bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract

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

Abstract
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&lt;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

Abstract
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

Abstract
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

Abstract

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&lt;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

Abstract

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) &gt;1.15 mW/cm3 and local minimum field intensity (LMiFI) &gt;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

Abstract

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 &gt;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

Abstract

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.