bluuebunny/crossref_metadata_2025_split huggingface dataset:
HOUT-14. PROGNOSTIC IMPACT OF FIRST PSEUDOPROGRESSION ON MRI IN GLIOBLASTOMA, AN 11 YEARS EXPERIENCE FROM A CANADIAN UNIVERSITY CENTER
Authors: Zeidan Elie , Assad Anis , Letourneau Guillon Laurent , Belanger Karl , Lemieux Blanchard Emilie , Lemieux Bernard , Bahary Jean-Paul , Roberge David , G Masucci Laura , Menard Cynthia , Lambert Carole , Moumdjian Robert , Berthelet France , Ben-Abdallah Meriem , De Guise Jacques , Florescu Marie 
Published: November 2019

Abstract

BACKGROUND
In glioblastomas (GBM) patients the first post-radiation MRI is usually difficult to interpret given the post-radiotherapy enhancement and possible pseudo-progression which is present in almost 50% of the patients.

METHODS
We retrospectively analyzed all patients with GBM treated between 2006 and 2017 at the CHUM (SARDO database). If the first brain MRI done within 3 months after the systemic treatment showed progression of contrast, these patients were considered pseudoprogressors (PsP) while the patients who had stable or response to treatment were the non-progressors (nP). If progression persisted in subsequent MRI with a change of treatment within 6 months, they were considered early progressors (eP). If subsequent MRI improved or was stable, they were classified as nP (or true pseudo-progression).

RESULTS
In our cohort of 470 patients with GBM, 57.7% were nP and 42.3% were PsP after the first post-treatment imagery. The median follow-up was 10 months. The nP had a longer mOS 15.3m vs 11.3m, p < 0.001, regardless of subsequent evolution. After the second assessment, 67.8% of PsP patients were then considered as eP and 36.4% of nP patients also progressed within 6 months. The nP either after the first or second evaluation had the same mOS (19.9m vs 18.3m), just like the eP (9.3m vs 8.6m), independently of the subsequent treatment. No demographic, molecular or clinical factor predicted PsP, except for tumor size (> 5cm, p=0.024). PsP incidence was similar between 2006–2011 (PsP 57.8%) and 2012–2017 (42.2%). The 1y OS with pseudo progression at the first MRI was 39.7% vs 54.8% with no progression (p=0.001) which has a meaningful impact for the patient.

CONCLUSION
Pseudo-progression is frequent (42%) in glioblastoma and predicts a poorer prognosis with 1y OS of 39,7%. In fact, PsP patients have more than two-thirds chance to progress precociously.
HOUT-18. TREATMENT STRATEGIES FOR GLIOBLASTOMA IN OLDER PATIENTS: AGE IS JUST A NUMBER
Authors: Youssef Michael , Ludmir Ethan , Mandel Jacob , Patel Akash , Jalali Ali , Treiber Jeffrey , Wu Jimin , McAleer Mary , DeGroot John 
Published: November 2019

Abstract

BACKGROUND
Optimal care for elderly patients with glioblastoma (GBM) remains in question due to their exclusion from and underrepresentation in clinical trials (including EORTC 22981) as well as their historically-poor overall survival.

METHODS
Retrospective chart review was conducted at a single high-volume cancer center for newly-diagnosed elderly (65 years old or older) GBM patients diagnosed from 2011 through 2017.

RESULTS
A total of 158 newly-diagnosed GBM patients aged 65 years and older were identified. 144 patients (91.1%) underwent radiation therapy. One-hundred thirty patient (90.3%) received concurrent temozolomide with radiotherapy. A minority of patients (23%) discontinued temozolomide during concurrent or adjuvant treatment due to side effects or complications of chemotherapy. Sixty-one patients (38.6%) completed concurrent chemoradiation and 6 cycles of adjuvant temodar. The median overall survival (OS) time for our cohort was 18.6 months, with estimated OS rates of 74.8%, 35.9%, and 9.5% at 1, 2, and 5 years, respectively. On multivariable analysis, higher KPS (p=0.002, HR 0.46; 95% CI: 0.63–0.82), completing planned course of radiation (p=0.01, HR 0.29; 95% CI: 0.11–0.75), and completing 6 cycles of adjuvant temozolomide (p=0.01, HR 2.62; 95% CI: 1.67–4.12) were associated with improved OS.

