bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-22. TARGETING NON-CANONICAL FUNCTION OF IDO1 IN GLIOBLASTOMA IMMUNOTHERAPY
Authors: Zhai Lijie , Bell April , Qian Jun , Ladomersky Erik , Lauing Kristen , Wainwright Derek 
Published: November 2019

Abstract
Recent failure of immune checkpoint blockade, anti-PD-1 therapy in patients suffering recurrent glioblastoma (GBM) indicates that development of novel immunosuppressive mediator-targeted therapeutic strategy is critical for more effective immunotherapies against GBM. Indoleamine 2, 3-dioxygenase 1 (IDO1) has been shown to mediate tumor-induced immunosuppression through its tryptophan catabolic activity. Surprisingly, pharmacological IDO1 enzyme inhibitors have not demonstrated any survival benefit in cancer patients either mono-therapeutically or in combination with other therapies. Previously we confirmed that tumor IDO1 mRNA expression is significantly upregulated in GBM patients compared to those from patients with lower grades gliomas. Furthermore, knockdown of IDO1 in mouse GBM cells significantly increased mouse survival and decreased tumor infiltrating Tregs, but did not affect tumor local tryptophan catabolism. Consistently, inhibition of IDO1 enzymatic activity on GBM-bearing mice did not yield any survival benefit. These findings indicate that IDO1 may suppress immune response through a non-enzymatic pathway. To test this hypothesis, IDO1-deficient mouse GBM cells were created and modified to stably express either wild-type (WT) or enzyme-null IDO1. Syngeneic mice intracranially engrafted with both WT and enzyme-null IDO1 overexpressing GBM cells showed significantly increase of tumor infiltrating Tregs and decreased survival in comparison to mice engrafted with IDO1-deficient GBM cells. In contrast, no difference was observed between WT-IDO1 GBM and enzyme-null IDO1 GBM groups. Additionally, when co-cultured with splenic monocytes, both WT and enzyme-null IDO1 overexpressing GBM cells induced more mature macrophages than IDO1-deficient GBM cells. Taken together, our data strongly imply an enzyme independent pathway associated with IDO1-driven immunosuppression in mouse GBM. Validation of this novel mechanism on human GBM cells is ongoing. A soluble molecule has been identified as a potential mediator for the non-enzymatic function of IDO1. Results from this study will provide innovative strategies for IDO1-based immunotherapy against GBM.
IMMU-28. TARGETING IMMUNOSUPPRESSIVE MYELOID DERIVED SUPPRESSOR CELLS VIA MIF/CD74 SIGNALING AXIS TO ATTENUATE GBM GROWTH
Authors: Alban Tyler , Bayik Defne , Otvos Balint , Grabowski Matthew , Ahluwalia Manmeet , Bucala Richard , Vogelbaum Michael , Lathia Justin 
Published: November 2019

Abstract
The immunosuppressive microenvironment in glioblastoma (GBM) enables persistent tumor growth and evasion from tumoricidal immune cell recognition. Despite a large accumulation of immune cells in the GBM microenvironment, tumor growth continues, and evidence for potent immunosuppression via myeloid derived suppressor cells (MDSCs) is now emerging. In agreement with these observations, we have recently established that increased MDSCs over time correlates with poor prognosis in GBM, making these cells of interest for therapeutic targeting. In seeking to reduce MDSCs in GBM, we previously identified the cytokine macrophage migration inhibitory factor (MIF) as a possible activator of MDSC function in GBM. Here, using a novel in vitro co-culture system to reproducibly and rapidly create GBM-educated MDSCs, we observed that MIF was essential in the generation of MDSCs and that MDSCs generated via this approach express a repertoire of MIF receptors. CD74 was the primary MIF receptor in monocytic MDSCs (M-MDSC), which penetrate the tumor microenvironment in preclinical models and patient samples. A screen of MIF/CD74 interaction inhibitors revealed that MN-166, a clinically relevant blood brain barrier penetrant drug, which is currently fast tracked for FDA approval, reduced MDSC generation and function in vitro. This effect was specific to M-MDSC subsets expressing CD74, and appeared as reduced downstream pERK signaling and MCP-1 secretion. In vivo, MN-166 was able reduce tumor-infiltrating MDSCs, while conferring a significant increase in survival in the syngeneic glioma model GL261. These data provide proof of concept that M-MDSCs can be targeted in the tumor microenvironment via MN-166 to reduce tumor growth and provide a rationale for future clinical assessment of MN-166 to reduce M-MDSCs in the tumor microenvironment. Ongoing studies are assessing the effects of MDSC inhibition in combination with immune activating approaches, in order to inhibit immune suppression while simultaneously activating the immune system.
IMMU-34. ATRX MUTATIONS PREDICT RESPONSE TO INNATE BASED THERAPY IN GLIOMA
Authors: Bowie Michelle , Hariharan Seethalakshmi , Hostettler Janell , Roso Kristen , He Yiping , Pirozzi Christopher , Roskoski Martin , Keir Stephen , Brown Michael , Zhang Gao , Gromeier Matthias , Yan Hai , Ashley David 
Published: November 2019

