bluuebunny/crossref_metadata_2025 huggingface dataset:
DISP-03. HEALTH DISPARITIES IN NEURO-ONCOLOGY
Authors: Budhu Joshua , Michaelson Nara , Watsula Amanda , Bakare Anu , Mohamadpour Mali , Chukwueke Ugonma
Published: November 2024

Significant disparities in diagnosis, research, and treatment exist in neuro-oncology. Patients who identify as racial or ethnic minorities, sexual or gender minorities, elderly, rural, or have low socioeconomic status are more likely to have adverse outcomes. Using PubMed and expert opinion, we summarized the existing literature on health disparities in neuro-oncology. We categorized disparities based on primary central nervous system tumors (CNS), secondary CNS tumors, pediatric neuro-oncology, clinical trial enrollment and diversity, and financial toxicity. For patients with primary CNS tumors, we found that marginalized groups faced delays in diagnosis, lower rates of resection, and lower rates of postoperative radiation. For secondary CNS tumors, marginalized groups had lower rates of indicated cancer screening, less access to genetic testing, less access to advanced imaging, and lower rates of stereotactic radiosurgery and targeted therapies. Pediatric neuro-oncology patients had differences in morbidity and mortality based on socioeconomic status and race and faced substantial delays in diagnosis. Financial toxicity, the side effects of the high financial cost of a cancer diagnosis, disproportionately affects marginalized populations. This may be further exacerbated by the use of long-term medications such as IDH inhibitors. There is also unequal representation of diverse populations in neuro-oncology clinical trials. Compared to other cancer subspecialties, there is less available data on disparities, however, the types of disparities such as delays in diagnosis and outcomes are similar. Notably, there are not many interventions focused on mitigating these disparities. There needs to be additional research on health disparities in neuro-oncology, including both descriptions of existing disparities, but also on methods and interventions to address these disparities.
DISP-04. SEX DIFFERENCES IN LUNG CANCER BRAIN METASTASES ADVERSE EVENTS
Authors: Dmukauskas Mantas , Cioffi Gino , Waite Kristin , Mammoser Aaron , Sloan Andrew , Ma Patric , Barnholtz-Sloan Jill
Published: November 2024

While sexual dimorphism is evident among adverse events (AEs) in response to treatments for many cancers, including brain tumors, little is known about sexual dimorphism among AE in brain metastases (BrM). As over 50% of BrM cases arise from lung cancer (LC), we examined sex differences in AEs associated with LC-BrM among individuals in the SEER-Medicare dataset aged ≥66 years at the time of LC diagnosis. Multivariable logistic regression models adjusted for demographic variables and Elixhauser comorbidity scores were used to analyze sex differences in AEs among individuals with BrM derived from primary LC. Analyses were stratified by the following histological subtypes: small-cell, adenocarcinoma, squamous cell carcinoma, or other non-small cell carcinomas. Additional variables analyzed included BrM treatment, age at BrM diagnosis, and year of diagnosis (at or before 2013/after 2013) to account for the introduction of targeted therapies. Differences in AE profiles, based by sex, in individuals diagnosed with LC-BrM were observed. Females diagnosed after 2013 with either small-cell, squamous cell, or other non-small cell carcinoma BrMs were more likely to experience headaches compared to males. Males diagnosed after 2013 with adenocarcinoma were more likely to experience brain herniation compared to females. Additionally, females aged 76 and older with small-cell BrM demonstrated an elevated risk of developing vision difficulties relative to males, whereas no significant sex difference observed in those under 76 years. Risk of most AEs decreased across all histological subtypes with receiving treatment after BrM diagnosis when compared to no treatment. This study underscores the existence of sex-specific differences in AEs among individuals aged 66 years and older diagnosed with LC-BrM. The AEs observed varied across histological subtypes, age cohorts, year of diagnosis, and treatment. Notably, receipt of treatment demonstrates consistent reduction in AE risk across all histological subgroups, underscoring the therapeutic benefit of treatment.
DISP-09. IMPROVING ADHERENCE TO CANCER CARE IN UNDERSERVED PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Elshiekh Cleopatra , Phillips Ashley , Rodriguez Ashley , Narang Bharat , Gany Francesca , Budhu Joshua
Published: November 2024

Patients with central nervous system tumors have disease-specific symptoms such as aphasias, motor symptoms, neuropsychiatric symptoms, or seizures that make treatment adherence difficult. This is further exacerbated by the social determinants of health – patients from historically marginalized groups or those with lower socioeconomic status have additional barriers to treatment. The Integrated Cancer Care Access Network (ICCAN) is a multi-institutional patient navigation program assisting patients who express socioeconomic needs during cancer treatment. In this pilot program, we assessed the impact of ICCAN on treatment adherence and quality of life of CNS cancer patients from marginalized backgrounds. 42 participants with primary brain tumors or brain metastases were recruited from inpatient and outpatient services at Memorial Sloan Kettering Cancer Center to enroll in ICCAN-CNS. Patients were eligible if they were 18 years or older, receiving active treatment or under active surveillance, and screened positive for an essential need. Through standardized patient interviews and questionnaires, we evaluated their needs such as food access, housing, and financial needs. The clinical research coordinator interviewed the patients via phone, taking approximately 60 minutes. The interviews comprised an Essential Needs Assessment, Health Related Social Needs Assessment, NCCN Distress Thermometer, and an ICCAN-CNS questionnaire focused on neurology-specific symptoms. Caregivers helped complete the questions for patients with cognitive impairments. Patients were then matched with resources based on their initial needs assessment. The interviewer conducted 2, 4, and 6-month follow-ups to see if new needs emerged for which resources were provided. Response to the program was overwhelmingly positive with many patients expressing gratitude for the resources provided to them. This pilot demonstrates the feasibility of CNS tumor patients participating in the ICCAN intervention and the need for additional patient navigation programs and interventions that focus on the social determinants of health.
DISP-14. THE IMPACT OF DISTANCE IN TREATING GLIOBLASTOMA: A RETROSPECTIVE SINGLE CENTER STUDY
Authors: Kropp Samantha , Tenhoeve Sam , Zhao Yuxin , Chen Ann , Mendez Joe , Malani Rachna
Published: November 2024

INTRODUCTION

Glioblastoma (GBM) is an aggressive primary brain tumor associated with poor survival. Research shows that patients living in rural areas have poorer outcomes than those in metropolitan areas; however, little is known about how distance between patients and their subspecialist impacts outcomes. We explored the effect of distance from a National Cancer Institute-designated Comprehensive Cancer Center (CCC) has on overall survival (OS) and clinical trial enrollment for patients with GBM.