CONCLUSIONS
Our cohort of elderly GBM patients were predominately treated with a standard of care based on EORTC 22981. Despite their age, these patients tolerated treatment well and had a favorable overall survival compared to outcomes reported for patients treated on EORTC 22981. Using age alone as the reason to de-escalate treatment or as an exclusionary criteria in clinical trials should be discouraged.
HOUT-28. FIRST-LINE TEMOZOLOMIDE VS PCV FOR LOW GRADE GLIOMAS: A 11 YEARS REAL-WORLD DATA FROM CHUM, UNIVERSITY CENTER
Authors: Nait Ajjou Myriam , Assad Anis , Letourneau Guillon Laurent , Belanger Karl , Lemieux Blanchard Emilie , Lemieux Bernard , Bahary Jean-Paul , G Masucci Laura , Roberge David , Menard Cynthia , Lambert Carole , Moumdjian Robert , Berthelet France , Ben-Abdallah Meriem , De Guise Jacques , Florescu Marie 
Published: November 2019

Abstract

BACKGROUND
Before 2012, Temozolomide (TMZ) was used for low-grade gliomas (LGG) to avoid Lomustine toxicity. After 2012 RTOG data, Procarbazine, Lomustine and Vincristine (PCV) given sequentially with radiotherapy became standard treatment with the side effects burden associated.

METHODS
We retrospectively reviewed our SARDO clinical database of patients with low-grade glioma LGG grades 2 and 3 between 2006 and 2017 at CHUM University Health Center. Molecular profile for these tumors is reflex and standard in our institution since 2016.

RESULTS
A total of 123 patients were identified with grade 2 and grade 3 LGG; 37 (30%) treated with PCV and 86 (70%) received TMZ. Median follow up was 11mo for PCV 11mo vs 22mo TMZ. Both groups were balanced in terms of median age, sex, neurologic symptoms and surgery rate. 53% patients had tumor untested for IDH1-2 and codeletion1p19q because of diagnostic before 2016. Disparities were noted with a predominance of grade 3 in the TMZ group (74% vs 27%, p< 0.01). TMZ was the preferred regimen before 2012 (100% vs 43%) and PCV became the standard of care after 2012 (0% vs 57%). Radiation use as first line treatment was 90%. The 4y OS was not significantly longer for PCV 50% compared with TMZ 47% with mOS between both groups (PCV NR vs TMZ 39.9mo, p=0.158). When controlled for tumor grade, the 2y OS was 80% for PCV vs 64% for TMZ,p=0.542. The 4y PFS was trendly longer for PCV group 78% than TMZ group 45%, p=0.148.

CONCLUSION
As we are still waiting for the prospective ongoing prospective trials comparing these 2 regimens, PCV and radiation are still standard of care regimens for grade 2 and 3 LGG. This retrospective data is not reassuring for a replacement for PCV with TMZ.
IMMU-01. MYELOID-DERIVED SUPPRESSOR CELL HETEROGENEITY DRIVES GLIOBLASTOMA PROGRESSION IN A SEX-DEPENDENT MANNER
Authors: Bayik Defne , Silver Daniel , Park Chihyun , Watson Dionysios , Sorensen Mia , Roversi Gustavo , Lauko Adam , Alban Tyler , Lo Alice , Sims Peter , Barnholtz-Sloan Jill , Kristensen Bjarne , Hyun Hwang Tae , Khalil Ahmad , Iavarone Antonio , Cheng Feixiong , Lathia Justin 
Published: November 2019

