders and trended toward having fewer CD206+ macrophages. When mice were injected with GL261 tumor cells and treated with one dose of anti-PD-1, there was a trend for an increase in Nos2+ CD11b+ cells in both frequency and count compared to nonresponders, indicating an early and robust anti-tumor myeloid response in the responders. In summary, these results show how variations in the microbiota of HuM mice impact the immune environment across multiple organs in the baseline and tumor states, which potentially accounts for the positive response to anti-PD-1 therapy in the glioma model.
IMMU-45. MYELOID-ASSOCIATED WILD-TYPE IDH1 PROMOTES IMMUNOSUPPRESSION IN GLIOBLASTOMA
Authors: Dussold Corey , Tripathi Shashwat , Mahajan Akanksha , Tommasini-Ghelfi Serena , Hurley Lisa , Jarvis Rachel , Najem Hinda , Chalastanis Alexandra , Sooreshjani Moloud , Du Ruochen , McCornack Colin , Giles David , Turunen Jillyn , billingham leah , Kim Seunghyun , Broom Wendy , Dadali-Abel Tulin , Murnan Kevin , Horbinski Craig , Thorp Edward , Kim Albert , Li Yang , Miska Jason , Heimberger Amy , Stegh Alexander
Published: November 2024

Tumor-associated myeloid cells (TAMCs) promote immunosuppression in the GBM tumor microenvironment (TME) and resistance to immune checkpoint therapy (ICT). However, the metabolic and epigenetic mechanisms underlying TAMC activation and the therapeutic potential of fine-tuning TAMC activation remain largely unexplored. Our analyses of GBM patient single-cell RNA sequencing (scRNA-Seq) datasets demonstrated that in addition to tumor cells, wild-type isocitrate dehydrogenase (wt-IDH1) is also highly expressed in TAMCs. Using a murine model with myeloid cell-specific deletion of wt-IDH1 (LysM-cre-ERT2; wt-IDH1L/L), we demonstrated that the loss of wt-IDH1 promoted inflammatory myeloid phenotypes, increased CD8+ T cells in the TME, improved survival of GBM tumor-bearing mice, and enhanced anti-tumor effects of PD1 checkpoint blockade. Further, the pharmacological inhibition of wt-IDH1 using systemic administration of a first-in-class wt-IDH1-specific, brain-penetrant small molecule inhibitor or intrathecal delivery of siRNA targeted to wt-IDH1 mirrored the functional phenotype of wt-IDH1-deleted myeloid cells, overcame ICT resistance, and promoted long-term survival and anti-tumor immune memory. Mechanistically, in myeloid cells, the genetic or pharmacological inactivation of wt-IDH1 inhibited oxidative phosphorylation, reduced myeloid cell proliferation, increased their tumoricidal activity, and altered chromatin accessibility of key transcription factors implicated in the regulation of myeloid cell states, including AP-1, IRFs, STAT1/2, NFATs, and CEPBPs. These studies define wt-IDH1 as a metabolic checkpoint of myeloid cell activation and credential the inhibition of wt-IDH1 as a novel immunotherapeutic strategy to increase ICT efficacy for patients with GBM.
IMMU-53. ANTIGEN PRESENTATION BY TUMOR-ASSOCIATED MACROPHAGES MEDIATES PROGENITOR TO TERMINAL EXHAUSTION TRANSITION IN GBM AND OTHER SOLID TUMORS
Authors: Waibl-Polania Jessica , Hoyt-Miggelbrink Alexandra , Tomaszewski William , Wachsmuth Lucas , Lorrey Selena , Wilkinson Daniel , Lerner Emily , Woroniecka Karolina , Finlay John , Fecci Peter
Published: November 2024

While terminally exhausted T cells (Tex_term) retain important anti-tumor cytotoxic function, it is the relative preservation of renewable, stem-like progenitor exhaustion (Tex_prog) that better indicates immunotherapeutic responsivity. Although restraining the progression from Tex_prog to Tex_term thus takes on clinical significance, the cellular interactions in a tumor microenvironment (TME) governing such progression remain less established. Employing glioblastoma (GBM) and other solid tumors as models of severe exhaustion, we provide a detailed characterization of the progression from Tex_prog to Tex_term within the TME, where we observe a striking and disproportionate loss of Tex_prog over time, leading to a low progenitor exhaustion to terminal exhaustion ratio (PETER). We find exhaustion concentrated within tumor-specific T cell subsets, with cognate antigenic exposure requisite for acquisition of the Tex_term phenotype. However, we implicate tumor-associated macrophages (TAM), and not tumor cells, as the source of antigenic exposure governing the Tex_prog to Tex_term transition. Using cell – cell interaction analysis, we additionally highlight candidate receptor–ligand communications that may be specifically mediating the progression to Tex_term and resultant decline in PETER within the TME.
IMMU-57. METHYL-B-CYCLODEXTRIN PARTIALLY REVERSES THE IMMUNOSUPPRESSIVE EFFECTS OF GLIOBLASTOMA DERIVED EXTRACELLULAR VESICLES ON LYMPHOCYTES
Authors: Inocencio Julio , Aoki Minori , Mitrasinovic Stefan , Asad Mohammad , Himes Benjamin
Published: November 2024