METHODS

Retrospective data was collected from patients with newly diagnosed GBM per the World Health Organization 2021 who received treatment at Huntsman Cancer Institute (HCI) from 2018 to 2022. Distance was evaluated as a categorical (near: 0-25 miles, intermediate: 25-40 miles, far: >40 miles) and continuous variable for analyses. In addition to univariable models, multivariable models adjusting for known prognostic factors were also performed.

RESULTS

A total of 167 patients were identified. Baseline characteristics including age, sex, race, and KPS scores were similar across groups. The univariable COX regression model found no significant difference in OS when comparing the near group to the intermediate (p=0.125) and far (p=0.599). However, the multivariable model found poorer OS in the intermediate group that was statistically significant when compared to the near group (HR (95% CI) = 1.55 (1.01, 2.39), p = 0.047). When comparing distances as a continuous variable, patients in the far group had statistically significant lower clinical trial enrollment rates (near group 43%, intermediate 35%, far 18%; p=0.0001).

DISCUSSION

Patients with GBM seeing a neuro-oncologist at our CCC did have a difference in OS as well as clinical trial enrollment when considering distance traveled. Clinical trials are standard of care for patients with GBM; our data provides evidence that distance from a CCC significantly affects trial enrollment, underscoring the importance of ensuring availability of resources for clinical trial participants.
DISP-16. EXPLORING SEX-BASED DIFFERENCES IN RESPONSE TO IMMUNOTHERAPY IN GLIOBLASTOMA: A RETROSPECTIVE REVIEW
Authors: Westergaard Catharina , Nakhate Vihang , Lasica Aleksandra Beata , Muzikansky Alona , Barlow Brooke , Russ Alyssa , Nwagwu Chibueze , Lee Eudocia , Chukwueke Ugonma , Nayak Lakshmi , Castro Luis Nicolas Gonzalez , Figueroa Jose Ricardo McFaline , Aquilanti Elisa , Beroukhim Rameen , Batchelor Tracy , Reardon David , Wen Patrick , Youssef Gilbert
Published: November 2024

BACKGROUND

The prognostic implication of sex is unclear in glioblastoma. A recent preclinical study suggested that T-cell exhaustion in males confers improved response to anti-PD1 therapy (PMID: 37378557). We conducted a retrospective study of patients with newly diagnosed (nGBM) and recurrent (rGBM) glioblastoma enrolled on immunotherapy trials at Dana-Farber Cancer Institute from 2014 to 2022 to determine whether sex influences the response to immunotherapy.

METHODS

Clinical, molecular, and radiographic data were collected, and their association with progression-free survival (PFS) and overall survival (OS) was evaluated using log-rank.

RESULTS

We evaluated 299 subjects with nGBM (172 male, 127 female) and 539 with rGBM (329 male, 210 female). In the nGBM cohort, median PFS for males vs females was 9.1 [7.2, 13.8] months vs 8.8 [6.5, 10.1] months (p=0.59) among subjects on immunotherapy trials (N=106), and 6.9 [6.1, 8.0] vs 6.5 [5.8, 8.1] months (p=0.44) in those on non-immunotherapy trials (N=193). Median OS was 18.6 [15.4, 24.0] in males vs 18.8 [15.9, 23.1] months in females (p=0.85) in immunotherapy trials and 15.6 [14.7, 17.3] vs 15.3 [13.1, 16.9] months (p=0.77) in non-immunotherapy trials. There was also no statistically significant difference in OS and PFS between sexes in the rGBM cohort: median PFS was 3.6 [3.0, 4.1] months in males vs 4.1 [3.8, 5.2] months in females and median OS was 8.4 [7.4, 9.6] vs 9.6 [8.2, 12.1] months in immunotherapy trials (N=254); median PFS was 1.8 [1.7, 2.1] vs 1.9 [1.8, 2.4] months and median OS was 8.6 [7.5, 9.6] vs 8.5 [7.3, 9.6] months in non-immunotherapy trials (N=285).

CONCLUSION

Sex did not have a prognostic impact on survival outcomes, regardless of the treatment modality. The impact of other clinical variables such as corticosteroid use, performance status, lymphocyte counts, and tumor burden will be reported.
IMMU-01. DE NOVO-DESIGNED BINDER-BASED CAR T CELLS ENABLE EFFECTIVE TARGETING OF GLIOBLASTOMA
Authors: Xie Qi
Published: November 2024

Glioblastoma is a devastating disease with poor responses to all current therapies. Chimeric antigen receptor (CAR) T cell therapy has achieved impressive success against hematological malignancies but produces responses in only a limited number of glioblastoma patients. Here, we developed a novel platform for CAR constructs using de novo designed protein binders to target tumor antigens. We firstly designed a binder CAR targeting epidermal growth factor receptor (EGFR), which is highly expressed in glioblastoma, to validate the feasibility of our platform. Our EGFR binder CAR design promoted CAR T cell proliferation, cytotoxic cytokine secretion and exhaustion resistance, leading to better antitumor performance both in vitro and in vivo. Bulk and single-cell transcriptional profiling of binder CAR T cells revealed an underlying mechanism involving enhanced effector activity and reduced exhaustion responses. Mechanismly, the binder CARs exhibited higher surface expression and greater resistance to degradation triggered by tumor antigens. Moreover, we designed and engineered a novel CD276 binder CAR T cell product and verified its antitumor function, further demonstrating the general applicability of our binder-based CAR platform. Overall, our study provides an alternative avenue for the design of a CAR antigen-binding domain to potentiate CAR T cell antitumor efficacy.
IMMU-03. EXPLORING CANCER-SPECIFIC T CELLS AND ANTIGENS IN GLIOBLASTOMA BASED ON SINGLE-CELL SEQUENCING OF CD8+ TILS
Authors: Okamoto Takanari , Mizuta Ryo , Demachi-Okamura Ayako , Muraoka Daisuke , Sasaki Eiichi , Masago Katsuhiro , Onoguchi Kazuhide , Yamashita Yoshiko , Muto Osamu , Yamaguchi Rui , Takahashi Yoshinobu , Hashimoto Naoya , Matsushita Hirokazu
Published: November 2024