Abstract
An immunosuppressive tumor microenvironment is a major factor facilitating glioblastoma (GBM) progression and therapeutic resistance. 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. Our group previously demonstrated that myeloid-derived suppressor cells (MDSCs) expand in GBM patients and infiltrate tumors, where they suppress the activity of cytotoxic cells. However, the mechanisms by which individual MDSC subsets promote tumorigenesis remain understudied. Using the syngeneic mouse glioma models GL261, CT-2A and SB28, we show that monocytic MDSCs (mMDSCs) are prevalent in tumors and that their frequency is significantly higher in males, who constitute 60% of GBM patients and have a worse prognosis than females. mMDSC abundance was further associated with poor survival, and male mice reached morbidity endpoint earlier. Consistent with preclinical observations, male GBM patient specimens had significantly more IBA+CD204+ immunosuppressive myeloid cells compared to female GBM tissue. In contrast, female tumor-bearing mice had a two-fold increase in circulating granulocytic MDSC (gMDSC) frequency, while this population remained unchanged in males. Female-to-male bone marrow chimeras demonstrated that intrinsic discrepancies in immune cell characteristics drive the sex differences in survival. Consistent with the differential MDSC accumulation pattern, targeting gMDSCs with anti-Ly6G neutralizing antibodies extended the lifespan of female mice without providing a survival advantage to males. However, mMDSCs were protected from the anti-Ly6C depletion strategy due to their systemic and local proliferation, as indicated by ex vivo Ki-67 staining and subsequently confirmed by gene expression analysis. Drug-prediction algorithms using the differential RNA sequencing profiles demonstrated that mMDSCs can be targeted by chemotherapeutics, while immunomodulatory drugs are effective against gMDSCs. Collectively, these findings indicate that MDSC subset variation might represent a therapeutic opportunity for improved therapeutic efficacy of immunotherapies while accounting for sex as a biological variable.
IMMU-03. SUPPRESSION OF ONCOMETABOLITE 2-HYDROXYGLUTRATE PRODUCED BY MUTANT IDH1 GLIOMA WITH AGI-5198 ENHANCES THE EFFICACY OF RADIOTHERAPY AND IMMUNE CHECKPOINT BLOCKADE ELICITING IMMUNOLOGICAL MEMORY
Authors: Kadiyala Padma , Nunez Felipe , Garcia-Fabiani Maria , Nunez Fernando , Li Dan , Schwendeman Anna , Lowenstein Pedro , Castro Maria 
Published: November 2019

Abstract
Patients with mutant IDH1 gliomas survive ~3.8 year longer than patients harboring wildtype IDH1 glioma, irrespective of histology or genetic lesions, making mutant IDH1 an essential prognostic indicator. Mutant IDH1 gliomas are highly infiltrative with a high incidence of relapse. We are studying a low grade glioma subtype, genetically characterized by inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) gene, TP53 and gain of function mutations in isocitrate dehyrdogenase 1 (mIDH1). Mutation in IDH1 converts α-ketoglutrate (αKG) to 2-hydroxyglutarate (2HG), an oncometabolite that inhibits histone and DNA demethylases, leading to a hypermethylated tumor phenotype [1]. This leads to epigenetic reprograming of the tumor transcriptome. The role of 2HG as an immune regulator in the mIDH1 glioma tumor microenvironment remains to be elucidated. Herein, we investigate whether 2HG produced by mIDH1 glioma in the tumor microenvironment mediating antitumor immunity. We used mIDH1 inhibitor AGI-5198 to abrogate the neomorphic enzymatic activity of IDH1R132H in a transplantable mIDH1 glioma mouse model. Animals were implanted with mIDH1 tumor neurospheres and they were systemically administered with AGI-5198. Our results indicate that pharmacological inhibition of IDH1R132H enzymatic function significantly prolongs the median survival (MS) of mIDH1 glioma bearing mice (~1.5-fold vs controls); eliciting strong antitumor activity, eradicating 40% of the established mIDH1 gliomas. Our results also demonstrate that antitumor immunity induced by 2HG inhibition is enhanced when combined with standard of care (temozolomide and radiation) and anti-PDL1 immune checkpoint blockade. In addition, when the long-term survivors (>90 days) were rechallenged with mIDH1 tumor cells in the contralateral hemisphere, without further treatment, all the mice remained tumor free, indicating the development of anti-glioma immunological memory. Collectively, these findings support the clinical testing of AGI-5198 as an adjuvant therapy and a novel immunotherapeutic strategy for treating patients with mIDH1 glioma.
IMMU-04. TEMPORAL AND SPATIAL MODULATION OF THE IMMUNE RESPONSE OF THE MURINE GL261 GLIOMA TUMOUR MICROENVIRONMENT
Authors: McKelvey Kelly , Hudson Amanda , Kumar Ramyashree , Long Georgina , Scolyer Richard , Wilmott James , Attrill Grace , Clarke Stephen , Wheeler Helen , Diakos Connie , Howell Viive 
Published: November 2019

