bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPID-05. TREATMENT PATTERNS OF GLIOMAS: AN EPIDEMIOLOGICAL STUDY
Authors: Bajwa Mohammad Hamza , Imran Noor , Shah Mashal , Baig Erum , Laghari Altaf Ali , Bin-Anis Saad , Akhunzada Naveed Zaman , Gilani Jaleed , Jawed Noyan , Khalid Usman , Qadeer Namra , Lutfi Areeb , Tahir Izza , Bajwa Rameen , Rashid Huzaifa , Sadia Haleema , Ghazi Kinzah , Gillani Mishal , Consortium Pakistan Brain Tumor , Siddiqi Sameen , Enam Syed Ather 
Published: November 2021

Abstract

INTRODUCTION
Gliomas are the most common malignant brain tumors of the central nervous system in adults. Specialized treatment modalities have improved morbidity and mortality within high-income countries. In lower- and middle-income countries (LMICs), the overall mortality rate is still seen to be alarmingly high. As there is a shortage of statistical data available regarding the epidemiology of these tumors and their management within the country, the objective of this study is to define the landscape of treatment patterns and current epidemiological data regarding gliomas in Pakistan.

METHODS
As part of the Pakistan Brain Tumor Epidemiology Study (PBTES), data was collected from major neurosurgical centers across the country, consisting of 35 hospitals in all 4 provinces. Our retrospective study looked at patients who underwent surgical procedures for gliomas in 2019, where a surgical pathology was available. The data was collated and analyzed using appropriate statistical methods.

RESULTS
791 patients with gliomas were identified (61.8 % in public sector hospitals, 39.1% in private sector). The most common histopathological subtypes were glioblastoma (33.5%), followed by astrocytoma (18.8%) and oligodendroglioma (11.9%). Gender distribution was skewed towards men (65%). The most commonly performed initial surgical procedure was gross total resection (50% in public hospitals, 41% in private hospitals). Private institution hospitals performed surgical biopsies as the first surgical procedure (23%) more often than public hospitals (9%). Regarding adjuvant treatments, only 26% of patients were given chemotherapy, and there was no data regarding 53% of patients. Similarly, only 15% of patients received radiation therapy, and there was no data for 60% of patients.

CONCLUSIONS
Our study was able to identify the gaps in glioma management within Pakistan, particularly with regards to chemoradiotherapy. Identifying these unmet needs is the first step in developing comprehensive care for glioma patients.
EPID-27. GEOGRAPHIC BURDEN OF CNS TUMORS AND DENSITY OF NEURO-ONCOLOGISTS IN THE UNITED STATES
Authors: Gregory Timothy , Graber Jerome 
Published: November 2021

Abstract
CNS cancer care relies heavily on exam and imaging interpretation skills distinctive to a neurology-trained oncologist, and access to this subspecialty is increasingly more essential as targeted molecular therapies evolve. We sought to explore the supply of neuro-oncologists in terms of geographic CNS tumor incidence. Using the UCNS online directory, we generated a heat map representing the location (set to 75-mile radius) and density of active neuro-oncologists. We overlaid this data upon yearly incidence of CNS tumors per neuro-oncologist for each state using most recent CBTRUS data. We highlight the significant distance Americans outside of urban areas must travel for care and that isolation from academic centers and exclusion from clinical trials are substantial barriers to cancer care for a significant proportion of the population. Telemedicine may in part improve patient access to care and clinical trial participation, but significant state-to-state legal variability for providing telehealth services across state lines remains a national challenge. Short-term strategies for equitably meeting this subspecialty need may require policy changes that optimize employment of telemedicine, and long-term must ensure a robust fellowship pipeline with thoughtful incentivization and allocation of resources.
IMMU-03. IMMUNE CHECKPOINT INHIBITORS IN SMALL CELL LUNG CANCER PATIENTS DEVELOPING BRAIN METASTASES
Authors: Jessurun Charissa , Tewarie Ishaan , Hulsbergen Alexander , Broekman Marike , Smith Timothy , phillips John 
Published: November 2021

Abstract

INTRODUCTION
Small cell lung cancer (SCLC) is known for rapid growth, and about 40-50% of SCLC patients will develop brain metastases (BM). The addition of immune checkpoint inhibitors (ICI) to the standard chemotherapy, which is the current backbone of first-line therapy, has resulted in more prolonged survival than chemotherapy alone in SCLC patients.

PURPOSE
This study aimed to assess the effect of ICI before BM development in SCLC patients on time to BM development and survival.