BACKGROUND

The effectiveness of cancer immunotherapy against glioblastoma (GBM) remains limited. This study aims to identify cancer-specific antigens to develop antigen-based cancer immunotherapies for GBM. We investigated candidate tumor antigen-specific T cells in GBM by single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq), and we explored candidate antigens through genetic analysis of tumor tissues.

METHODS

Flow cytometry analysis was conducted on fresh tumor digest samples to evaluate tumor-infiltrating lymphocytes (TILs) of GBM. Single-cell RNA and TCR sequencing were performed on CD8+ T cells in TILs. Both data generated by Cell Ranger software were loaded into Seurat at R studio. The dimensional reduction for clustering was performed with uniform manifold approximation and projection (UMAP). Additionally, we performed bulk RNA sequencing (RNA-seq) and whole exome sequencing (WES) on tumor tissues.

RESULTS

Two out of 20 patients (10%) exhibited abundant TILs in GBM. From these two patients, approximately 20,000 CD8+ T cells in total were analyzed in single-cell analysis. Clustering based on UMAP revealed a predominance of clusters expressing exhaustion markers, with high TCR clonality centered on exhausted T cell (TEX) clusters, like our previous date of lung cancer TILs recognizing tumor antigens. Moreover, within the TEX clusters, the expression of CXCL13, often reported as an antigen-specific marker in recent years, was significantly higher in our data compared to two publicly available datasets. Subsequently, based on RNA-seq and WES, 61 candidate neoantigens were estimated using machine-learning prediction algorithms from NEC Corporation. Furthermore, 5 overexpressed cancer/testis antigens, and 3 bacterial species-derived microbial peptides using Kraken2 were selected as antigen candidates.

CONCLUSIONS

We identified prospective tumor antigen-specific T cell subsets with high CXCL13 expression from two GBM patients. We plan to identify cancer-specific T cells and antigens from these candidates by T cell activation assay.
IMMU-06. H-FERRITIN AFFECTS IMMUNE CELL INFILTRATION INTO THE GLIOBLASTOMA TUMOR MICROENVIRONMENT IN A SEX-BIASED MANNER
Authors: Pappus Sahu Aurosman , Palsa Kondaiah , Shenoy Ganesh , Helmuth Timothy B , Slagle-Webb Becky , Neely Elizabeth , Connor James R
Published: November 2024

Glioblastoma (GBM) is an aggressive brain cancer that is sexually dimorphic in nature, with females less susceptible to developing it, responding better to therapy, and gaining a survival advantage. Iron metabolism is also sexually dimorphic and has been shown previously to contribute to sex bias in GBM. Ferritin is an iron-storing protein that has elevated expression in tumor cells and is essential to GBM growth. Here, we used an in vivo GBM model consisting of heterozygous FTH1 knockdown (FTH1-KD) mice and GL261 cells to study the role of host ferritin in GBM progression. We have previously published that FTH1 knockdown in female mice decreased overall survival compared to WT (P = 0.03). This work delves into potential mechanisms that contribute to this survival difference. GBM was induced in 6-8 weeks-old mice by injecting 2*10^4 GL261 cells intracranially by a stereotaxic apparatus. The tumor volume was measured 3 weeks post-injection by magnetic resonance imaging, followed by image segmentation. We observed that FTH1 knockdown did not affect tumor volume. Flow cytometry was used to examine the immune infiltrating cells (CD45high) population in the tumor-bearing hemisphere. In females, there was an increase in CD11b+ cells in FTH1KD mice compared to WT mice (P = 0.0607). Similarly, Female FTH1-KD mice had a lower T cell (CD3+) population than Female WT mice (P = 0.0033). This decrease in infiltrating CD3 cells was due to a reduction of CD4 T cells (CD3+ CD4+) in female FTH1-KD mice compared to female WT mice (P = 0.0375). We observed no difference in CD8 T cells (CD3+ CD8+). These data indicate that host ferritin affects immune infiltration into GBM cells in a sex-biased manner.
IMMU-08. PRECLINICAL EVALUATION OF GAL-1-SPECIFIC CAR-T CELL FUNCTION IN AN IN VITRO AND EX VIVO MODEL OF GLIOBLASTOMA
Authors: Das Arabinda , Zukas Alicia M , Santos Jaime Martinez , Stephens Heather R , Mark Joseph , Sekerak Penny , Infinger Libby Kosnik , III William A Vandergrift , Varma Abhay K , Patel Sunil J , Cachia David , Lindhorst Scott M
Published: November 2024

BACKGROUND

Human glioblastoma (GBM), especially those exhibiting anti-VEGF resistance, overexpress the carbohydrate-binding protein galectin-1 (Gal-1). To develop novel anti-GBM approaches, we developed Gal-1 targeted CAR-T cells to investigate potential antitumor effect with in vitro and ex vivo slice culture models.

METHODS

Uniform GBM brain slice cultures were collected using NICO’s Myriad resection tool and their Automated Preservation System (APS), designed to obtain fresh brain tumor samples maintaining tumor cytoarchitecture and microenvironment. To prepare Gal-1 CAR-T cells, we used creative laboratory to utilize a third-generation Gal-1-CAR construct with high binding and codon optimized scFv-Gal-1 fragment fused with CD3ζ and co-stimulatory cytoplasmic domains of CD28 and 4-1BB (Gal-1 scFv-CD28-4-1BB-CD3ζ). We then transfected into the T cells, from peripheral blood, mononuclear cells using a lentiviral system. The anti-tumor capabilities of CAR-T cells were evaluated by co-culturing with GBM cells and ex vivo APS-GBM slices.