Extracellular vesicles (EVs) derived from glioblastoma (GBM) have been demonstrated in multiple studies to contribute to tumorigenesis, invasion, and immunosuppression. Our prior results demonstrate that EVs can induce the differentiation of myeloid-derived suppressor cells (MDSCs), which in turn impair T cell activation and proliferation in vitro. Methyl-B-Cyclodextrin (MBCD), a cholesterol depleting agent, can interfere with lipid rafts, which are cholesterol rich microdomains on the cellular membrane that act as a docking mechanism for EV uptake. Herein we demonstrate that MBCD can inhibit EV uptake and partially reverse the immunosuppressive effects of EVs on both monocytes and T cells.

METHODS

EVs were isolated using stepwise ultracentrifugation from GBM cultures. GBM derived EVs were then added to extracted monocytes from donor samples with or without MBCD for 72 hours under hypoxic conditions. The EV exposed monocytes were then co-cultured with T lymphocytes and cell proliferation was measured via flow cytometry.

RESULTS

Exposure to GBM-derived EVs induced MDSC differentiation in monocytes by at least 50% while the addition of MBCD reduced MDSC levels similar to that of the control group. Moreover, MBCD exposure resulted in increased T cell proliferation in the presence of EV treated monocytes compared to untreated samples.

CONCLUSION

MBCD can be used as a therapeutic agent to reverse MDSC induction by GBM derived EVs and can partially rescue T cell activation and proliferation.
IMMU-70. GLIOBLASTOMA DERIVED IL-8 INSTRUCTS IMMUNE CELL IDENTITY IN LATERAL VENTRICLE CONTACTING TUMORS
Authors: Medina Stephanie , Brockman Asa A , Cross Claire E , Hayes Madeline J , Mobley Bret C , Mistry Akshitkumar M , Chotai Silky , Weaver Kyle D , Thompson Reid C , Chambless Lola B , Ihrie Rebecca A , Irish Jonathan M
Published: November 2024

Adult IDH-wildtype glioblastoma (GBM) is an aggressive brain tumor with no established immunotherapy. Glioblastoma tumors that contact the ventricular-subventricular zone (V-SVZ) stem cell niche have especially poor clinical outcomes (PMC5771712, PMC5262526) and abnormal immune microenvironments filled with CD32+ HLA-DRhi macrophages that have displaced resident microglia (PMC10371245). Identifying the origin and role of these CD32+ macrophages is likely critical to developing successful GBM immunotherapies. Here, we present a mechanistic origin for these CD32+ cells as M_IL-8 macrophages. In ex vivo experiments with conditioned medium from primary human tumor cells, IL-8 was sufficient and necessary for tumor cells to instruct healthy macrophages, and inhibitory antibodies to IL-8 blocked the generation of CD32+ CD163+ M_IL-8 cells. Additionally, IL-8 protein was present in GBM tumor cells in vivo and especially common in tumors contacting the V-SVZ (p<0.0001, N=192 cores from 73 patients). Surface proteins CXCR1 and CXCR2, the primary receptors for IL-8, were detected on cells that were spatially separated from IL-8+ glioblastoma cells in tumors contacting the V-SVZ. These results suggest the hypothesis that glioblastoma-cell IL-8 instructs incoming CXCR1+ hematopoietic macrophages to adopt a suppressive M_IL-8 identity in V-SVZ-contacting GBM. Abundant HLA-DR (MHC II) observed on the CD32+ M_IL-8 cells closely matched the signature phenotype of cells in human tumors (PMC10371245) and contrasted with lower surface MHC II expression typically observed on human myeloid derived suppressor cells (PMC6608074). M_IL-8 cells might especially target CD4+ helper T cells required for effective cancer immunotherapy (PMC5312823). IL-8 and CD32+ macrophages should now be explored as targets in combination with GBM immunotherapies, especially for patients whose tumors present with radiographic contact with the V-SVZ stem cell niche. Some results here have been shared in a bioRxiv preprint by the these authors (PMC10996638).
IMMU-71. CRANIOENCEPHALIC FUNCTIONAL LYMPHOID UNITS IN GLIOBLASTOMA
Authors: Dobersalske Celia , Rauschenbach Laurèl , Hua Yichao , Berliner Christoph , Hermann Ken , Rambow Florian , Cima Igor , Sure Ulrich , Scheffler Björn
Published: November 2024

