bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDRE-11. SECOND GENERATION IDO INHIBITORS FOR IMPROVING IMMUNOTHERAPEUTIC EFFICACY IN PATIENTS WITH GLIOBLASTOMA
Authors: Bollu Lakshmi , Bommi Prashant , Wainwright Derek , Ladomersky Erik , Zhai Lijie , Bell April , Lauing Kristen 
Published: November 2021

Abstract

INTRODUCTION
Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is a rate-limiting enzyme that metabolizes tryptophan and is expressed in &gt;90% of patient-resected glioblastoma (GBM). IDO-mediated tryptophan metabolism has been the proposed mechanism for suppressing the immune response in GBM. Recently, we discovered that IDO also possesses non-enzymic functions that contribute to suppress the anti-GBM immune response. This finding motivated us to develop IDO-Proteolysis Targeting Chimeras (IDO-PROTACs) to degrade IDO protein rather than simply inhibiting IDO enzyme activity.

METHODS
Western blot analysis was used to determine IDO-PROTAC efficiency of IDO protein degradation among human and mouse GBM cell lines and PDX. Our lead IDO-PROTAC was tested for toxicity, blood brain barrier penetration, and pharmacokinetics (PK) in wild-type C57BL/6 mice.

RESULTS
IDO-PROTACs degrade IDO protein in both tumor and non-tumor cells with a DC50 value of ~0.5µM in human GBM tumor cells. Biolayer interferometry (BLI) studies show that IDO-PROTAC forms a binary complex with IDO protein with similar affinity comparable to parental compound – BMS986205. IDO-PROTACs induced IDO ubiquitination and the pretreatment with ubiquitin proteasome inhibitors, MG132 or MLN4924, inhibited IDO protein degradation. In vivo toxicity studies showed that treatment with IDO-PROTAC at 25 mg/kg for 3-weeks did not develop any apparent toxicity in C57BL/6 mice. PK analysis revealed that IDO-PROTAC bioavailabilty reached a peak serum and brain concentration within 30 minutes after intraperitoneal administration.

CONCLUSIONS
This study developed a lead IDO-PROTAC compound that efficiently degrades IDO protein in human GBM cells with a moderate bioavailability and blood-brain barrier (BBB) penetration. Future work will focus on the enhancement of BBB penetration, increased bioavailability, and route of administration to improve IDO-PROTAC potency for combination with other forms of immunotherapy for GBM patient treatment.
DDRE-44. TIRABRUTINIB MONOTHERAPY FOR RELAPSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: HIGH RESPONSE RATE, COMMON SKIN-RELATED DISORDERS, AND DURABLE REMISSION IN A SUBSET OF PATIENTS
Authors: Sasaki Nobuyoshi , Kobayashi Keiichi , Saito Kuniaki , Onoda Ryo , Seiya Yousuke , Yamagishi Yuki , Suzuki Saki , Nakatomi Hirofumi , Shiokawa Yoshiaki , Nagane Motoo 
Published: November 2021

Abstract

BACKGROUNDS
Prognosis of relapsed primary central nervous system lymphoma (rPCNSL) is poor ranging between 2.2 and 16 months, and the optimal treatment strategy has not been established. Tirabrutinib is a second generation Bruton’s tyrosine kinase (BTK) inhibitor, approved by the Japanese Pharmaceutical and Medical Devices Agency (PMDA) for relapsed and refractory (r/r) PCNSL in March 2020. While an overall response rate (ORR) of 64% and progression-free survival (PFS) of 2.9 months was reported in a phase 1/2 study, the real-world treatment results of rPCNSL treated with tirabrutinib have not been investigated yet.

METHODS
Treatment results of rPCNSL patients treated with tirabrutinib at the author’s institution including response rate, PFS, overall survival (OS), and toxicity profiles were retrospectively analyzed.