METHODS
A single-institutional retrospective review of SCLC patients that underwent cranial radiation therapy between January 2014 and June 2020 was performed to assess the impact of ICI therapy on time to BM development, overall survival (OS), and time to failure of BM treatment (defined as local or distant BM recurrence) using a multivariable Cox Proportional Hazards model.

RESULTS
Among 197 included patients, 23 patients (11.7%) received ICI before BM development. Extensive stage of SCLC at diagnosis was observed in eighteen patients (78.2%) in the ICI group and 133 (76.4%) in the non-ICI group. In total, seventeen patients (8.6%) received prophylactic cranial irradiation, of which seven patients (30.4%) also received ICI. ICI were associated with prolonged time to BM in comparison with the non-ICI group (HR = 0.29, 95% CI: 0.18-0.47). ICI were also associated with an increased OS (HR = 0.56, 95% CI: 0.32-0.97) and prolonged time to BM treatment failure (HR = 0.32, 95% CI: 0.15-0.71) in comparison with patients who did not receive ICI.

CONCLUSION
The use of ICI before BM development was associated with a longer time to BM. Additionally, ICI therapy was associated with an increased OS and prolonged BM treatment failure. These results are a proof of concept of the potential benefit of ICI therapy in SCLC patients, and the presented results should be further validated in larger cohorts.
IMMU-13. COMBINED MODULATION OF THE TGF-Β PATHWAY AND GITR IMMUNE CHECKPOINT SIGNALING PROMOTES ANTI-TUMOR IMMUNITY IN SYNGENEIC GLIOMA MODELS
Authors: Lorizio Daniela , Weller Michael , Silginer Manuela , Epstein Alan , Roth Patrick 
Published: November 2021

Abstract
The profound local immunosuppressive microenvironment is one hallmark of glioblastoma, which results in resistance to most immunotherapeutic strategies that have been explored so far. Reverting this condition in order to reinvigorate anti-glioma immunity might be a promising therapeutic approach. Transforming growth factor (TGF)-β signaling is deregulated in different cancer types and contributes to the malignant phenotype of glioma cells. Glioma-derived TGF-β is also a major immunosuppressive factor in the tumor microenvironment. Furthermore, intratumoral regulatory T (Treg) cells and activated T effector cells express high levels of the co-stimulatory immune checkpoint glucocorticoid-induced tumor necrosis factor receptor (GITR). Agonistic anti-GITR antibodies have been explored in preclinical tumor models and are under investigation in clinical trials for the treatment of solid tumors. We evaluated the effect of TGF-β and GITR targeting on anti-tumor immune responses in syngeneic mouse glioma models. In co-culture settings, GITR modulation with a GITR ligand (GITRL)-Fc fusion protein, given alone or in combination with a pharmacological TGF-β receptor inhibitor, led to increased T cell activation. Furthermore, the combined targeting of the two pathways resulted in significantly higher immune cell-mediated tumor cell killing than either treatment alone. In vivo, TGF-β inhibition and GITR signaling modulation resulted in a higher fraction of long-term surviving glioma-bearing mice than single-agent treatment. Surviving mice were resistant to tumor re-challenge, suggesting adaptive immunity as an underlying mechanism. These data support the assumption that combined immunotherapeutic strategies may represent a promising approach for the treatment of glioma.
IMMU-16. CHARACTERISTICS OF EGFRVIII-DIRECTED CART CELL INFUSION PRODUCT ASSOCIATED WITH CLINICAL RESPONSE IN RECURRENT GLIOBLASTOMA
Authors: Tang Oliver , Binder Zev , Tian Lifeng , Chang Wan-Jung , Yoder Todd , Lacey Simon , Melenhorst Jos , O’Rourke Donald M 
Published: November 2021

Abstract

BACKGROUND
A therapeutic approach for chimeric antigen receptor T (CART) cell therapy in glioblastoma is targeting the epidermal growth factor receptor variant III (EGFRvIII), present in approximately 30% of glioblastomas. While earlier research demonstrated that phenotypic and genotypic characteristics in patient T cells and CART product may predict therapeutic success for hematologic malignancies, no study has investigated such determinants for clinical response in glioblastoma.

METHODS
We analyzed apheresis and infusion products for patients in the first-in-human trial of EGFRvIII-directed CART for recurrent glioblastoma (NCT02209376, n=9). Inherent T cell phenotypes were characterized by flow cytometry assay using a panel of 27 markers. Clinical response was quantified via engraftment in peripheral circulation and time-on-trial (ToT).