RESULTS

The collected APS- GBM slices samples were clear of debris and blood product, not requiring post-surgical mechanical slices, and exhibited viability up to 12 days over traditionally prepared ex vivo cultures. With this, we found Gal-1-CAR-T cells grew exponentially in the presence of cytokines and maintained phenotypic and biological attributes such as cell viability, potency, migration, and T cell activation. Gal-1 scFv-CD28-4-1BB-CD3ζ -CAR-T cells killed more than 80% of GBM tumor cells within 24 hours in Gal-1+ve, but not Gal-1-ve GBM cells in vitro. Additionally, these CAR-T cells selectively caused significant release of IL-2, IFN-γ and TNF-α only from Gal-1+ve co-cultures and induced significant Gal-1+ve GBM cell death in an ex vivo model without any general toxicity.

CONCLUSION

Based on in vitro cell culture and ex vivo APS-brain slice culture results, we conclude that the novel Gal-1 scFv-CD28-4-1BB-CD3ζ CAR-T cell therapy may offer an effective therapeutic option. Further pre-clinical and clinical studies need to be performed to validate this novel approach
IMMU-09. REVERSING SYSTEMIC T CELL DYSFUNCTION TO LICENSE IMMUNOTHERAPY IN INTRACRANIAL TUMORS
Authors: Wachsmuth Lucas , Lorrey Selena , Finlay John , Neff Corey , Ayasoufi Katayoun , Price Mackenzie , Reesman Rachael , Ostrom Quinn , Fecci Peter
Published: November 2024

Intracranial tumors present unique challenges for immunotherapy. These can include both local and systemic modes of immune suppression, the mechanistic underpinnings of which are incompletely understood. Our work reveals that intracranial tumors elicit systemic increases in circulating catecholamine levels, and that this chronic sympathetic hyperactivity results in T cell dysfunction that impedes immunotherapeutic efficacy. We show that treatment with b-adrenergic blockade can partially overcome the negative impacts of chronic sympathetic hyperactivity by increasing NF-kB activity in immune cells, restoring T cell polyfunctionality, favorably modifying the tumor microenvironment, and extending survival in murine models of glioblastoma treated with immune-based therapies. Furthermore, we demonstrate that extended survival is also observed in glioblastoma patients receiving b-adrenergic blockade, as well as in patients with melanoma and lung cancer brain metastases who received b-blockade alongside concomitant immune checkpoint inhibition. Importantly, while local sympathetic hyperactivity in the tumor microenvironment and b-blockade also impact the anti-tumor immune response in the context of extracranial disease, these effects are markedly more pronounced in intracranial disease. Taken together, these data reveal that sympathetic hyperactivity facilitates systemic immune dysfunction in the setting of intracranial tumors and highlight a novel role for the application of b-adrenergic blockade to license immunotherapy in intracranial malignancies.
IMMU-24. GLIOBLASTOMA ENRICHED GLYCOSPHINGOLIPIDS MODULATE THE FUNCTION OF HUMAN INKT CELLS
Authors: Coombs Morgan , Dowdy Tyrone , Alam Md Masud , Khayrullina Guzal , Joshi Vibhuti , Keretsu Seketoulie , Jung Jinkyu , Hara Ayaka , Steffke Emily , Latifi Laila , Kim Hye , Spurgeon Jo , Malik Nargis , Hancock John , Smith Kelsey , Gumperz Jenny , Larion Mioara , Terabe Masaki
Published: November 2024

Glioblastoma is an aggressive primary brain tumor highly resistant to currently available immunotherapies. A deeper understanding of its underlying immunoregulatory mechanisms is paramount to developing future immunotherapeutic treatments. Invariant natural killer T (iNKT) cells are unconventional T cells that recognize lipid antigens presented by an MHC-like molecule called CD1d. Although iNKT cells have been shown to regulate tumor immunity in other cancer types, their role in glioblastoma is not well characterized. Given the lipid-rich nature of the brain and the unique metabolic activity of glioblastoma cells, we hypothesized that interactions between glioblastoma and iNKT cells through glioblastoma-produced lipids could contribute to the immunosuppressive nature of the disease. We report multiple lipid species enriched in aggressive human glioblastoma stem-like cell (GSC) lines that activate human iNKT cells and modulate their functions. Lipidomic LC-MS analysis of GSCs, low-grade glioma stem-like cell lines, and normal human astrocytes revealed various glycosphingolipid species, including sulfatides, highly enriched in the GSCs. Multiple enriched sulfatide species, when presented by CD1d, were recognized by and activated iNKT cells in a dose-dependent manner. Additionally, cytokine analysis of stimulated human PBMC-derived iNKT cells demonstrated that the enriched sulfatides did not induce Th1 cytokine production, but rather many non-Th1 cytokines that potentially counteract Th1-type immune responses. This modulation of iNKT cell function by glioblastoma-enriched glycosphingolipids may contribute to the immunosuppression of glioblastoma and could highlight sulfatide production as a potential therapeutic target for glioblastoma treatment.
IMMU-29. B7-H3-TARGETED CAR-T AND CAR-NK CELLS AGAINST HUMAN GLIOBLASTOMA
Authors: Tachi Tetsuro , Kijima Noriyuki , Kuroda Hideki , Murakami Koki , Hosen Naoki , Kishima Haruhiko
Published: November 2024