RESULTS
Eleven patients were identified (median age: 73 [range: 50-83], median PFS: 70 [range: 40-90]). Response was CR in four (36.4%), PR in five (45.4%), PD in two (18.2%) patients, providing with an ORR of 81.8%. At a median follow up of 25.7 months, relapse was observed in seven patients (63.6%), and median PFS was 3.0 months. Durable remission of more than six months was obtained in four patients (36.4%). As for toxicities, six patients (54.5%) had skin-related disorders, which lead to tirabrutinib interruption in two (18.2%), dose reduction in three (27.3%), and discontinuation in two patients (18.2%). Grade 3/4 hematological toxicities were grade 4 neutropenia in one, and grade 3 lymphopenia in five patients (45.4%). No deaths have been observed.

DISCUSSION
Tirabrutinib monotherapy achieved a high response rate in rPCNSL, while skin-related disorders appeared to be the major obstacle leading to treatment interruption or discontinuation. Overall median PFS was in line with the phase 1/2 study. A subset of patients achieved durable remission, suggesting its strong benefit in certain patients. Further investigation of predictive biomarkers for response to tirabrutinib is warranted.
DDRE-46. REDUCED CANCER CELL SENSITIVITY TO TUMOR TREATING FIELDS (TTFields) THROUGH ACTIVATION OF THE PI3K/AKT/mTOR SIGNALING PATHWAY CAN BE MITIGATED USING PI3K INHIBITORS OR PI3K/mTOR DUAL INHIBITORS
Authors: Klein-Goldberg Anat , Voloshin Tali , Zemer-Tov Efrat , Paz Rom , Koren Lilach , Wainer-Katsir Kerem , Volodin Alexandra , Koltun Bella , Brant Boris , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: November 2021

Abstract

INTRODUCTION
Tumor Treating Fields (TTFields) therapy is an approved anti-cancer treatment modality applied non-invasively and loco-regionally to the tumor region. TTFields have been demonstrated to extend life, however, most patients do eventually progress. The current study aimed to identify potential molecular mechanisms involved in reduced cellular sensitivity to TTFields.

METHODS
Cancer cells that exhibit reduced sensitivity to TTFields were generated by continuous long duration application of TTFields (7 or 13 days, depending on the cell line). Changes in cellular signaling pathways were evaluated in ovarian A2780 and glioblastoma U-87 MG cancer cells exposed to long-term relative to short-term (3 or 7 days, depending on the cell line) treatment with TTFields using Luminex multiplex assay followed by Western blot validation. The relevance of the affected pathways was confirmed through evaluation of the response to long-term application of TTFields in combination with pharmacological pathway inhibitors by measuring cell counts, apoptosis, and clonogenicity. Relevant pathway markers in tumor sections from tumor-bearing rats treated with TTFields were examined using immunohistochemistry.

RESULTS
Continuous long-term application of TTFields reduced cellular sensitivity to TTFields and was accompanied by increased levels of phosphorylated AKT, mTOR and additional proteins from the PI3K/AKT/mTOR signaling pathway. Increased phosphorylation of AKT was also evident in tumor sections from rats treated with TTFields. Concomitant use of TTFields with PI3K inhibitors or PI3K/mTOR dual inhibitors sensitized A2780 cells to long-term TTFields application.

CONCLUSION
Our study demonstrates that decreased cancer cell sensitivity to long-term TTFields application is mediated by activation of the PI3K/AKT/mTOR signaling pathway and provides a rationale for further examining the potential benefit of combining TTFields with PI3K or PI3K/mTOR dual inhibitors.
EPID-07. EPIDEMIOLOGICAL CHARACTERISTICS AND SURVIVAL OF PATIENTS WITH DIFFUSE GLIOMA IN BRAZIL: PRELIMINARY RESULTS OF A MULTICENTRIC RETROSPECTIVE STUDY - LACOG 0619
Authors: Yamada Camilla , Vasques Carolina , Coutinho Rodrigo , Maldaun Marcos , Baldotto Clarissa , Viola Fabiana , Maluf Fernando , Santos Vanessa , Pessoa Carolina , Pacheco Patrícia , Matias Danielli , Oliveira Daniela , Peria Fernanda , de Jesus Rafaela , Rebelatto Taiane , Malheiros Suzana 
Published: November 2021

Abstract

INTRODUCTION
In Brazil, most of the 9,196 deaths due to brain cancers in 2017 were gliomas. There is a dearth of epidemiological data on diffuse glioma in Brazil.