Abstract

BACKGROUND
Innate based immunotherapies are becoming increasingly important for treating brain tumor patients. Gliomas carry recurrent mutations in regulatory genes that control innate immune signaling responses. About 71% of adult WHO grade II and III gliomas and 57% of secondary glioblastomas also carry a loss-of-function mutation in the ATRX gene. ATRX is a SWI-SNF chromatin remodeling protein that has major roles in processes such as cell cycle regulation and maintenance of genomic stability. Recent studies have implicated ATRX in dysfunctional innate immune signaling in cancer cells. However, the role of ATRX in mediating innate immune responses has not been investigated in gliomas.

METHODS AND RESULTS
Human and mouse glioma cell lines from a variety of genetic contexts have been examined including models which carry IDH/ATRX mutations, IDH 1p-/19q- and ATRX -/- status. Additionally, using Crispr-Cas9 technology and cloning cell lines with ATRX deletions, we have derived a series of immune competent and nude mice models. Treating these cell lines with double-stranded RNA based innate stimuli led to an enhanced early induction in phospho-interferon regulatory factor 3 (IRF3) and late induction in phospho-STAT1 in the ATRX knockout (KO) cell lines. A differential increase in interferon-stimulated gene 15 (ISG15) release was also noted in the ATRX KO cell lines, further suggesting that ATRX deletion may enable a potent activation of type I interferon production. A combination of patient-derived glioma cell lines in xenograft models and syngeneic murine glioma models derived from ATRX KO cell lines and controls confirm a survival advantage in both immuno-competent mice and xenografts. Our models are under evaluation with PVSRIPO and other innate based RNA therapies.

CONCLUSION
Our data suggests that ATRX mutations may confer sensitivity to RNA-based innate immune signaling agonists in gliomas. This potential vulnerability can be targeted in future therapies.
IMMU-42. CD8+ T-CELLS MEDIATE IMMUNOEDITING, AND INFLUENCE GENOTYPE, TUMOR ONCOGENIC PATHWAYS AND MICROENVIRONMENT DURING PROGRESSION OF MURINE GLIOMAS
Authors: Robert Kane J , Zhao Junfei , Tsujiuchi Takashi , Laffleur Brice , Mahajan Aayushi , Rao Ganesh , Mela Angeliki , Dmello Crismita , Arrieta Victor A , Chen Li , Zhang Daniel Y , Lee-Chang Catalina , Xiao Ting , Rothschild Gerson , Basu Uttiya , Horbinski Craig , Lesniak Maciej S , Heimberger Amy , Rabadan Raul , Canoll Peter D , Sonabend Adam 
Published: November 2019

Abstract
Cancer immunoediting shapes tumor progression by the immunological selection of tumor cell variants that can evade immune recognition. Given the immune evasive cellular diversity of glioblastoma, we hypothesized that CD8+ T-cells mediate immunoediting in this tumor. We evaluated tumor progression in the absence of CD8+ T-cells by depleting this immune cell population in a transgenic murine glioma model. Tumors generated in the absence of CD8+ T-cells developed poorly in recipients with intact immunity, implying a more immunogenic profile. These tumors demonstrated increased chromosomal instability, gene fusions, MAPK signaling, and macrophage infiltration. These observations were stochastic, suggesting variability in the mode of tumor evolution in the absence of this immune effector. MAPK activation was correlated with macrophage recruitment in two transgenic murine models and the human disease. Our results indicate that CD8+ T-cells mediate a strong immunoediting selection in glioblastoma that protect against the hallmarks of cancer and drive immune evasion.
IMMU-44. INHIBITING IMMUNOSUPPRESSIVE IDO1 IN ADULTS WITH MALIGNANT GLIOMA – A MOVING TARGET THAT CHANGES WITH TREATMENT, CELL OF ORIGIN, AND AGING
Authors: Ladomersky Erik , Zhai Lijie , Lauing Kristen , Qian Jun , Bell April , Otto-Meyer Sebastian , Dussold Corey , Lukas Rimas , Wainwright Derek 
Published: November 2019