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor, necessitating novel therapies. Chimeric antigen receptor (CAR) T-cell therapy has recently shown efficacy against GBM. However, this approach is costly and time-consuming due to its personalized nature. Alternatively, CAR-transduced natural killer (NK) cells offer a potential “off-the-shelf” immunotherapy option, as they do not cause graft-versus-host disease. This study aimed to assess the anti-GBM efficacy of CAR T and NK cells targeting B7-H3, a protein highly expressed in GBM. To achieve this, CAR T cells targeting B7-H3 were developed using known anti-B7-H3 scFv sequences. Additionally, cord blood-derived NK cells were transduced with the B7-H3 CAR. Both types of CAR-modified cells were tested for their anti-GBM activity in vitro. Moreover, their anti-tumor effects were evaluated in an in vivo xenograft model using patient-derived GBM cells. The results demonstrated that both B7-H3 CAR T cells and CAR NK cells exhibited significant cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of these CAR-modified cells into the xenograft model significantly reduced tumor growth. In conclusion, B7-H3 targeted CAR T cells and cord blood-derived CAR NK cells both show potential in eliminating GBM cells, suggesting promising avenues for future GBM treatment strategies.
IMMU-30. IGV-001: A BIOLOGIC-DEVICE COMBINATION PRODUCT ELICITS POTENT ANTI-GBM RESPONSES AS A MONOTHERAPY AND IN COMBINATION WITH CHECK POINT INHIBITION
Authors: Zilberberg Jenny , Exley Mark
Published: November 2024

INTRODUCTION

Imvax is developing GoldspireTM, a personalized immunotherapy that combines whole tumor-derived cells with an antisense oligonucleotide against insulin-like growth factor 1 receptor (IGF-1R; IMV-001) in biodiffusion chambers (BDCs; 0.1 µm pore). BDCs are irradiated and implanted at abdominal sites for ~48h to deliver an antigenic payload and immunostimulatory factors that together train the immune system to attack tumor cells. The lead product, IGV-001, was evaluated in newly diagnosed glioblastoma (ndGBM) patients in a phase 1b study. Median overall survival (OS) of highest exposure IGV-001-treated Stupp-eligible patients (n=10) was 38.2 mos compared with 16.2 mos in standard-of-care-treated patients (p=0.044; ClinicalTrials.gov NCT02507583). A Phase 2b study in ndGBM is currently underway (ClinicalTrials.gov NCT04485949), where a primary endpoint of progression-free survival and key secondary endpoints of overall survival and safety will be evaluated.

METHODS

The orthotopically implanted GBM (luciferase-expressing GL261-luc2) model was utilized to evaluate the efficacy of mIGV-001 (the murine version of IGV-001) alone or in combination with anti-PD-1 immunotherapy. The following four groups were compared: mIGV-001 or BDC placebo + isotype or anti-PD-1 antibody (4 doses total every 3-4 days). GL261-luc2 cells were treated with IGF-1R antisense IMV-001. The treated cell suspension was loaded into clinical-grade BDCs (0.1-µm pore size, polyvinylidene difluoride membrane) at a density of 1 × 106 cells per BDC and then irradiated with 5–6 Gy. mIGV-001 or BDCs filled with saline were administered 28 days prior to tumor challenges and tumor progression and survival were monitored for an additional 100 days.

RESULTS

Preventative treatment with mIGV-001 limited tumor progression and extended OS in mice orthotopically (i.e., intracranially) challenged with GL261-luc2 cells. The therapeutic benefit of mIGV-001 was enhanced with anti-PD-1 treatment and the combination therapy was superior to either monotherapy.
IMMU-32. DIPEPTIDYL PEPTIDASE-4 (DPP-4) MEDIATED CD8+ T-CELL REGULATION IN GLIOBLASTOMA
Authors: Teran Pumar Oriana Y , Ruiz Clara Lopez , Colon Bruno , Rafie Christine Isabelle , Khatwani Natasha Karishma , Stelekati Erietta , Watson Dionysios C , Bayik Defne
Published: November 2024

Glioblastoma (GBM) remains to be one of the deadliest cancers with poor prognosis and limited treatment options. While immunotherapies have revolutionized the field for other cancers, GBM remains resistant to these types of interventions partly due to its highly immunosuppressive tumor microenvironment, which is characterized by accumulation of exhausted CD8+ T cells. Therefore, there is a pressing need to identify molecular targets for improve anti-tumorigenic T cell response. Previous studies in our laboratory identified dipeptidyl peptidase-4 (DPP-4), an exopeptidase and a membrane-bound signaling receptor, as a potential marker of immunosuppression in GBM. While DPP-4 is well-drugged due to its role in insulin metabolism, the function of DPP-4 in immune regulation and cancer remains poorly defined. I observed that DPP-4 is highly expressed by CD8+ T cells GBM patients and preclinical models. Furthermore, DPP-4 levels increased with the exhaustion or memory differentiation of effector T cell. Pharmaceutical inhibition of DPP-4 enriched expression of genes related to lymphocyte activation and mitochondrial metabolism. These transcriptional changes were accompanied by enhanced T cell proliferation, cytotoxic function, and effector mediator production under exhaustion conditions. These findings suggest that pharmacological inhibition of DPP-4 promotes anti-tumorigenic function of CD8+ T-cell by preventing exhaustion and support future translational efforts to repurpose DPP-4 inhibitors as immunotherapy agents in GBM, given their favorable safety profiles.
IMMU-38. LEVERAGING INNATE IMMUNE SENSORS TO GENERATE DURABLE ANTI-GLIOMA ADAPTIVE IMMUNE RESPONSES
Authors: Lea Spencer , Najem Hinda , Chen Chao-Hsien , Wei Jun , William Ivana , Tripathi Shashwat , Hurley Lisa , Heimberger Amy , Curran Michael
Published: November 2024