The general accessibility of the brain to immune cells has been a subject of intense debate and reinterpretation within the last decade. While glioblastoma’s brain tumor ecosystem is typically considered immunosuppressed, we report the presence of a tumor-reactive immune cell niche within the cranial bone marrow (CB) situated adjacent to treatment-naive tumors. At time of initial diagnosis, glioblastoma patients underwent clinical and anatomical imaging, which revealed an unexpected co-morbid association between the CB and the tumor. Following this observation, we conducted an extensive experimental study including multiplex immunofluorescence, immunoprofiling, functional assays, and single-cell analysis, which identified an active lymphoid niche within the patient’s CB. CD8+ T cell effector cells residing in this niche exhibited acute and durable antitumor responses, and, compared to cells from the distal bone marrow, showed increased expression of the lymphoid egress marker S1PR1. Single-cell T cell receptor sequencing revealed a rich reservoir of non-exhausted tumor-shared CD8+ T cell clonotypes within the CB lymphoid niche, suggesting re-circulation between the proximal bone and the tumor tissue. These clonotypes were characterized by a high predicted tumor-reactivity, significantly surpassing levels found in blood and distal bone marrow. We discovered the entire developmental spectrum of CD8+ T cells in the CB, indicating that anatomical proximity may play a critical role in the process of early anti-tumor response. Correspondingly, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker, indicating focal association with improved progression-free survival. Our findings support the preservation and further exploitation of these cranioencephalic units to improve clinical care in glioblastoma patients.
INNV-06. ADULT GLIOBLASTOMA WITH MISMATCH REPAIR DEFICIENCY FORMS A DISTINCT HIGH-RISK MOLECULAR SUBGROUP FOR WHICH TREATMENT WITH IPILIMUMAB-NIVOLUMAB SHOWS SURVIVAL ADVANTAGE
Authors: Georgescu Maria-Magdalena
Published: November 2024

Glioblastoma is the most frequent and malignant primary brain tumor. Although the survival is generally dismal for glioblastoma patients, risk stratification and the identification of high-risk subgroups is important for prompt and aggressive management. The G1-G7 molecular subgroup classification based on the MAPK pathway activation has offered for the first time a non-redundant, all-inclusive classification of adult glioblastoma. Five patients from the large, 220-patient prospective cohort showed germline mutations in mismatch repair (MMR) genes and significantly worse median survival (3.25 months post-surgery) than those from other subgroups or from the rest of the cohort adjusted for age. These tumors were assigned to a new subgroup, G3/MMR, a spin-off from the major G3/NF1 subgroup, as they generally show genomic alterations leading to RAS activation. An integrated clinical, histological, immunohistochemical and molecular analysis of the G3/MMR tumors showed distinct characteristics as compared to other glioblastomas, including those with iatrogenic high tumor mutation burden (TMB), warranting a separate subgroup. Among these, prior history of cancer, midline location or multifocality, presence of multinucleated giant cells, positive p53 and MMR immunohistochemistry, and specific molecular characteristics, including high TMB, alert to this high-risk G3/MMR subgroup. High TMB constitutes the criterium for treatment with immune checkpoint inhibitors in solid cancers. The FDA-approved first-line therapy for advanced non-small cell lung cancer and high-TMB colorectal cancer is with the dual ipilimumab-nivolumab regimen. One of the five G3/MMR subgroup patients received the dual ipilimumab-nivolumab regimen and survived much longer than the rest of the G3/MMR patients, setting a proof-of-principle example for the treatment of these very aggressive G3/MMR glioblastomas.
INNV-09. DISTANT PARENCHYMAL RECURRENCE DURING LONG-TERM USE OF TTFIELDS TREATMENT FOR GLIOBLASTOMA
Authors: Takido Yuhei , Ohka Fumiharu , Deguchi Shoichi , Motomura Kazuya , Mitsuya Koichi , Shiba Yoshiki , Takeuchi Kazuhito , Nagata Yuichi , Yamaguchi Junya , Kibe Yuji , Fuse Yutaro , Maeda Sachi , Shimizu Hiroki , Nohira Shota , Yamamoto Ryo , Ito Shohei , Nakamura Akihiro , Saito Ryuta
Published: November 2024

BACKGROUND

Tumor treating fields (TTFields) treatment has been an important option for the treatment of glioblastoma. The introduction of novel treatment options may lead to distinct recurrence patterns compared to those observed with conventional therapies; however, the specific recurrence pattern during TTFields treatment has not been elucidated.

METHODS AND RESULTS

Here, we analyzed 39 cases of glioblastoma treated with TTFields. Although a usage rate of more than 75% is recommended, among 39 cases, 18 discontinued TTFields treatment owing to requests by patients with lower usage rates. In these discontinued cases, patients exhibiting sensory aphasia were more frequently included compared to those who continued TTFields (44.4%, p<0.001). Among 21 cases involving patients who continued TTFields, tumor recurrence was observed in 15 of those cases. Five out of 15 cases (33.3%) exhibited recurrence in distant parenchyma from the primary lesion. A higher usage rate and relatively longer use of TTFields were observed in these five cases, along with more favorable progression-free survival than those in the other 10 cases (p=0.019, p=0.040, and p=0.024, respectively). In one case, recurrent tumors with lower-grade glioma histology but molecular markers characteristic for glioblastoma, IDH-wildtype were identified. This tumor arose in an area that received a lower local minimum power density of TTFields compared to the primary lesion, following long-term TTFields therapy