RESULTS
Mean area under the curve (AUC) peripheral CART engraftment for the study period was 213 log10 copies/μg (SD=173) and mean ToT was 134 days (SD=173). For the CAR+/CD4+ population in the infusion product, PD1 positivity was positively associated with AUC engraftment (r=0.753, P=0.012) and ToT (r=0.800, P=0.010). On immune checkpoint inhibitor analysis, CTLA-4, TIM3, and LAG3 did not exhibit significant associations with AUC engraftment or ToT. For activation markers, PD1/GRZB (r=0.794, P=0.011) and PD1/HLA-DR (r=0.769, P=0.016) were directly associated with ToT. PD1/GRZB was also predictive of AUC engraftment (r=0.794, P=0.011). For the CAR+/CD8+ population, PD1 positivity correlated with elevated AUC engraftment (r=0.639, P=0.047). In the CAR-/CD4+ population, PD1 remained positively correlated with AUC engraftment (r=0.690, P=0.027) and ToT (r=0.726, P=0.027). No significant associations were observed for apheresis products.

CONCLUSION
PD1 in CART infusion products predicted peripheral engraftment and ToT in recurrent glioblastoma. Double-positive cells for PD1 and activation markers also displayed a positive correlation, suggesting PD1 highlights a population of activated CAR T cells. Further characterization of predictors of EGFRvIII-directed CART treatment efficacy may improve selection of patients and starting T cell populations for clinical expansion.
IMMU-17. SYSTEMIC IMMUNOSUPPRESSION OF CD4+ T HELPER CELLS IN GLIOMA
Authors: Mohme Malte , Maire Cecile , Rünger Alessandra , Glau Laura , Tolosa Eva , Westphal Manfred , Lamszus Katrin 
Published: November 2021

Abstract
Cancer is a systemic disease. Due to the exceedingly rare occurrence of metastasis of cerebral glioma, systemic alterations have, however, not been considered to play a major role in disease progression of glioma. CD4+ T helper (TH) cells orchestrate the adaptive immune response in an antigen-specific, cytokine mediated manner. The aim of our study was to investigate how far cerebral glioma impacts the systemic CD4+ immune repertoire. We therefore analyzed the peripheral blood CD4+ TH cell phenotype and cytokine production in 100 patients with IDHwt, 30 IDHmut and 16 IDHmut 1p19q co-deleted gliomas in comparison with age-matched healthy donors (HD). We found a significant skewing of the peripheral phenotype in IDHwt glioma patients, showing a TH1 expansion and reduced numbers of T follicular helper cells (TFH), TH1* and mucosa associated invariant T (MAIT) cells, while TH2 and TH17 percentages remained stable compared to IDHmut and HD. Interestingly, although TH1 cells were dominant in IDHwt patients, intracellular cytokine staining showed a distinct reduction of IFNg and TNFa production after in vitro stimulation, while IL-4 was significantly increased compared to HD. No alterations between all groups were observed in IL-2, IL-10 or IL-17 production. Profiling of metabolic surface markers further revealed three distinct groups of CD4+ T cells which are altered in IDHwt patients, indicating a metabolic shift in the CD4+ repertoire compared to HD. Taken together, our results show a CD4+ TH cell type specific skewing of the peripheral immune repertoire in patients with IDHwt gliomas. Our data highlights the importance of considering malignant glioma as a systemic disease that fundamentally alters the immune repertoire in affected patients.
IMMU-20. HYDROGEL-CXCL9 VACCINE RESULTS IN MRNA DELIVERY TO DENDRITIC CELLS AND POTENT ANTI-TUMOR RESPONSES IN GBM
Authors: Dastmalchi Farhad , Karachi Aida , Mehkri Yusuf , O’Malley Ashley , Subramaniam Vignesh , Angelini Thomas , Mitchell Duane , Rahman Maryam 
Published: November 2021

Abstract

INTRODUCTION
Our group and others have shown mRNA-vaccines have significant anti-tumor efficacy in the treatment of brain tumors and are currently being tested in first-in-human trials. To further enhance mRNA delivery, a hydrogel platform was developed with the addition of CXCL9 to promote immune cell trafficking.

METHODS
We generated the vaccine by utilizing a hydrogel platform. CXCL9 and Nano-mRNA were loaded into the hydrogel. In vitro recruitment of DCs and NK was evaluated by fluorescence microscopy. In vivo recruitment of immune cells was analyzed by flowcytometry after collecting the fat pad, spleen, and tumor samples from KR158b-luc and Gl261-gp100 tumor-bearing animals 3, 5 and 10 days after vaccine delivery. The efficacy of the vaccine was evaluated by measuring overall survival, and tumor growth was measured by IVIS live-imaging.