Abstract
We previously demonstrated that glioblastoma (GBM) cell IDO1 increases intratumoral immunosuppressive regulatory T cells (Tregs; CD4+CD25+FoxP3+) and decreases overall survival (OS) in the syngeneic GL261 model. IDO1 is characterized as an enzyme that converts the amino acid, tryptophan, into kynurenine. With the finding that IDO1 expression by GBM cells promotes intratumoral Treg accumulation, it was surprising to find that this process was unaffected by the pharmacological treatment with an IDO1 enzyme inhibitor (IDO1i). This led us to question the optimal therapeutic strategy for leveraging an IDO1i against GBM. Utilizing simultaneous whole brain radiation (RT), anti-PD-1 mAb, and an IDO1i, we discovered a long-term survival advantage in ~40% of young WT mice engrafted with either GL261 or CT-2A (n=9–10/group; p< 0.01). Unexpectedly, dual treatment with RT and anti-PD-1 achieved a similar long-term survival advantage in IDO1KO-, but not in WT mice with GBM (n=14/group; p< 0.01), confirming that the therapeutic target of IDO1i was in non-GBM cells. Notably, the triple immunotherapeutic treatment was less effective in elderly mice analogous to the median age of a GBM patient diagnosis (n=20–22/group; p< 0.01) and coincident with increased IDO1 expression in the elderly human brain (n=1,152; p< 0.01). Our working hypothesis is: (i) advanced aging increases IDO1 levels in the brain; (ii) RT elicits the release of GBM cell neoantigens; (iii) IDO1+ lymph node (LN) DCs process/present GBM cell neoantigens to cognate CD8+ T cells; (iv) IDO1i treatment decreases the suppression of IDO1+ DC:CD8+ T cell priming; (v) anti-PD1 treatment enhances LN priming initialized by RT + IDO1i; (vi) brain-resident IDO1+ DCs accumulate during advanced aging and suppress the newly-generated brain-infiltrating CD8+ GBM-specific T cells independent of IDO1i. Our work highlights the immunosuppressive role of advanced aging and the need to better understand gero-neuro-immuno-oncology interactions for enhancing future immunotherapeutic efficacy in adults with GBM.
IMMU-46. EXAMINATION OF THE EFFECTS OF DEXAMETHASONE ON THE EFFICACY OF IMMUNOTHERAPY IN GLIOMA USING GENE-MEDIATED CYTOTOXIC IMMUNOTHERAPY
Authors: Koch Marilin , Zdioruk Mykola , Oskar Nowicki M , Aguilar Estuardo , Aguilar Laura , Guzik Brian , Chiocca Ennio , Lawler Sean 
Published: November 2019

Abstract

RATIONALE
Dexamethasone is frequently used in symptomatic treatment of glioma patients, although it is known to cause immune suppression. Checkpoint inhibitor immunotherapies have not yet been successful in glioma treatments. Gene-mediated cytotoxic immunotherapy (GMCI) is an immunotherapeutic approach that uses aglatimagene besadenovec with an anti-herpetic prodrug to induce immunogenic tumor cell death and immune cell attraction to the tumor site with potent CD8 T cell activation. GMCI is currently in clinical trials for solid tumors including glioblastoma, where it showed encouraging survival results in a Phase 2 study that did not limit the use of dexamethasone. However, the effects of dexamethasone on its efficacy have not been explored.

METHODS
We investigated the effects of dexamethasone on GMCI in vitro using cytotoxicity and T-cell-killing assays in glioblastoma cell lines. The impact of dexamethasone in vivo was assessed in an orthotopic syngeneic murine glioblastoma model.