METHODS
LACOG 0619 is a multicentric retrospective cohort study, which included patients from nine tertiary oncology centers. Patients aged ≥18 years with histologically proven astrocytoma, oligodendroglioma, oligoastrocytoma or glioblastoma diagnosed from June 2010 to June 2019 were included. The study protocol was approved by each Institutional Review Board.

RESULTS
642 patients were included in the analysis. Median age was 51.0 (19-91) years. Most patients were male (n=364, 56.8%), 175 (27.3%) had ECOG 0-1, and 480 (74.8%) had private healthcare insurance. Neurological symptoms were present in 568 (88.5%) patients at diagnosis, and 263 (41.0%) had a history of seizure before surgery. Regarding histology, 361 (56.2%) had glioblastoma, 162 (25.2%) had astrocytoma, 90 (14.0%) had oligodendroglioma, and 23 (3.6%) had glioma NOS. Gross total resection was performed in 168 (26.2%), subtotal resection in 292 (45.5%), biopsy in 108 (16.8%), conventional radiotherapy in 380 (59.2%), and hypofractionation in 44 (6.9%) patients. Concomitant chemoradiotherapy was administered to 370 (57.6%) patients, mostly with temozolamide (n=362, 97.8%). Furthermore, 434 (67.7%) patients received maintenance chemotherapy, 398 with temozolamide (&lt; 6 cycles in 112 [28.4%], 6 cycles in 75 [18.8%], and &gt;6 cycles in 214 [3.8%]). Median follow-up was 29 months (26-33). Median OS according to histology was: 35 months (95%CI 26-46) for glioblastoma, 91 months (95%CI 35-NR) for glioma NOS, and not reached for astrocytoma and oligodendroglioma. Median OS by number of temozolamide maintenance cycles was 18 months (95%CI 15-24) for &lt; 6 cycles and not reached for 6 cycles or more.

CONCLUSIONS
This is the first multicentric cohort evaluating Brazilian patients with diffuse glioma, providing important data on epidemiology, treatment patterns, and survival in the country.
EPID-11. A POPULATION STUDY OF CLINICAL TRIAL ACCRUAL FOR WOMEN AND MINORITIES IN NEURO-ONCOLOGY FOLLOWING THE NIH REVITALIZATION ACT
Authors: Reihl Sheantel , Patil Nirav , Morshed Ramin , Mehari Mulki , Aabedi alexander , Chukwueke Ugonma , Porter Alyx , Fontil Valy , Cioffi Gino , Waite Kristin , Kruchko Carol , Ostrom Quinn , Barnholtz-Sloan Jill , Hervey-Jumper Shawn 
Published: November 2021

Abstract

INTRODUCTION
The NIH Revitalization Act, implemented 29 years ago, set to improve the representation of women and minorities in clinical trials. In this study, we investigate the progress made in neuro-oncology in all phase therapeutic clinical trials for neuro-epithelial central nervous system tumors in comparison to their demographic-specific age-adjusted disease incidence and mortality.

METHODS
Registry study of all published clinical trials for World Health Organization (WHO) defined neuro-epithelial CNS tumors between January 2000 and December 2019. Study participants for trials were obtained from PubMed and ClinicalTrials.gov. Population-based data from the CBTRUS for incidence analyses. SEER-18 Incidence-Based Mortality data was used for mortality analysis. Descriptive statistics, Fisher exact, and c2 tests were used to analyze the data.

RESULTS
Among 662 published clinical trial articles representing 49, 907 accrued participants, 62.5% of study participants were men and 37.5% were women (P&lt; 0.0001) representing a mortality specific over-accrual for men (P= 0.001) and under-accrual for women (P= 0.001). Whites, Asians, Blacks, and Hispanics represented 91.7%, 1.5%, 2.6%, and 1.7% of trial participants. Compared with their US cancer mortality, Blacks (47% of expected mortality, P=.008), Hispanics (17% of expected mortality, P&lt; .001) and Asians (33% of expected mortality, P&lt; .001) were underrepresented compared with Whites (114% of expected mortality, P&lt; .001).