RESULTS
Dendritic cells(DCs) and natural killer(NK) cells were able to efficiently migrate within the hydrogel-CXCL9 platform and uptake and express mRNA in vivo. In vitro, the hydrogel-CXCL9 was combined with nanoparticles loaded with total tumor RNA, and the vaccine was delivered to KR-158-luc and GL261-gp100 tumor-bearing animals via mammary fat pad SQ injection. Flow cytometry of the fat pad and draining lymph nodes demonstrated showed significant recruitment of endogenous DCs including inflammatory-DC(P= 0.0035), conventional-DC1(P= 0.0076), pDC(P=0.0028), NK(p= 0.0025 compared to the control group. In two different tumor models, a single dose of the vaccine resulted in significant survival benefits compared to control animals (n=10,P&lt; 0.0001). SQ injection was superior to intracranial injection of the vaccine. Vaccinated animals showed an increased number of antigen-specific CD8 T cells in spleen(P= 0.0001) and tumor-microenvironment(P= 0.0070).

CONCLUSION
The hydrogel-CXCL9 platform results in efficient delivery of mRNA loaded nanoparticles to endogenous DCs and also causes an upregulation of NK cells with resultant improved survival in murine GBM models including the highly resistant KR158 model with a single dose. Further studies are ongoing.
IMMU-21. DIFFERENTIAL EXPRESSION OF ADHESION MOLECULES DEFINES MYELOID CELL INFILTRATION IN GLIOBLASTOMA AND COMPRISES A THERAPEUTIC TARGET
Authors: Bayik Defne , Bartels Cynthia , Lovrenert Katreya , Watson Dionysios , Kay Kristen , Lauko Adam , Scacheri Peter , Lathia Justin 
Published: November 2021

Abstract
A potently immunosuppressive tumor microenvironment facilitates progression of glioblastoma (GBM). Immunotherapies have had variable success in improving the outcome of GBM patients, suggesting that there is a need to gain insight into the mechanisms of immunosuppression. Myeloid-derived suppressor cells (MDSCs) associate with poor prognosis and treatment resistance of GBM patients, but the distinct role of individual populations is not well-defined. We previous showed that monocytic MDSCs (mMDSCs) accumulated in tumors of mice and patients, while granulocytic MDSCs (gMDSCs) mainly remained in the circulation. Furthermore, nonspecific targeting of mMDSCs with chemotherapies provided therapeutic benefit in preclinical models of GBM, suggesting that mMDSCs drive disease progression. To investigate the differential function of mMDSCs versus gMDSCs in GBM, we adoptively transferred bone marrow-derived MDSC subsets into tumor-bearing mice. Mice that received mMDSCs succumbed to disease sooner compared to control mice, which was not observed with gMDSC transfer. To determine the basis of this pro-tumorigenic activity of mMDSCs, we performed ATAC-sequencing and comparison of differentially accessible regions indicated that cell adhesion pathways were significantly upregulated in mMDSCs. Aligned with this epigenetic profile, mMDSCs from bone marrow and blood had significantly higher surface integrin β1 and integrin β7 expression compared to gMDSCs. To evaluate the role of integrins in MDSC behavior, we pre-treated mMDSCs with anti-integrin β1 prior to adoptive transfer. Blockade of integrin β1 interfered with the pro-tumorigenic role of mMDSCs compared to isotype controls. Similarly, blockade of integrin β1 and integrin β7 systemically extended the survival duration of tumor-bearing mice. Finally, high expression of integrin β1 and integrin β7 served as a poor prognostic indicator in GBM patients. Our findings indicate that modulation of immunosuppressive myeloid cells by leveraging differences in adhesion mechanisms represents a potential immunotherapeutic option for GBM.
IMMU-24. IMPROVING OUTCOMES IN OLDER ADULTS WITH GLIOBLASTOMA BY REVERSING AGE-RELATED CHANGES
Authors: Ladomersky Erik , Zhai Lijie , Bollu Lakshmi , Bell April , Lauing Kristen , Lukas Rimas , Wainwright Derek 
Published: November 2021