Abstract

INTRODUCTION
Glioma is a debilitating and early fatal cancer arising in the glial cells of brain. Glioblastoma, the most aggressive form of gliomas, has a 5-year survival rate of 5% with treatment options limited to surgery, radiotherapy or chemotherapy with temozolomide.

OBJECTIVE
While radiation and immunotherapies are routinely studied in the murine Gl261 glioma model, little is known about its inherent immune response. In this study we quantified the temporal and spatial localisation of immune cell populations and mediators during glioma development.

METHODS
Mice were inoculated with 1x106 Gl261 cells at AP0.1mm, ML1.0mm, DV2.6mm Bregma. Tumour morphology, local and systemic immune cell populations were assessed at Day-0, 1, 3, 7, 14, and 21 post-inoculation by MRI, immunohistochemistry for Ki67+ proliferation and CD31+ vessel density; local immune infiltrate by multiplex immunofluorescence (VECTRA®;PerkinElmer); systemic immunity in spleen, bone marrow and peripheral blood by 16-parameter flow cytometry (LSRFortessa™;BD Biosciences); and multiplex immunoassay (Bio-Plex®;Bio-Rad) for plasma cytokines/chemokines.

RESULTS
From Day-3 tumours were distinguishable with high Ki67+ (> 30%) and increased tissue vascularisation (26.38±1.45 vessels/field; p< 0.05). Ki67 remained high until Day-21 with visible necrotic regions, increased vessel density and lumen area within tumour region. Increasing tumour proliferation/malignancy and vascularisation were associated with significant temporal changes in immune cell populations within the tumour (p< 0.05) and systemic compartments (p=0.02- p< 0.0001). Of note, at Day-14 NK, M1, PMN-MDSCs and M-MDSCs in the tumour infiltrate declined, coinciding with a decrease in 16/24 plasma cytokine/chemokines levels. Tumour infiltrating immune cell populations did not correlate with peripheral blood populations. However, a decrease in plasma cytokine/chemokine levels may indicate ‘immune exhaustion’.

CONCLUSIONS
The data derived provide baseline characteristics to study changes associated with multi-modal treatment strategies and to sequence therapies to maintain immune modulation. This information will contribute to the identification of novel combination therapies.
IMMU-06. TTFIELDS INDUCES IMMUNOGENIC CELL DEATH AND STING PATHWAY ACTIVATION THROUGH CYTOPLASMIC DOUBLE-STRANDED DNA IN GLIOBLASTOMA CELLS
Authors: Chen Dongjiang , Thomas Nagheme , Ren Jie , Le Son , Sebstian Mathew , Deng Changwang , Jin Dan , Tran David 
Published: November 2019

Abstract

OBJECTIVES
Glioblastoma (GBM) is the most common and deadliest malignant brain cancer in adults. Tumor Treating Fields (TTFields) was approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed GBM patients. The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. In many patients, a transient stage of increased peritumoral edema is often observed early during TTFields treatment followed subsequently by objective radiographic responses, suggesting that a major component of therapeutic efficacy by TTFields may be an immune mediated process. We hypothesize that TTFields activate the immune system by triggering pyroptosis and type I Interferon (IFN) response.