CONCLUSIONS
Nearly 30 years since the Revitalization Act, minorities and women are consistently underrepresented when compared with their demographic-specific incidence and mortality in therapeutic clinical trials for neuroepithelial tumors. This study provides a framework for investigating cancer clinical trial accrual and offers guidance regarding workforce factors associated with enrollment of vulnerable patients.
EPID-22. IMPROVED SHORT-TERM OUTCOMES AND LONG-TERM SURVIVORSHIP IN RELATION TO IMMUNOTHERAPY FOR PATIENTS WITH GLIOBLASTOMA BASED ON ANALYSIS OF THE NATIONAL CANCER DATABASE (NCDB)
Authors: Zhu Ping , Du Xianglin , Tandon Nitin , Esquenazi Yoshua , Zhu Jay-Jiguang 
Published: November 2021

Abstract

OBJECTIVES
To explore the impact of immunotherapy on short-term outcomes and long-term survival rates, and the predictors of immunotherapy receipt in patients with glioblastoma (GBM) using NCDB.

METHODS
A total of 74245 GBM patients were derived from the NCDB from 2004 to 2014. Analyses include short-term outcomes (at least 6-month, 1-year, or 2-year after diagnosis) and long-term survivorship (at least 3-year). The Kaplan-Meier method and accelerated failure time (AFT) models were performed for survival analysis. The multivariable binary logistic regressions were applied to identify predictors of immunotherapy receipt. Random survival forest was conducted to validate the variable importance and decision tree as well.

RESULTS
A total of 766 (1.0%) GBM patients received immunotherapy as the first-line treatment. The multivariable binary logistic regressions identified the significant predictors related to immunotherapy receipt, including the recent years of diagnosis (especially 2013 and 2014), age &lt; 65 years, higher income, private insurance, residence-hospital distance &gt;50 miles, care transition, treatment at the facility located in South regions or academic facilities, and adjuvant therapy. After adjusting socio-demographics, facility characteristics, and clinical treatments (surgery and adjuvant therapy), patients received immunotherapy experienced the significantly prolonged OS compared to those who didn’t [OS (months): 16.0 vs. 9.8, log-rank test p-value: &lt; 0.001; Time Ratio (TR): 1.26 vs. 1.00 (Ref.), multivariable AFT p-value: &lt; 0.001]. In multivariable logistic regressions, compared to patients without immunotherapy, the likelihoods of 6-month (OR: 3.89, p&lt; 0.001), 1-year (OR: 2.38, p&lt; 0.001), and 2-year (OR: 1.58, p=0.001) survival rates were significantly increased for those received immunotherapy. Regarding the long-term survivorship, immunotherapy was significantly associated with a 68% higher likelihood of 3-year survival rate (p=0.004).

CONCLUSIONS
Our findings demonstrated that immunotherapy in GBM patients, albeit small sample size, was significantly associated with improved short-term outcomes and 3-year survivorship after adjusting traditional clinical treatments and other covariates.
IMMU-04. UNVEILING THE TUMOR-METABOLOME-IMMUNITY AXIS OF GLIOMA
Authors: Friedrich Mirco , Bunse Lukas , Sankowski Roman , Wick Wolfgang , Prinz Marco , Platten Michael 
Published: November 2021