CONCLUSIONS

Long-term use of TTFields might be correlated with a high frequency of distant parenchymal recurrence in cases with favorable response.
INNV-26. FEASIBILITY EVALUATION OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY FOR BRAINSTEM GLIOMAS
Authors: Shi Wenyin , Berger Brian , Urman Noe
Published: November 2024

BACKGROUND

Tumor Treating Fields (TTFields) therapy is a novel anti-mitotic therapy that is FDA-approved for use in patients with newly diagnosed and recurrent glioblastoma (GBM). However, TTFields therapy is currently only approved for supratentorial GBM, and the feasibility of TTFields therapy for treating infratentorial GBM remains unknown. TTFields values of average local minimum power density (LMiPD) >1.15 mW/cm3 and local minimum field intensity (LMiFI) >1.06 V/cm, were associated with improved OS and PFS based on a posthoc analysis of the EF-14 study. This is a dosimetric planning evaluation of the feasibility of TTFields therapy for brainstem gliomas.

METHODS

MRIs of patients with brainstem gliomas were used for this dosimetric evaluation, with planning conducted using MAXPOINT (Novocure, Switzerland). Gross tumor volume (GTV) for TTFields planning was defined as enhancing tumor on T1 post contrast MRI. Clinical target volume (CTV) was defined as GTV expanded by a 3 mm margin around sum total of resection cavity, necrotic core, and enhancing tumor. LMiPD and LMiFI to the GTV and CTV were evaluated.

RESULTS

A total of 5 patients with brainstem gliomas were included in this study. The median GTV volume was 8.2 cc (range: 3.8 – 13.5 cc), and median CTV volume was 18.6 cc (range: 9.1 – 23.4 cc). The median LMiPD for GTV and CTV were 1.9 (range: 1.1 – 2) and 1.9 (range: 1-2.1) mW/cm3, respectively. The median LMiFI for GTV and CTV were 1.3 (range: 1.1-1.6) and 1.2 (range: 1.1-1.6) V/cm, respectively.

CONCLUSION

LMiPD and LMiFI values for brainstem gliomas achieved levels that are consistent with those associated with improved OS and PFS in posthoc analyses in supratentorial GBM. This dosimetric planning study suggests feasibility and theoretical benefit of TTFields for brainstem gliomas. Further clinical evaluation is warranted to validate its efficacy.
INNV-37. REAL-WORLD OUTCOMES AMONG HIGH GRADE IDH1-MUTANT GLIOMA PATIENTS TREATED WITH AN IDH INHIBITOR
Authors: Ziv Michal Nisnboym , Patel Mallika P , Minor Maria , Johnson Margaret O , Batich Kristen , Low Justin , Shoaf Madison L , Khasraw Mustafa , Desjardins Annick , Friedman Henry S , Ashley David M , Peters Katherine B
Published: November 2024

BACKGROUND

Isocitrate dehydrogenase (IDH) inhibitors are transforming the treatment of patients with non-enhancing grade 2 IDH-mutant gliomas. Uncertainty remains on the utility of IDH-inhibitors in high-grade IDH-mutant glioma patients that had prior therapies and have progressive disease.

METHODS

From October 2020 to December 2023, we identified high-grade IDH1-mutant patients treated with off-label ivosidenib, a mutant IDH1 inhibitor. We report their clinical and imaging characteristics.

RESULTS

In our cohort (n=18), the patient age range was 29-68 years with male predominance (n=11). Diagnoses included astrocytoma grades 3 (n=9) or 4 (n=2), and oligodendroglioma grade 3 (n=7). The median number of progressions prior to ivosidenib initiation was 2 (range 1-7). Fifteen patients had prior surgical resection, three had biopsy. Prior treatment exposures included radiation therapy (n=15), temozolomide (n=18), lomustine (n=5), bevacizumab (n=3), etoposide (n=1), optune (n=1) and a clinical trial (n=1). Mean time from diagnosis to ivosidenib treatment was 9.6 years (95% CI, 6.7 to 16.4 years). Karnofsky performance-status score upon initiation was 80 (n=6) or 90 (n=12). Thirteen patients had >1 cm enhancing disease, five had non-enhancing disease. Ivosidenib was initiated due to enhancing disease progression (n=11), non-enhancing disease progression (n=4), a combination of both (n=2) or temozolomide intolerance (n=1). Best radiographic responses per RANO criteria were partial response (n=2), minor response (n=3), stable disease (n=7), and progressive disease (n=6). Nine patients continue ivosidenib without disease progression, with a median treatment duration of 27.5 months (95% CI, 18.0 to 33.0 months). All had FLAIR stabilization/improvement and 45% (n=4) had improved enhancing disease. Nine patients discontinued ivosidenib due to progression, with a median treatment duration of 7 months (95% CI, 3 to 9 months).