RESULTS
Cyotoxicity assays showed that Dexamethasone has a slight impact on GMCI in vitro. In contrast, we observed a highly significant effect in T-cell-functional assays in which killing was greatly impaired. Immune cell response assays revealed a reduced T-cell proliferation after co-culture with supernatant from dexamethasone or combination treated glioblastoma cells in contrast to GMCI alone. In a murine model, the combination of GMCI and dexamethasone resulted in a significant reduction in median symptom-free survival (29d) in comparison to GMCI alone (39.5d) (P = 0.0184).

CONCLUSION
Our data suggest that high doses of dexamethasone may negatively impact the efficacy of immunotherapy for glioma, which may be a consequence of impaired T cell function. These results support the idea that there is a need in identifying possible alternatives to dexamethasone to maximize the effectiveness of immunostimulatory therapies such as GMCI.
INNV-01. KETOGENIC METABOLIC THERAPY SIGNIFICANTLY IMPROVES RADIOGRAPHIC AND CLINICAL RESPONSE TO SALVAGE TEMAZOLAMIDE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS
Authors: Smith Kris 
Published: November 2019

Abstract
Ketogenic Metabolic Therapy (KMT), by the proposed Warburg effect, has been shown in animal studies to augment responses to chemotherapy in laboratory models of high grade gliomas. Anecdotal responses in human patients have also been reported. We advised patients in our clinic to adhere to a low-carbohydrate, high-fat diet to obtain a state of nutritional ketosis while undergoing temazolamide (TMZ) chemotherapy for recurrent high-grade gliomas. A registered dietitian, specifically trained in KMT was utilized as a consultant for all of these patients. Blood ketone levels were checked frequently to assure ketone levels above 0.5 mmol/L. Nine patients have documented a near-continuous state of ketosis for at least 3 months while on TMZ therapy and have shown significant radiographic resolution of recurrent disease based on serial high resolution MRI surveillance imaging. All of these patients had shown progressive recurrent disease on serial MRI imaging prior to initiation of KMT. 4 of the 9 patients obtained a complete response, while the other 5 experienced a partial response. None of the patients failed to show any improvement in their imaging follow-up while on KMT. Three of the 9 patients also had salvage radiation therapy to some local area of recurrence prior to initiating KMT. There were no adverse effects related to the KMT diet. Most patients stated that they felt an overall improvement in quality of life while on the diet and embraced the diet as a means of feeling more in control of their disease. The diet was well tolerated and not felt to be a hardship or burdensome after an initial learning curve transition period was overcome. Based on these highly positive preliminary results, we suggest that KMT be included in larger prospective randomized trials for up-front and recurrent high-grade glioma trials to augment standard and experimental therapies.
INNV-05. SOCIAL MEDIA AND “TWEET CHAT ANALYSES” TO INFORM QOL AND PALLIATIVE CARE NEEDS IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Salmi Liz , Otis-Green Shirley , Hayden Adam , Taylor Lynne , Kwan Bethany 
Published: November 2019

Abstract

BACKGROUND
Despite a standard of care protocol for the treatment of brain cancer, patients often suffer motor and cognitive deficits and chronic exposure to stress and anxiety, detrimental to patient quality of life (QOL). Palliative care addresses patient and care partner (caregiver) QOL needs as a complement to curative treatment, using a team-based, multidisciplinary approach. Elements of palliative care that are highest priority for patients with brain cancer are not known.

METHODS
A multi-stakeholder group including clinicians, researchers, patients, and care partners convened (hereafter: “stakeholders”), led jointly by a brain cancer patient and health services researcher. The stakeholders identified QOL needs for patients with brain cancer and their care partners, and mapped these needs onto a brain cancer-specific palliative care model. In 2018, patients, researchers, and clinicians participated in two moderated “tweet chats” to test and further inform QOL definitions and palliative care needs (n=79).

RESULTS
Thematic analysis of tweet chat transcripts revealed patients and care partners were most concerned by: challenging behaviors resulting from tumor and resulting treatment; depression and anxiety; changes in sexuality/intimacy loss; grief over the loss of identity and things one previously enjoyed/was able to do; financial toxicity; changes in close relationships; and dependence on a broader social network. The stakeholders used this work to inform a set of QOL needs and corresponding palliative care elements. Each need was mapped onto a corresponding element for development of a palliative care model. Further research questions were identified to inform further research in this area.