Abstract
The glioma microenvironment orchestrates tumor evolution, progression, and resistance to therapy. In high-grade gliomas, microglia and monocyte-derived macrophages constitute up to 70% of the tumor mass. However, the dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype. We report the unexpected and clinically highly relevant finding that human as well as murine gliomas with Isocitrate Dehydrogenase (IDH)1-R132H, a key oncogenic driver mutation of glioma, subdue their innate immune microenvironment by prompting a multifaceted reprogramming of myeloid and T cell metabolism. We employed integrated single-cell transcriptomic, time-of-flight mass cytometry and proteomic analyses of human healthy cortex control and glioma samples to identify myeloid cell subsets with distinct fates in IDH-mutated glioma that diverge from canonical trajectories of antigen-presenting cells as a result of a monocyte-to-macrophage differentiation block. Moving beyond single time point assessments, we now longitudinally describe differential immune cell infiltration and phenotype dynamics during glioma progression that are orchestrated by a fluctuating network of resident microglial cells and educated recruited immune cells. IDH mutations in glioma induce a tolerogenic alignment of their immune microenvironment through increased tryptophan uptake via large neutral amino acid transporter (LAT1)-CD98 and subsequent activation of the aryl hydrocarbon receptor (AHR) in educated blood-borne macrophages. In experimental tumor models, this immunosuppressive phenotype was reverted by LAT1-CD98 and AHR inhibitors. Taken together with direct effects on T cell activation, our findings not only link this oncogenic metabolic pathway to distinct immunosuppressive pathways but also provide the rationale and novel molecular targets for the development of immunotherapeutic concepts addressing the disease-defining microenvironmental effects of IDH mutations.
IMMU-07. REPROGRAMMING OF MICROGLIA/MACROPHAGES IN GLIOBLASTOMA IMPROVES ANTI-TUMOR T CELL RESPONSES
Authors: Fermi Valentina , Warta Rolf , Jungk Christine , Trong Philip Dao , Unterberg Andreas , Herold-Mende Christel 
Published: November 2021

Abstract
Glioblastoma (GBM) still remains incurable. In search for new treatment modalities immunotherapy might be attractive but highly depends on a sufficient infiltration and function of effector T cells in an immunosuppressive microenvironment. In this study, we analyzed if blocking or reprogramming M2polarized glioma-associated microglia/macrophages (GAMs) could improve spontaneous effector T cell responses and thus enhance the effectiveness of immunotherapy. This was tested by sorting patient-derived CD11b+ cells from GBM tissues and treating these GAMs with small molecule inhibitors (SMI) targeting the colony stimulating factor1 receptor (CSF1R). Especially CD11b+ cells treated with the SMI GW2580 presented with a reduced expression of the M2 marker CD163 (p &lt; 0.01) and an increased expression of HLA-DR (p &lt; 0.05). Conditioned media of SMI-treated GAMs also contained significantly higher levels of nitrite (p &lt; 0.001) and a reduced concentration of the immunosuppressive cytokine IL-6 (p &lt; 0.05). Moreover, gene expression profiles of GW2580-treated GAMs showed a shift from an immunosuppressive towards a pro-inflammatory phenotype. Most importantly, the addition of conditioned media of GW2580-treated GAMs to a co-culture of autologous tumor and T cells significantly reduced the number of live tumor cells as compared to the use of conditioned media of untreated GAMs (p &lt; 0.05). Interestingly, in some cases the ability of T cells to transmigrate through a dense barrier of autologous tumor-derived endothelial cells could also be increased. In summary, we showed that CSF-1R blockade with the SMI GW2580 can reprogram GAM phenotype and thereby improve T cell activation. This strongly suggests further studies on the use of GW2580 in combination with immunotherapeutic approaches for the treatment of GBM.
IMMU-12. TUMOR CELL IDO ENHANCES IMMUNE SUPPRESSION AND DECREASES SURVIVAL INDEPENDENT OF TRYPTOPHAN METABOLISM IN GLIOBLASTOMA
Authors: Zhai Lijie , Bell April , Ladomersky Erik , Lauing Kristen , Bollu Lakshmi , Nuygen Brenda , Genet Matthew , Kim Miri , Mi Xinlei , Kocherginski Masha , Wu Jennifer , Schipma Matthew , Wray Brian , Griffiths John , Unwin Richard , Clark Simon , Acharya Rajesh , bao Riyue , Horbinski Craig , Lukas Rimas , Schiltz Gary , Wainwright Derek 
Published: November 2021

Abstract

OBJECTIVE
Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is an immune checkpoint that’s characterized as a potent immunosuppressive mediator through its ability to metabolize tryptophan and wild-type IDH patient-resected glioblastoma (GBM) expresses IDO in ≥ 95% of cases. Recent findings from our group led us to investigate the alternative hypothesis that IDO possesses immunosuppressive effects that are independent of its associated metabolic activity.