CONCLUSIONS

These data suggest that treatment with an IDH inhibitor can provide disease control for some high-grade IDH-mutant glioma patients who had prior therapies and progressive disease. Future studies are needed to investigate this patients population.
INNV-38. 3 DAYS-ON-1 DAY-OFF FRACTIONATED USE PROTOCOL FOR IMPROVED COMPLIANCE AND PREVENTATIVE SKIN SAFETY FOR USE OF TUMOR TREATING FIELDS: PRACTICE IMPROVEMENT STRATEGY IN NEURO-ONCOLOGY
Authors: Gatson Na Tosha , Leese Erika , Ornelas Sara , Tadipatri Ramya , Manikowski Jesse , Patel Chirag , Odia Yazmin
Published: November 2024

BACKGROUND

Compassionate care delivery requires that providers understand patient values and adopt practices aimed to improve the quality of extended survival. Many brain tumor clinical trials measure survival outcomes based on therapeutic interventions, but often fail to anticipate patient noncompliance and the provider’s ability to communicate the plan. Tumor Treating Fields (TTFields) is an FDA-approved locoregional, noninvasive therapy worn on the scalp to treat glioblastoma (GBM). When worn, TTFields therapy disrupts cancer cell viability and delays tumor progression but is complicated by mild-moderate skin irritation and real-world inconvenience of the unclear recommendation to wear the device an average of “≥18 hours/day or 75% of the time”. We simplified the physician instructions to encourage patient compliance and skin safety on TTFields.

METHODS

Adults with GBM were provided an easy-to-follow flow chart and advised across multiple centers to follow the 3-days-on (72 hours) and 1-day-off (16–24 hours) TTFields therapy use schedule and given skin-specific wound prevention guidance (cleansing selenium-based shampoo and reparative skin-barrier moisturizing) during the ‘off day’. We evaluated the ease to explain the 3-on-1-off schedule, patient adherence, and the presence and severity of skin AEs during follow-up visits.

REAL-WORLD PRACTICE OUTCOMES

Seventy-six patients received TTFields therapy using the 3-on-1-off protocol between 2015 and 2021 at two US healthcare centers. The median age was 57 years (range 25–81). The mean time on TTFields therapy was 73 weeks. Skin AEs occurred in 5% of patients on the 3-on-1-off protocol, as compared to 16% and 52% reported on EF-11 (NCT00379470) and EF-14 (NCT00916409) GBM studies, respectively. Majority of AEs were mild, and no patients discontinued TTFields therapy or modified electrode placement due to skin AEs while on the 3-on-1-off protocol.

CONCLUSION

We report real-world data confirming a practice improvement for patient compliance using a novel 3-on-1-off protocol which minimizes skin AEs and treatment interruptions to improves patient outcomes. An ounce of prevention is worth a pound of cure.
PATH-02. MESENCHYMAL-TYPE GENETIC MUTATIONS ARE LIKELY PRE-REQUISITE FOR GLIOBLASTOMA TO METASTASIZE OUTSIDE THE CENTRAL NERVOUS SYSTEM: AN ORIGINAL CASE SERIES AND SYSTEMATIC REVIEW OF THE LITERATURE
Authors: Laurin Bryce , Treffy Randall , Connelly Jennifer , Straza Michael , Mueller Wade , Krucoff Max
Published: November 2024

Glioblastoma multiforme (GBM) is locally aggressive, yet it metastasizes outside the central nervous system (CNS) in only 0.4% of cases. Little is known about what enables this subset of GBMs to survive outside the CNS, so we conducted a PRISMA-compliant systematic review of metastatic GBM wherein we reviewed 3579 search results and 1080 abstracts, ultimately analyzing data from 139 studies and 211 unique patients. Additionally, we analyzed four modern-day cases treated at our institution. In our patients, primary GBM lesions revealed consistent mutations in NF1, TERT, TP53, CDK4, and RB1/PTEN genes. Unique to the metastatic lesions were amplifications in integral cell-cycle regulating genes such as p53 and PDGFRA/KIT, as well as increased vimentin and Ki-67 expression. These data support the hypothesis that glial cells likely underwent mesenchymal-like mutations prior to extra-CNS involvement. How these cells reach the extra-axial environment is still under debate. In our systematic review, we found that metastases were discovered near previous surgical sites in at least 36.9% of cases, suggesting tumor seeding into the scalp during surgery may facilitate mesenchymal-type mutation in some cases. However, this is unlikely to be sole mechanism of spread as there are several reports of spread without surgery, and other hypothesized mechanisms include spontaneously circulating cells and glymphatics. Other sites of GBM metastasis included bone (47.9%), lung (25.6%), lymph nodes (25.1%), and liver (14.2%). On average, metastases were diagnosed 12.1 months after the most recent resection, and the mean survival from discovery was 5.7 months. In sum, there is strong evidence that GBMs acquire novel mutations to survive outside the CNS, are spread spontaneously or iatrogenically, and portend a poor prognosis once disseminated. Routine genetic and molecular characterization of both primary and metastatic GBMs and widespread reporting will help further characterize mechanisms of spread for this rare but deadly pathology.
PATH-05. CLINICAL, PATHOLOGICAL AND MOLECULAR DISEASE CHARACTERISTICS OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Le Rhun Emilie , Bink Andrea , Felsberg Joerg , Gramatzki Dorothee , Brandner Sebastian , Benhamida Jamal K , Wick Antje , Tonn Joerg C , Mohme Malte , Tabatabai Ghazaleh , Capper David , Snuderl Matija , Razis Evangelia , Ronellenfitsch Michael , Neidert Nicolas , Ng Ho-Keung , Pohl Ute , Bale Tejus , Quach Stefanie , Rieger David , Schüller Ulrich , Onken Julia , Drueschler Katharina , Maurage Claude Alain , Regli Luca , Healy Estelle , Graham Maya , Hortobagyi Tibor , Paine Simon , Ansorge Olaf , Bridges Leslie , Lausova Tereza , Medici Valentina , Sievers Philipp , Schrimpf Daniel , Wick Wolfgang , Sahm Felix , Reifenberger Guido , von Deimling Andreas , Weller Michael
Published: November 2024