Glioblastoma harbors a tumor microenvironment (TME) that is mostly devoid of T cell effector infiltration but is dominated by immune suppressive microglia, macrophages, and myeloid-derived suppresser cells. The innate immune cells in the TME have impaired phagocytosis and antigen presentation and are inadequate for triggering the subsequent immune activating signals needed for anti-tumor effector responses. Phagocytic activity can also be blocked by the upregulation of CD47 on the tumor cells. In the immune checkpoint resistant Qki-/- Pten-/- P53-/- (QPP) glioma model, intratumoral treatment with the synthetic cyclic di-nucleotide STING agonist IACS-8803 (8803) induces global immunological reprogramming and long-term survival resistant to tumor rechallenge. More specifically, in the infiltrating myeloid stroma 8803 increases costimulatory protein CD86 while reducing the expression of suppressive markers CD163 and CD206. Conventional type 1 dendritic cells are increased in both the TME (p<0.05) and the draining cervical lymph node (p<0.01). Intratumoral infiltration of both CD8 T (p<0.05) and NK (p<0.001) cells increases. However, only T cells, but not NK cells, are necessary for 8803 therapeutic activity when assessed with in vivo NK cell depletion studies and treatment in the RAG-/- background. STING activation increases microglial phagocytic capacity, but also induces a compensatory increase in SIRPα expression (p<0.001) – the ligand for CD47. 8803 synergizes with anti-CD47 blockade to enhance microglia phagocytosis of QPP glioblastoma cells in vitro. Finally, the combination of 8803 and anti-CD47 synergizes to extend both median survival and the fraction of long-term survivors in orthotopic QPP-bearing mice (QPP8v; vehicle control MS=39d, anti-CD47 MS=40d, 8803 MS=67d 20% long-term survival, 8803 + anti-CD47 MS=107.5d 40% long-term survival). These data demonstrate that 8803 induces proinflammatory conversion of the glioblastoma TME, generates T cell-dependent survival benefits in QPP-bearing mice, and synergizes with anti-CD47 blockade to enhance microglia phagocytosis of glioblastoma cells and extend survival in QPP-bearing mice.
IMMU-46. CROSS-TALK OF INNATE IMMUNE CELLS IN GLIOBLASTOMA PATHOPHYSIOLOGY: UNDERSTANDING NLRP3 AND NLRP12
Authors: Rajkhowa Sushmita , Meena Durgesh , Jha Sushmita
Published: November 2024

Glioblastoma (GBM) are malignant gliomas with an average survival of less than 14 months after diagnosis, despite surgery, chemotherapy, and radiotherapy. Tumor survival is aided by the heterogeneous cell populations in the tumor microenvironment. Two crucial innate immune cells of the brain, namely microglia and macrophages, favor a tumor-promoting microenvironment IN GBM. The nucleotide-binding domain leucine-rich repeat-containing receptor (NLR) family in astrocytes and microglia cells recognizes pathogen- and damage-associated molecular patterns that induce inflammation. NLRP3, upon activation, leads to cleavage and activation of Caspase-1, causing the proteolytic cleavage-mediated activation and conversion of pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18, leading to pyroptosis. NLRP12 downregulates inflammatory responses in microglia and macrophages by regulating the NF-kB pathway. NLRP3 and NLRP12 have tumor-promoting and anti-tumour functions in various cancers. NLRP12 is a prognostic marker for glioblastoma, and its increased expression correlates with poor survival in GBM patients. However, the cellular and molecular mechanisms of NLRP3 and NLRP12 in GBM pathophysiology are largely unknown. This study aims to understand the effect of NLRP3 and NLRP12 expression in GBM, to interpret the pathophysiology, and to help develop future targeted therapeutic interventions. To understand the baseline expression of NLRP3 and NLRP12 in cell lines and patient-derived GBM cells, PCR, western blotting, and Immunocytochemistry were performed comparing WT and nlrp3-/- and nlrp12-/- cells. Differential expression of NLRP3 and NLRP12 in patient-derived cells can be compared to GBM, astrocyte, and microglia cell lines. This may be the underlying cause for intra and inter-tumor heterogeneity and resultant differential therapy outcomes. To understand cell-to-cell communication in GBM-like tumor microenvironments, heterocellular 3D organoids, and patient-derived tumor organoids were developed. Cell viability in 3D patient-derived tumor organoids decreased by up to 10% with Doxorubicin and 40% with Carboplatin treatment decreases compared to untreated controls. This suggests the scope of developing drugs targeting inflammation regulatory genes.
IMMU-47. HUMAN MICROBIOTA INFLUENCE THE GLIOMA-IMMUNE LANDSCAPE AS DETERMINED BY SINGLE CELL RNA-SEQUENCING IN A MURINE MODEL OF GLIOMA
Authors: Green George , Cox-Holmes Alexis , Marlow Gillian , Potier Anna Claire , Wang Yong , Zhou Lianna , Chen Dongquan , Morrow Casey , McFarland Braden
Published: November 2024

We recently identified immunotherapy responder and nonresponder human microbiota compositions in the murine model of glioma. In this study, we sought to understand how human microbiota in mice influence the immune landscape in glioma. To test this, we utilized our novel humanized microbiome (HuM) mouse model (human microbiota transplanted into gnotobiotic mice) to determine the effect of immunotherapy in a mouse model of glioma utilizing single-cell RNA sequencing and 16S rRNA microbiome sequencing. We focused on two HuM mouse lines in this study: HuM1 (nonresponder) and HuM2 (responder). To confirm microbiota differences,16S rRNA sequencing revealed significant differences between alpha and beta diversity between HuM1 and HuM2 groups. HuM2 responder mice also displayed a significant increase in the relative abundances of Odoribacter, Muribaculaceae, and Ruminococcus genera compared to HuM1 mice. HuM1 and HuM2 mice were then injected with GL261 glioma cells into the brains, treated with one dose of anti-PD-1 or isotype control on day 13, and all mice were euthanized on day 14 for scRNA-sequencing of CD45+ cells in the tumors. We identified 21 clusters of immune cells in the tumors. Furthermore, we found significant differences between HuM1 and HuM2 mice in isotype control conditions including higher percentages of immature B cells, neutrophils, and microglia in HuM2 mice. In anti-PD-1 treated tumors, there was a robust increase in the percentage of innate immune cells in the tumor following, specifically the monocyte/macrophage (MM1; Cxcl10+) population in both HuM1 and HuM2 mice. However, the HuM2 MM1 cluster showed an increase in gene expression of Nos2 and decrease in Arg1, indicating that the MM1 population in HuM2 mice are more inflammatory (anti-tumor) compared to HuM1. Ultimately, our data demonstrate that the gut microbiome influences the tumor-immune landscape, and harnessing positive microbial compositions remains a viable translational avenue to pursue.
IMMU-49. TARGETING ALTERNATIVE SPLICING VARIANTS TO STIMULATE ANTI-TUMOR IMMUNITY IN A NOVEL SYNGENEIC MOUSE MODEL OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Wang Anthony , Owens Geoffrey , Pan Yang , Kim Wi-Jin , Sun Matthew , Peeters Sophie , Treger Janet , Lee Alexander , Armellini Amber , Na Brian , Everson Richard , Daniels David , Nathanson David , Liau Linda , Prins Robert , Xing Yi
Published: November 2024