METHODS
A panel of GBM cell lines were treated with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system. Cells were analyzed for the production of micronuclei and activation of both pyroptosis and STING pathways using immunostaining, quantitative PCR, ELISA and cytometry.

RESULTS
TTFields resulted in a significantly higher rate of micronuclei structures released into the cytoplasm, which were co-localized with two upstream dsDNA sensors AIM2 and cGAS. TTFields-activated micronuclei-dsDNA sensor complexes led to i) induction of pyroptotic cell death, as measured by LDH release assay, and through AIM2-recruited caspase1 and cleavage of pyroptosis-specific Gasdermin D; and ii) activation of STING pathway leading to the release of type I IFNs and pro-inflammatory cytokines downstream of the NFκB pathway. In a co-culture experiment of bone marrow cells with cells/supernatants obtained from GBM cells treated with TTFields, GBM cells depleted of AIM2 and STING failed to induce bone marrow cells.

CONCLUSIONS
These results provide compelling evidence that TTFields activates the innate immune system in GBM cells, and a strong rationale for combining TTFields with immune checkpoint inhibitors to create a therapeutic synergy.
IMMU-08. THE ANTIGENIC LANDSCAPE OF GLIOBLASTOMA - REFINING THE TARGETS FOR IMMUNOTHERAPY
Authors: Kapolou Konstantina , Katharina Freudenmann Lena , Friebel Ekaterina , Bichmann Leon , Becher Burkhard , Stevanović Stefan , Rammensee Hans-Georg , Weller Michael , Christoph Neidert Marian 
Published: November 2019

Abstract
We provide a comprehensive analysis of the antigenic landscape of glioblastoma using a multi-omics approach including ligandome mapping of the Human Leukocyte Antigen (HLA) ligandome, next generation sequencing (NGS) as well as an in-depth characterization of tumor-infiltrating lymphocytes (TIL) using mass cytometry and ultra-deep sequencing of the T-cell receptor (TCR). Tumor-exclusive HLA class I and class II ligands (immune precipitation and LC-MS/MS) of 24 isocitrate dehydrogenase 1 wild type glioblastoma samples and 10 autologous primary glioblastoma cell lines were defined in comparison to an HLA ligandome normal tissue reference database (n > 418). We found 11,496 glioblastoma exclusive HLA class I ligands (2,064 shared with cell lines; 3,754 on ≥ 2 glioblastoma samples). On the source protein level, 239 glioblastoma exclusive proteins were identified; among them 54 were also found in cell lines. For HLA class II ligands the analysis revealed 11,870 glioblastoma exclusive peptides (444 shared with cell lines; 3,420 on ≥ 2 glioblastoma samples) and 278 glioblastoma exclusive proteins; among which 18 were present also in cell lines. Moreover, whole-exome sequencing and whole RNA sequencing of 13 tumor samples was performed with the aim to predict neoantigens. On average 5,662 somatic missense effects were identified per patient (min: 4,258; max: 7,479). Candidate peptides are grouped into (i) in silico predicted neoepitopes, (ii) tumor-exclusivity on HLA, (iii) gene expression (e.g. cancer testis antigens). Top-ranking candidates from each group will be tested with regards to their immunogenicity in an autologous setting (TIL, peripheral blood mononuclear cells, patient derived tumor cells). Finally, the peptide and immunogenicity data is correlated with the immune phenotype of the TIL compartment as well as the TCR repertoire of the sample.
IMMU-15. A UNIQUE SELF-STIMULATIVE PROPERTY OF CD70 CAR ADVANCES T CELL FUNCTION AND ANTI-TUMOR RESPONSE IN GLIOBLASTOMA
Authors: Jin Linchun , Hou Alicia , Tao Haipeng , Karachi Aida , Na Meng , Lin Zhiguo , Deleyrolle Loic , Sayour Elias , Mitchell Duane , Huang Jianping 
Published: November 2019

Abstract

BACKGROUND
Glioblastoma (GBM) is a refractory brain tumor that desperately needs new therapeutic interventions. Our group identified CD70 as a novel target of CAR-T therapy for this malignancy. We demonstrate that CD70 is overexpressed by low-/high-grade gliomas and associated with poor survival for patients; CD70 promotes CD8 specific cell death and tumor-associated macrophage infiltration in gliomas. The CD70 CAR (using CD27, a natural costimulatory receptor of T cells as an antigen-binding region) T cells can efficiently eradicate CD70 positive tumors in syngeneic and xenograft mouse models.