BACKGROUND

Diffuse hemispheric glioma, histone 3 (H3) G34-mutant, is a pediatric-type diffuse high-grade glioma newly defined in the World Health Organization (WHO) classification of central nervous system tumors 2021. Here we sought to define the prognostic roles of clinical, neuroimaging, pathological, and molecular features of these tumors.

METHODS

We retrospectively assembled a cohort of 114 patients with diffuse hemispheric glioma, H3 G34-mutant and profiled the imaging presentation and the molecular landscape of their tumors.

RESULTS

Compared with glioblastoma, H3 G34-mutant tumors exhibited less avid contrast enhancement, less necrosis and less edema on MRI. Comprehensive analyses of mutational and DNA copy number profiles revealed recurrent mutations in TP53 and ATRX, homozygous deletions of CDKN2A/B, and amplifications of PDGFRA, EGFR, CCND2, and MYCN. MGMT promoter methylation was detected in 79 tumors (75%); 11 tumors (13%) showed DNA copy number profiles suggestive of circumscribed deletions on 10q26.3 involving the MGMT locus. Median survival was 21.5 months (95% CI 15.3-27.7) and eight patients (7.0%) survived for ≥ five years. Female sex, gross total resection, and MGMT promoter methylation were positive prognostic factors on univariate analysis. Among radiological, pathological and molecular features, absence of pial invasion, and presence of microvascular proliferation and CDK6 amplification were positive prognostic factors on univariate analyses.

CONCLUSION

This study refines the clinical and molecular landscape of H3 G34-mutant diffuse hemispheric gliomas. Dedicated trials for this novel tumor type are urgently needed.
PATH-09. CLINICAL CHARACTERISTICS AND MOLECULAR CHARACTERISTICS OF 244 MEDULLOBLASTOMAS IN JAPAN
Authors: Go Kohichi , Katsuma Asako , Makino Yasuhide , Yamamoto Etsuko , Yoshioka Ema , Shofuda Tomoko , Kanematsu Daisuke , Takada Shigeki , Sano Noritaka , Tanji Masahiro , Mineharu Yohei , Fukuoka Kohei , Kodama Yoshinori , Mano Masayuki , Ichimura Koichi , Sasaki Atsushi , Hirato Junko , Inoue Takeshi , Nishikawa Ryo , Date Isao , Nonaka Masahiro , Nagane Motoo , Arakawa Yoshiki , Kanemura Yonehiro
Published: November 2024

BACKGROUND

Medulloblastomas are at least classified into four core subgroups, including WNT-activated, SHH-activated, group 3 and group 4. These molecular subgroups have been introduced in the WHO classification, which has become fundamental and indispensable. The JPMNG is co-organized by the Japan Society for Neuro-Oncology and the Japanese Society for Pediatric Neurosurgery, and we have summarized clinical and molecular characteristics of Japanese MBs.

METHODS

We enrolled 267 cases of medulloblastoma from 44 centers participating in the JPMNG study. Central histopathological diagnosis was performed by three neuropathologists, and molecular genetic diagnosis was performed by NanoString nCounter system or DNA methylation array, and their single nucleotide mutations and copy number aberrations have been also examined.

RESULTS

A total of 244 cases were finally analyzed, and the 4-subgroup classification was WNT: 39 (16%), SHH: 61 (25%), group3: 42 (17%), and group4: 102 (41.8%), respectively. In cases of less than 3 years old, no WNT have been found and 62.2% cases were SHH. In cases of WNT-MB, the majority being children (6-18 years) (31/39: 79.5%), and 8 cases (8/39: 20.5%) in adults older than 18 years. In cases between 3 to 17 years old, Group 4 is the most (48.6%), and these trends is almost consistent with published. references. Metastatic or MYC gain Group 3 MBs were poor prognosis, while Group 4 MBs with loss of chromosome 11 or whole chromosomal aberration were good prognosis.