The prognosis for pediatric high-grade gliomas associated with mutations in the H3-A3 histone gene is very poor. To investigate whether peptide-pulsed dendritic cells (DC) together with checkpoint blockade might be a potential treatment modality for diffuse hemispheric glioma, H3 G34-mutant (DHG), we have developed a novel mouse model, and utilized a novel bioinformatics pipeline to identify tumor-associated peptide antigens (TAs). We used the RCAS/tv-A system to target the expression of H3/G34R and PDGFb, and to knock out p53 in neural progenitors in transgenic C57BL/6 neonatal mice. Three independent cell lines were obtained that expressed transcripts associated with oligodendrocyte and interneuron lineages, and formed lethal tumors after intracranial implantation. To identify TAs, we implemented a new computational workflow to identify nonapeptides generated from alternative splicing of mRNAs that were highly enriched in the tumor transcriptomes of two DHG patients, and predicted to bind the HLA-A*2:01 class I allele carried by these patients. Three of the candidate peptides were conserved in the mouse and also predicted to bind the H2-Kb MHC I allele carried by C57/BL6 mice. Using our syngeneic mouse model, we showed that DCs pulsed with these peptides together with anti-PD1 mAb provided a significant survival benefit compared with checkpoint inhibitor and DCs pulsed with peptides that were not predicted to bind the H2-Kb allele. Splenocytes isolated from successfully treated mice were analyzed through bulk TCR sequencing, and in comparison with control mice and publicly-accessible TCR libraries, 6 highly-represented TCR clonotypes were identified only in treated mice. In summary, we demonstrate that effective TAs can be extracted from RNAseq data, and can be targeted with DC vaccination to generate a systemic anti-tumor cytotoxic T cell response to eliminate DHG in a novel immunocompetent mouse model.
IMMU-54. THERAPEUTIC TARGETING OF STING IN MENINGIOMAS
Authors: Youngblood Mark , Tripathi Shashwat , Najem Hinda , Gomez Mateo , Sadagopan Nishanth , Sears Thomas , Hurley Lisa , Wang Wenxia , Congivaram Harrshavasan , Choudhury Abrar , Steffens Alicia , Oyon Daniel , Fernandez Luis , Selner Ashley , Fares Jawad , Hagan Matthew , Palmer Aaron , Karras Constantine , Trybula Joy , Zhang Peng , Stegh Alexander , Curran Michael , Ashley David , Magill Stephen , Horbinski Craig , Chandler James , Lesniak Maciej , Miska Jason , Dunn Gavin , Raleigh David , Heimberger Amy
Published: November 2024

Up to one-quarter of meningiomas recur within five years of resection; however, there are currently no established adjuvant therapies for lesions that are intractable to surgery and radiation. To identify novel treatment approaches, scRNA-sequencing datasets were reanalyzed from thirteen meningiomas and nine adjacent dura samples including >30,000 immune cells from varying WHO grades and molecular subtypes. In contrast to gliomas, immune-inducing STING (stimulator of interferon genes) was expressed within the meningioma tumor cells, consistent with DNA methylation profiling that showed hypomethylation of the STING promotor in 93% of cases (267 of 288 meningiomas; beta < 0.2). Meningiomas in the immune-enriched subgroup additionally exhibited significant hypomethylation in the 3’ UTR of this gene (p = 1.9 x 10-9). Using sequential multiplex immune fluorescence, STING expression was confirmed in neoplastic, myeloid, and endothelial cells within all grades of meningiomas, but not in adjacent dura and brain. Downstream STING pathway activation markers such as p-IRF3 were partially expressed, suggesting that further activation of the STING pathway may offer therapeutic benefits. Ex vivo single-cell suspensions of resected human meningiomas treated with the STING agonist 8803 induced 25-45% growth inhibition in 7/8 cases within 72 hours (p < 0.001; two-way ANOVA). There was no growth inhibition of the meningioma cell lines IOMM-LEE and CH157 treated with 8803, which lack immune cells and contain only clonal neoplastic cells. However, when the IOMM-LEE meningioma cells were implanted in vivo, a single dose of 8803 induced a >50% reduction in tumor volume relative to the vehicle control injection at multiple time points (p < 0.001; two-way ANOVA) indicating that the immune system is an essential component of STING efficacy in these tumors. Our results reveal widespread expression of STING in neoplastic and myeloid populations in meningiomas and clarify a new treatment indication for use of the STING agonist 8803.
INNV-04. SINGLE INSTITUTION RETROSPECTIVE STUDY TO DETERMINE TIME TO FIRST PROGRESSION IN MGMT METHYLATED GLIOBLASTOMA PATIENTS WHO RECEIVED STANDARD OF CARE
Authors: Thakkar Jigisha , Ng Isaac , Jani Ronak , Goyal Abhishek , Prabhu Vikram , Anderson Douglas , Wainwright Derek , Borys Ewa , Mallik Atul , Barton Kevin
Published: November 2024

MGMT methylated glioblastomas respond well to standard of care with temozolomide, have a longer survival as well as increased risk of pseudo-progression as compared to unmethylated patients. Shorter survival in these patients despite effective treatments is due to misdiagnosis of true progression (in cases with pseudo-progression) that leads to overtreatment or discontinuation of effective treatments. There are limited non-invasive diagnostic tools to distinguish true progression from pseudo-progression. Knowing the expected time to first true progression will aid with interpretation of MRI changes and serve as an additional tool to distinguish true from pseudo-progression.