OBJECTIVE
To evaluate the properties of CD70 CAR-transduced T cells in GBM treatment.

METHODS
CD70 CAR or IL13Rα2 CAR was linked with fluorescent reporter gene EGFP, and cloned into a retroviral vector (pMSGV8). In vitro T cell culture and flow cytometry were used to evaluate the self-enrichment property and susceptibility to TCR stimulation of the CAR T cells. KI67, Bcl-2, CD70 gene expression was tested by qPCR to measure the proliferation/apoptosis properties of the CAR T cells. Cytokine profile was analyzed by ELISA. The anti-tumor response was evaluated using Xenograft mouse models.

RESULTS
Compared with IL13Rα2 CAR T cells, the frequency of CD70 CAR T cells was significantly increased 3 weeks post transduction, and approximately 100 to 150-fold CD70 CAR T cell expansion without additional stimuli was achieved in vitro. The expanded CD70 CAR T cells were mostly (up to 85%) CD8+ T cells three weeks post CAR transduction. Enhanced proliferative capacity and production of IL-2, IFN-γ, and TNF-α of the CD70 CAR-transduced T cells upon anti-CD3/CD28 stimulation were also revealed. Results from animal models show that the CD70 CAR T cells present superior in vivo persistence and antitumor efficacy.

CONCLUSION
We show the auto-stimulative property, as well as superior T cell function and antitumor efficacy of CD70 CAR T cells in GBM models.
IMMU-17. TARGETING GLIOBLASTOMA WITH DNAM-1-BASED CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS
Authors: Weiss Tobias , Meister Hanna , Weller Michael , Sentman Charles , Roth Patrick 
Published: November 2019

Abstract

BACKGROUND
Genetically engineered T cells that express a chimeric antigen receptor (CAR) have shown powerful anti-tumor activity in extracranial malignancies. This concept is now also being explored against glioblastoma. However, many single target antigens used for CAR cell therapy are non-homogeneously expressed. We assessed the therapeutic potential of CAR T cells targeting 2 antigens which are homogeneously expressed by glioma cells which reduces the probability of tumor immune escape due to antigen loss.

METHODS
We analyzed the expression of CD112 and CD155, which are ligands to the activating immune cell receptor DNAX Accessory Molecule-1 (DNAM-1), in a panel of mouse and human glioma cell lines as well as in human glioblastoma samples and generated glioma cells with a CD112 or CD155 knock-out. To exploit the specific binding properties of DNAM-1, we generated first or second-generation CAR T cells that use DNAM-1 as an antigen-binding domain and investigated their anti-tumor activity in vitro and in vivo using syngeneic orthotopic mouse glioma models.

RESULTS
CD112 and CD155 are homogeneously expressed in mouse and human glioma cell lines as well as human glioblastoma tissue specimens. CRISPR/Cas9-mediated knock-out of CD112 or CD155 affected the migration of glioma cells, but had no impact on the proliferation or susceptibility to irradiation or temozolomide. DNAM-1-based CAR T cells exerted high cytolytic activity and secretion of various effector cytokines in vitro. Upon intravenous administration, DNAM-1-based CAR T cells did not exert significant toxicity, homed to the tumor site in the brain and prolonged the survival of orthotopic glioma-bearing mice with durable anti-tumor responses in a fraction of mice.

CONCLUSION
CD112 and CD155 represent attractive targets for glioma immunotherapy using genetically engineered immune cells. Based on the data obtained from our preclincal assessment of DNAM-1-based CAR T cells, this immunotherapeutic strategy might also be explored in human glioma patients.