CONCLUSIONS

Clinical and molecular characteristics of Japanese WBT-MB were almost consistent with those reported in other countries, and the relationship between molecular properties and prognosis of group3/group4 MBs were also reproducible. These findings suggest importance of molecular properties of MBs are preserved beyond ethnic differences, and will contribute to develop new therapeutic strategies.
PATH-10. UTILIZATION OF TUMOR-DERIVED EXTRACELLULAR VESICLES FOR PATIENT STRATIFICATION AND BIOMARKER DISCOVERY
Authors: Havranek Katie , Seibold Claire , Seibold Tia , Kinnersley Margie , Van Vaerenberghe Kelley , Blohm Tre , Short-Miller Rachel , Lodmell Sean , Mast Amanda , Kemp Riley
Published: November 2024

Liquid biopsy is poised to play an increasingly important role in clinical decision making by enabling earlier cancer detection, diagnosis, patient stratification, and treatment monitoring. Most approaches rely on detection of cell-free circulating tumor DNA or circulating tumor cells in the peripheral blood of cancer patients. However, there are several limitations to these approaches, including miniscule abundance, unfavorable signal to noise ratios, and limited insight into mechanisms driving disease. Extracellular vesicles (EVs) are an alternative liquid biopsy analyte comprising lipid membrane encapsulated particles carrying diverse protein, nucleic acid, and metabolite cargos. Blood plasma of cancer patients contains EVs derived directly from tumor tissue that serve as rich sources of insight into tumor biology and disease pathology. We have developed a clinically applicable, multi-omic EV subpopulation interrogation pipeline that robustly profiles tumor-derived EVs in biofluids. We have demonstrated the ability of the platform to enrich cancer markers and detect activation of pathways driving oncogenesis across several different cancers, including brain cancer. There is a particularly compelling need for liquid biopsy-based solutions in neuro-oncology. We have applied our EV-omic (EVO) pipeline in combination with machine learning to distinguish adult high-grade gliomas from benign brain tumor and healthy patients, using blood-based EV proteomic and transcriptomic signatures. Marker profiles found to be most important for patient stratification combine markers known to be relevant in tumor tissue along with novel features. Furthermore, IDH status and MGMT methylation metadata derived from matched patient tissue for select cases was used to generate unique blood-based profiles for glioma subtypes. Lastly, we show preliminary longitudinal data demonstrating the utility of EVs to track tumor changes post-surgical resection and post-treatment. This work demonstrates that EV-omics can add significant value in the neuro-oncology space.
PATH-14. UTILITY OF DNA METHYLATION ANALYSIS IN HISTOLOGICALLY-CONFIRMED PA PATIENTS WITH POOR PROGNOSIS
Authors: suruga yasuki , Satomi Kaishi , Otani Yoshihiro , Fujii Kentaro , Ishida Joji , Uneda Atsuhito , Tsuboi Nobushige , Makino Keigo , Hirano Shuichiro , Kemmotsu Naoya , Imoto Ryoji , Mizuta Ryo , Tomita Yusuke , Yasuhara Takao , Washio Kana , Yanai Hiroyuki , Matsushita Yuko , Hibiya Yuko , Yoshida Akihiko , Ichimura Koichi , Tanaka Shota
Published: November 2024

INTRODUCTION

Pilocytic astrocytoma (PA) is a circumscribed low-grade astrocytic glioma, generally considered to be associated with a good prognosis. However, some PA patients experience unfavorable outcomes; advanced age was known as an independent poor prognostic factor. This study retrospectively reviewed PA patients and conducted molecular analyses for elderly patients.

METHODS

We analyzed data from 29 histologically confirmed PA patients treated at a single center from 2002 to 2021 and conducted integrated molecular analyses including DNA methylation profiling for elderly PA patients.

RESULTS

The median age at diagnosis was 14 years (range 3-82 years), with 4 patients (14%) being elderly (patients≥60years old). Elderly patients had significantly worse progression-free survival and overall survival. DNA methylation analysis was performed on 2 of the 4 elderly patients. Despite histological diagnoses of PA, methylation profiling classified one case as high-grade astrocytoma with piloid features (methylation class scores below 0.3 in both v11b4 and v12.5) and the other as glioblastoma, IDH-wildtype (score over 0.5 in both v11b4 and v12.5), using classifiers from the German Cancer Research Center and t-SNE analysis.