CONCLUSIONS
Patients with brain cancer have complex QOL needs beyond symptom management. A palliative care model for brain cancer should include a multidisciplinary care team including care partner support and education. In addition to the palliative care physician, additional disciplines may include a social worker, chaplain, mental health professional, and rehabilitative services therapists.
INNV-11. THE RISK OF HEMORRHAGE ASSOCIATED WITH THROMBOCYTOPENIA IN PATIENTS UNDERGOING OMMAYA RESERVOIR PLACEMENT FOR INTRATHECAL CHEMOTHERAPY: A SINGLE INSTITUTION RETROSPECTIVE ANALYSIS
Authors: Patel Arpan , Amar Surabhi , Lettieri Salvatore , Gridley Daniel , Bhattarai Bikash , Feiz-Erfan Iman 
Published: November 2019

Abstract

PURPOSE
Ommaya reservoirs are frequently inserted in patients requiring regular delivery of intrathecal medications. The incidence of intracranial hemorrhage following insertion ranges from 1–3% and is typically associated with thrombocytopenia. However, the exact platelet count at which it is considered safe to insert an Ommaya reservoir has not been previously reported. The purpose of this study is to investigate the nature of the relationship between thrombocytopenia and post-operative hemorrhage following insertion of Ommaya reservoirs for intrathecal chemotherapy.

METHODS
Consecutive patients requiring insertion of an Ommaya reservoir were enrolled in the study with no minimum platelet count as an exclusion criterion. Patients data were retrospectively reviewed with thrombocytopenia defined as platelet count < 100,000. All thrombocytopenic patients received at least one unit of intraoperative platelet transfusion. Post-operative incidence of hemorrhage, determined through CT scan, was compared between the thrombocytopenic group and normal platelet group.

RESULTS
53 patients were enrolled within the study with 23 patients determined to be thrombocytopenic at the time of insertion. Thrombocytopenic patients were found to have 18.6 times the odds of post-operative bleeding when compared to patients with normal platelet counts (p< 0.001). However, no patient in the thrombocytopenic group had a clinically significant bleed, defined as being symptomatic or requiring intervention.

CONCLUSIONS
Although thrombocytopenia increases the risk of post-operative hemorrhage associated with Ommaya reservoir placement, there is no increase in clinically significant bleeding. With concurrent platelet transfusion and use of neuronavigation, Ommaya reservoir may be safely placed in thrombocytopenic patients.
INNV-14. ADJUVANT CHEMOTHERAPY AFTER SEVERE MYELOTOXICITY DURING TEMOZOLOMIDE CHEMORADIATION IN GLIOMAS. IT IS FEASIBILE?
Authors: Villani Veronica , Fabi Alessandra , Gaviani Paola , Rudà Roberta , Lombardi Giuseppe , Simonetti Giorgia , Silvani Antonio , Pronello Edoardo , Minniti Giuseppe , Pace Andrea 
Published: November 2019

Abstract

INTRODUCTION
Malignant gliomas are aggressive primitive brain tumor in adults. Today, the standard of care is Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ. TMZ treatment has been considered to have a low toxicity profile. However, during concomitant treatment some patient may develop a severe myelosuppression. This toxicity may be in some cases prolonged and lead to treatment discontinuation.

METHODS
We have retrospectively collected data from 5 Italian neuro-oncological centers, about glioma patients who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy with TMZ. The purpose of this study is to evaluate: percentage of patients receiving adjuvant chemotherapy after severe myelotoxicity; rate of toxicity observed during adjuvant chemotherapy.

RESULTS
54 glioma patients who developed myelosuppression of grade 3 or 4 were considered. Histology was Glioblastoma in 45 patients (83%); 63% of patients were female. Myelotoxicity during concomitant phase occurred at a median of 4 weeks (range 1–8) from the start of treatment. After recovery of myelotoxicity 19 patients did not received any treatment while 35 (65%) were treated with chemotherapy (28 received standard TMZ, one TMZ with metronomic schedule, 2 lomustine and 4 other agents). Among patients treated with TMZ, 13 patients presented hematological toxicity grade 3–4 which required treatment discontinuation in 7 cases (20%).

CONCLUSION
the results of our study show that 80% of glioma patients presenting severe myelotoxicity during concomitant radiochemotherapy may be treated with maintenance TMZ after recovery of myelosuppression.