METHODS
Murine GBM cell lines that overexpress either wild-type or enzyme-null IDO were created for in vivo characterization of IDO enzyme-independent immunosuppressive function. Microarray was conducted to identify human IDO expression-correlated genes, which were further investigated in human GBM cell lines, patient GBM tissues and plasma, as well as the TCGA database. Ex vivo cell co-culture assays and syngeneic mouse orthotopic GBM models were employed to study immunosuppressive mechanisms.

RESULTS
Here, we demonstrate that non-enzymic IDO activity decreases survival in experimental animals and increases the expression of immunosuppressive complement factor H (CFH) in human GBM. CFH mRNA levels positively correlate with those of IDO and many other immunosuppressive genes in patient resected GBM and can be applied as a prognostic marker in both lower grade gliomas and GBM. Similar to IDO, the increased expression of CFH in patient-resected glioma was positively correlated with an increased signature for regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs). High expression of CFH in tumor cells increases intratumoral Tregs levels and decreases overall survival in mice with GBM, while inducing tumor associated macrophage cell differentiation.

CONCLUSIONS
Here, we demonstrated that glioblastoma (GBM) cell IDO promotes the accumulation of intratumoral FoxP3+ regulatory T cells (Tregs) and tumor progression while decreasing overall survival - independent of IDO enzyme activity. Our study reveals a targetable non-metabolic IDO-dependent mechanism for future therapeutic intervention in patients with GBM.
IMMU-18. GLIOBLASTOMA-DERIVED EXTRACELLULAR VESICLES INDUCE DRAMATIC CHANGES IN THE TRANSCRIPTOMIC LANDSCAPE OF MONOCYTES
Authors: Himes Benjamin , Nesvick Cody , Li Helen , Jung Mi-Yeon , Parney Ian 
Published: November 2021

Abstract
Glioblastoma (GBM) is the most common and deadly primary brain tumor. Novel therapeutic strategies are urgently needed to improve outcomes, but a number of disease-specific barriers pose challenges to innovation. Tumor-mediated immunosuppression is one such hurdle, and a growing body of evidence suggests that GBM-derived extracellular vesicles (EVs) play an important role in host immunosuppression. GBM-derived EVs have been shown to induce the formation of immunosuppressive monocytes, including myeloid-derived suppressor cells. Work by our group and others has increasingly shown that these immunosuppressive monocytes are a heterogenous group, and that many constellations of surface markers are inadequate to capture the changes wrought by EVs. In order to better understand the effects of GBM-EVs on monocytes, we conducted RNA-seq analysis on monocytes collected from four healthy donors treated with GBM-derived EVs harvested by ultracentrifugation from the patient-derived BT116 cell line. Following 72h of EV conditioning, total RNA was harvested from treated monocytes and untreated controls. RNA-seq was performed using the Illumina HiSeq4000 platform with paired end index reads. Analysis was performed using RNA STAR and the hg19 ENCODE reference sequence. Differential expression analysis was performed using DESeq2. Genes with a false-discovery rate (FDR)-corrected P value &lt; 0.05 and a log2 fold-change value of &gt;|1| were considered significantly different between groups. Pathway analysis was performed using ClueGO in Cytoscape (GO term fusion on, p&lt; 0.05). Unsupervised clustering analysis of the top 500 most differentially-expressed genes demonstrated grouping of BT116 EV-treated monocytes together versus untreated monocytes. Pathway analysis upregulated genes in pathways important for heparan sulfate proteoglycan synthesis and cholesterol synthesis, which could potentially point to positive regulation of EV uptake. Downregulated pathways included regulation of T cell differentiation and chemoattractant activity, underscoring the induction of a potentially immunosuppressive phenotype by GBM-derived EVs.