Abstract
Wild-type IDH glioblastoma (wtGBM) represents ≥90% of human GBM patient diagnoses with a median age of onset at 68-70 years of age. We previously found a decline of GBM patient survival with progressive age and that subjects ≥65 years of age had the poorest prognosis. We also showed an age-dependent enhancement of immune suppression in the brain that negatively affected immunotherapeutic efficacy in older adult mice with syngeneic brain tumors. Here, we extended those observations while studying C57BL/6 mice with intracranial CT-2A or GL261 between 80-110 weeks old - analogous to the age of a wtIDH GBM patient diagnosis. Overall survival of older adult mice with CT-2A or GL261 was significantly decreased when subjects were lymphopenic for CD4+ T cells as compared to an IgG Ab treatment group (n=12/group; p&lt; 0.01). CD8+ T cell or NK cell leukopenia had no effect on survival outcomes. The negative effect of CD4+ T cell lymphopenia in older adults was not observed in younger mice with brain tumors. We also investigated the increased immunosuppression in the brain and its relationship to the accumulation of senescent cells and the treatment with standard of care radiation/temozolomide (RT/TMZ). p16INK4A, a marker for senescent cells, was increased in non-tumor cells of the brain during advanced age and its expression was increased after treatment with RT/TMZ. Older adult mice with brain tumors and treated with senolytics showed decreased p16INK4A levels after treatment with RT/TMZ. Senolytic treatment also improved the efficacy of combination therapy with RT, anti-PD-1 mAb, and IDO enzyme inhibitor in older adults as compared to senolytics alone or the triple immunotherapeutic cocktail alone (n=12-15/group; p&lt; 0.01). Collectively, the results suggest that strategies aimed at reversing the effects of the aging combined with tumor eradication therapies may be particularly beneficial for older adult human patients with GBM.
IMMU-26. SAFETY AND EFFICACY OF PVSRIPO IN RECURRENT GLIOBLASTOMA: LONG-TERM FOLLOW-UP AND INITIAL MULTICENTER RESULTS
Authors: Desjardins Annick , Gromeier Matthias , Friedman Henry , Landi Daniel , Friedman Allan , Ashley David M , Curry William , Butowski Nicholas , Sloan Andrew , Wen Patrick , Cavaliere Robert , Gerstner Elizabeth , Berger Mitchel , Buerki Robin , Chiocca E Antonio , Sauvageau Eric , Kelly Andrea , Nichols W Garrett , Mixson Lori , Dickinson Adam , Orr Kristin , Learn Chris , Bigner Darell 
Published: November 2021

Abstract

BACKGROUND
Recurrent glioblastoma (rGBM) is rapidly fatal (median overall survival [mOS] of ~9 months; OS at 12 months [OS12] &lt; 35%) with approved therapies (lomustine±bevacizumab). PVSRIPO is an intratumoral immunotherapy targeting CD155 on antigen-presenting and malignant cells of solid tumors. Preclinically, PVSRIPO delivers a systemic, tumor antigen-specific, polyfunctional T-cell mediated anti-tumor response. Interim, single-center, phase (Ph) 1 results showed greater long-term survival with PVSRIPO vs. criteria-matched external control rGBM patients (Desjardins 2018). Updates to Ph1 safety (at the Ph2 dose) and efficacy and interim multicenter (Ph2) results are presented.

METHODS
Adults with histologically-confirmed rGBM, Karnofsky performance status ≥ 70, and an active, supratentorial, contrast-enhancing lesion (1-5.5cm) received PVSRIPO (5x107 TCID50) intratumorally via convection-enhanced delivery on Day 1, with a planned follow-up of 24 months. Safety (treatment-emergent adverse events [TEAEs]), efficacy (reported as OS12, OS24, mOS), and blood/tissue were assessed.

RESULTS
149 patients (&gt;90% with 1-2 prior progressions, including failure of SOC and patients with prior bevacizumab failure) received the Ph2 dose of PVSRIPO (n=30 received other doses in Ph1 with safety summarized previously). Follow-up durations for surviving patients were 51-74 months (Ph1) and 10-44 months (Ph2). No dose-limiting toxicities occurred; up to 97% of patients experienced mostly grade 1-2 related TEAEs; ≤ 23% patients experienced grade ≥ 3 related events. Neurologic symptoms related to peritumoral edema were most common ( &gt; 90% patients) and were effectively managed with low-dose bevacizumab/corticosteroids. Survival estimates were: OS12: 54%, 50%; OS24: 18%, 17%; mOS: 12.3 (95% CI 10,15.3), 12 (10.6,13.7) months, for the Ph1 and Ph2 trials, respectively. Baseline correlates of longer survival included smaller lesions and methylated MGMT-promoter status.

CONCLUSIONS
The multicenter/Ph2 study replicated the single-center/Ph1 results. Relative to published data with approved therapies, PVSRIPO was associated with greater long-term survival and mOS in patients with rGBM and was generally well-tolerated.