OBJECTIVE

We sought to define the time to first progression in MGMT methylated glioblastoma patients who were treated with standard of care/Stupp protocol (this has not been previously defined).

METHODS

We conducted a retrospective analysis of an IRB-approved database at our institution from 2019 to 2022 of all MGMT methylated glioblastoma patients who completed Stupp protocol. Time to first progression (time from initial surgery to first true progression) was determined by treating multidisciplinary team based on radiographic review +/- pathology. Eligible MGMT methylated glioblastoma patients had IDH status determined by NGS and completed standard Stupp protocol after surgery.

RESULTS

Approximately 30% (27) patients with IDH wild-type glioblastoma were MGMT methylated. 10 patients met eligibility criteria. 50% of MGMT methylated GBM patients had multifocal disease at presentation. Median time to first progression in MGMT methylated GBM who received standard of care was 28 months. 20% patients have not had first progression 3 years after initial surgery.

CONCLUSION

MRI changes on surveillance scans should be carefully interpreted in the first 28 months. Knowing time to first true progression will aid with management decisions and decrease unnecessary early aggressive interventions in MGMT methylated glioblastoma patients. We will validate these findings in a larger patient population at our institution.
INNV-08. PRE-CLINICAL AND CLINICAL EVIDENCE FOR THE TREATMENT OF DMG/DIPG USING EMULATE THERAPEUTICS’ ULTRA-LOW RADIO FREQUENCY MAGNETIC FIELD SIGNAL TECHNOLOGY
Authors: Figueroa Xavier
Published: November 2024

EMulate Therapeutics, Inc. (EMTx) has developed a technology that emulates the effects of chemical compounds via a magnetic field. Our research has led to the development of a radio frequency energy (RFE) signal (A1A) that emulates the effects of paclitaxel. Pre-clinical studies demonstrate an effect in slowing down and inhibiting tumor growth. The results of feasibility (Phase I/II) clinical trials testing the EMTx technology for treating recurrent GBM (rGBM) were published in CNS Oncology (CNS Oncol 2023 Pages CNS102, Accession Number: 37462385 DOI: 10.2217/cns-2022-0016). Reported results suggest that the A1A signal is non-inferior to best supportive care (BSC) and when the A1A signal is combined with BSC, a 3-month increase in overall survival (OS) was observed. Diffuse intrinsic pontine gliomas (DIPG) are a rare pediatric central nervous system (CNS) tumor. Survival is measured at under 12 months, with no clinical trials demonstrating a significant increase in OS in 20 years (9 months median survival post radiation therapy). EMTx’s compassionate use program (Hælo® medical device) demonstrated safety and suggested a clinical benefit, with 12 of 14 patients surviving more than 12 months, with median survival of 17 months. EMTx recently completed an orthotopic mouse model of DIPG at University of California San Francisco. The results from exposing the mice to the A1A signal demonstrated a significant survival advantage (P = 0.0163) via the slowing down of cell division. Data to be submitted for peer review publication. The animal model is encouraging and supports the observed results of our compassionate use program. EMTX will submit these results to the FDA for regulatory approval via the Humanitarian Device Exemption pathway. The company will conduct a study with DIPG patients from both the US and India. Subject to FDA protocol approval, 30-35 patients will be recruited to participate in this pediatric neuro-oncology trial, which will be a best supportive care + single therapy (Hælo®) clinical trial.
INNV-11. DELIVERY OF TTFIELDS TO THE INFRATENTORIAL BRAIN USING HFE ARRAYS
Authors: Ze’evi Oshrit , Naveh Ariel , Manzur Doron , Shapira Nadav
Published: November 2024

INTRODUCTION

Tumor Treating Fields (TTFields) therapy is a noninvasive, locoregional treatment comprising alternating electric fields delivered to the tumor via two pairs of skin-placed transducer arrays. TTFields physically disrupt cancer cell viability through a multimodal mechanism that includes antimitotic and antitumor immune effects. TTFields therapy is FDA-approved for glioblastoma (GBM) and CE marked for WHO grade 4 glioma. While clinically approved array layouts for GBM target supratentorial tumors, TTFields distribution depends on the arrays’ locations and dedicated layouts are needed to target infratentorial tumors. To increase patient comfort, Novocure developed HFE arrays that are thinner and lighter than existing INE arrays. Here, we evaluate innovative HFE array layouts for TTFields delivery to infratentorial tumors at therapeutic intensities (~1 V/cm).

METHODS

TTFields delivery was simulated using Sim4Life v6.2 in a male computational model. 32 layouts of HFE arrays were placed on the model’s scalp, neck, and scapulae, with one placed at a standard cerebral location. Local Average Field Intensity (LAFI) and Local Minimum Power Density (LMiPD) were calculated in the cerebrum, cerebellum and brainstem.

RESULTS

Standard cerebral layout provided LAFI of 2.47 V/cm to the cerebrum, while providing 1.50 and 1.10 V/cm to the cerebellum and brainstem, respectively (LMiPD 2.22, 1.34 and 0.64 mW/cm3). Layouts comprising arrays on the scapulae (right and left) paired in cross configuration with arrays on either the temples or forehead, provided LAFI of 1.87-2.17 V/cm (LMiPD 1.05-2.20 mW/cm3) to the cerebrum, while providing 1.64-2.13 V/cm (LMiPD 1.77-2.26 mW/cm3) to the cerebellum and 1.74-1.89 V/cm (LMiPD 2.28-2.89 mW/cm3) to the brainstem.

CONCLUSION

Lower array placement provides higher levels of field intensity in the cerebellum and brainstem versus standard cerebral layout, while still providing adequate field intensity to the cerebrum. This simulation-based study suggests feasibility of delivering therapeutic TTFields intensities to infratentorial tumors using dedicated HFE array layouts.