CONCLUSION

Elderly patients with PA morphology showed unfavorable outcomes in this cohort. In those patients, DNA methylation profiling revealed the possibility of high-grade astrocytic tumors, including newly defined entities.
PATH-17. MOLECULAR CLASSIFICATION OF H3K27-WILDTYPE SPINAL CORD GLIOMAS: IMPLICATIONS FOR PROGNOSIS AND THERAPEUTICS
Authors: Chai Ruichao , Chen Huiyuan , Chang Qing , Wang Yongzhi , Wang Jiguang
Published: November 2024

BACKGROUND

H3K27-wildtype spinal cord gliomas (H3WT-SCGs) are rare and heterogeneous tumors that present significant challenges in pathological classification. Traditional histologic diagnoses often do not align well with the underlying molecular characteristics of these tumors.

METHODS

We characterized 55 cases of H3WT-SCGs using a comprehensive approach that included DNA methylation array, whole-exome sequencing, transcriptome sequencing, proteomics, and single-cell RNA sequencing. Unsupervised clustering analysis was performed to identify distinct molecular subtypes.

RESULTS

The analysis identified seven distinct spinal cord methylation (SCM) clusters: pilocytic astrocytomas (PA-SPINE), PA-immune enriched (PA-IME), diffuse leptomeningeal glioneuronal tumor (DLGNT), subependymoma (SUBEPN-SPINE), glioblastoma-like (GBM-like), and pleomorphic xanthoastrocytoma-like (PXA-like). There was a 61.8% discordance between SCM classes and traditional histologic diagnoses. The new molecular classification provided a better correlation with molecular features and patient prognosis. BRAF fusions were enriched in PA-SPINE and DLGNT (p = 0.04), and DLGNT showed significant chromosomal alterations, including 1p loss (p = 6.5e-08) and 1q gain (p = 3.6e-05). Notably, we identified two distinct classes of PA-SPINE: adult (older than 18 years) and pediatric. Adult PAs exhibited lower frequencies of BRAF fusions (p = 1.4e-03), shorter tumor lengths (p = 3.7e-04), and longer progression-free survival (p = 0.062). Adult PA neoplastic cells were less differentiated, with higher expression of EGFR and neuronal markers, and lower cytokine and chemokine expression compared to pediatric cases. Single-cell analysis revealed reduced infiltration of monocyte-derived macrophages and proliferative myeloid cells in adult cases. Both PA-IME and PA-pediatric clusters were characterized as immune-hot tumors with high immune cell enrichment.

CONCLUSION

This study defined clinically relevant molecular classes of H3WT-SCGs that better reflect patient prognosis and molecular characteristics compared to traditional histologic diagnoses. The findings suggest potential therapeutic implications, especially in immune-hot tumors like IME and PA-pediatric, which could benefit from targeted immunotherapies.
PATH-18. CURRENT STATUS OF CANCER GENOMIC PROFILING (CGP) TESTS IN BRAIN TUMOR TREATMENT - COMPLEMENTING BRAIN TUMOR PATHOLOGICAL DIAGNOSIS WITH CGP-
Authors: Kurozumi Kazuhiko , Shinichiro Koizumi , Kida Satoru , Tomoya Oishi , Yamasaki Tomohiro , Baba Satoshi
Published: November 2024

INTRODUCTION

Cancer genomic profiling (CGP) tests are currently used in the search for therapeutic targets and have become an auxiliary tool in diagnosis according to the new WHO classification (WHO 2021), which requires the integration of pathomorphological and molecular diagnostics. Here, we report on brain tumor cases at our institution that underwent CGP testing.

METHODS

From May 2020 to the present, 27 brain tumor cases that underwent CGP testing at our institution were included in this study. There were 14 males and 13 females, ranging from 18 to 70 years (average 48.4 years). The tests conducted included Foundation One CDx, GeneMineTop, and NCC OncoPanel.

RESULTS

The cases that underwent CGP testing included 13 cases of glioblastoma IDH-wildtype, 3 cases of astrocytoma, IDH-mutant, grade 4, 4 cases of astrocytoma IDH-mutant, grade 3, 3 cases of oligodendroglioma, 1p/19q codeleted, grade 3, 1 case of astrocytoma, IDH-mutant, grade 2, 1 case of ependymoma, 1 case of pilocytic astrocytoma and 1 case of PitNEC. CGP testing enabled molecular diagnostics such as IDH mutation and TERTp mutation. Based on the results, therapeutic suggestions were possible for 5 out of 25 cases (20%) (BRAF V600E mutation 1 case, IDH1 R132H mutation 1 case, TMB high 3 cases). Checkpoint inhibitors were used in a case with high TMB. Genetic risk assessment by a genetic counselor was conducted for all cases, and one high TMB case was diagnosed as hereditary cancer. A germline pathogenic variant in MSH6 was detected, leading to a diagnosis of Lynch syndrome.

CONCLUSION

Molecular diagnostics through CGP testing served as an aid in diagnosis according to WHO2021. Cases where drug suggestions were feasible underwent treatment with targeted molecular therapies and checkpoint inhibitor. We experienced cases where hereditary cancer syndromes such as Lynch syndrome were diagnosed through the detection of germline pathogenic variants.