bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-47. IMMUNOGENIC AND IMMUNOSUPPRESSIVE ASPECTS OF HSV-TK/GCV-MEDIATED SUICIDE GENE THERAPY IN GLIOMA CELLS
Authors: Hossain Jubayer , Latif Abdul , Chaudhuri Romi , Solel Ege , Ystaas Lars , Bjerkvig Rolf , Miletic Hrvoje 
Published: November 2023

Abstract
Suicide Gene therapy (SGT) has been regarded as a promising experimental treatment modality for high-grade gliomas for several decades. However, large-scale clinical trials have failed so far. One hypothesis behind this failure is that, even though SGT directly kills the bulk of the tumor cells, it fails to activate an efficient anti-tumor immune response. Indeed, despite extensive research on SGT, the mechanism of cell death caused by SGT and its immunogenic significance are largely unknown. The most prominent form of SGT— HSV-TK/GCV— for example, is known to kill tumor cells mostly by apoptosis. The immunogenicity of apoptosis in general is controversial and not yet fully explored, especially in the context of SGT. We studied the immunogenic nature of cell death caused by HSV-TK/GCV with two widely used mouse glioma models. To exclude the potential influence of viral vectors on the immune system, we used genetically engineered tumor cells that expresses HSV-TK gene. After orthotopic tumor modelling and SGT with HSV-TK/VGCV, we analyzed the change in immune landscape by using ELISPOT, IHC, FACS and Hyperion in both models. Firstly, we observed that the efficacy of SGT is entirely different in the two glioma models. While in one model tumor growth is only decreased, SGT is curative in the second model. In the non-responding model, an immunosuppressive tumor microenvironment after SGT is observed. Further investigation of the responding model shows that the successful cure is dependent on the availability of an active immune system. We have also identified that the resultant anti-tumor immunity following SGT in this model is mounted by T cells. In conclusion, our data suggest that the immunogenic nature of SGT shows intertumoral heterogeneity and warrants more research to identify the inherent determining factors and mechanisms thereof.
IMMU-51. THE LANDSCAPE OF TUMOR INFILTRATING T CELLS (TILS) OF CHILDHOOD BRAIN TUMORS
Authors: Raphael Itay , Nisnboym Michal , Sneiderman Chaim , Xiong Zujian , Pollack Ian , Chikina Maria , Rajasundaram Dhivyaa , Kohanbash Gary 
Published: November 2023

Abstract
T lymphocytes have a unique ability to recognize a vast array of antigens prompt by an enormous T cell receptor (TCR) repertoire. Characterization of tumor-infiltrating T cells (TILs) and their TCRs is key to understand MHC-restricted anti-tumor immunity and for developing T cell centered immunotherapies such as adoptive cell therapy and tumor vaccines. In the current work, we investigated RNAseq data from nearly 1,000 pediatric brain tumor patients and performed the first large-scale comprehensive examination of the immunogenomic and TCR landscape of TILs across the spectrum of pediatric brain tumors. We show that the relative ratio between T cell diversity (clonality) and T cell abundance within each sample, represented by the clonal expansion index (CEI), is a strong predictor of prognosis across tumor types and molecular subtypes. Interestingly, we found that CEI was strongly associated with molecular subgroups of medulloblastoma but not with known genomic features of these subgroups. Analysis of single-cell (sc)RNAseq and scTCRseq data of TILs across several tumor types, validated clonal expansion of TILs which were frequently associated with effector-cytotoxic T cell phenotypes, whereas non-expanded TILs were associated mostly with CD4 T cell phenotypes. Investigation of T cell clones recognizing a common recurrent tumor-antigen across patients based on CDR3 homology and characteristics, reveals several T cell specificity groups which are tumor type restricted with defined HLA dominance. Using machine learning investigations of genomic profiles of the patients which contain these T cell specificity groups identified novel putative HLA-restricted tumor antigens shared across patients. Importantly, our framework grounded the foundations for developing a precision medicine approach of T cell centered immunotherapies. In all, our findings have major implications for understanding the interplay between T cell and tumor genomic, and for improving immunotherapy strategies for childhood brain tumors.
IMMU-58. CHARACTERIZATION OF MYELOID CELL POPULATIONS IN PEDIATRIC HIGH-GRADE BRAIN TUMORS: THE MIMIC PROGRAM
Authors: Carvalheiro Tiago , Meesters-Ensing Joyce , Hoogendijk Raoull , Kranendonk Mariëtte , Van Baarsen Kirsten , Hoving Eelco , Calkoen Friso , van der Lugt Jasper , Nierkens Stefan 
Published: November 2023

Abstract

BACKGROUND
Pediatric high-grade brain tumors (pHGBT) pose treatment challenges with limited options. Myeloid cells, particularly tumor-associated macrophages (TAMs) in the tumor-microenvironment (TME), exhibit potent immunosuppressive features inhibiting effective anti-tumor T-cell responses. Targeting these cells holds promise to improve outcomes, however the underlying mechanisms of myeloid cell dysfunction remain poorly understood. This study aimed to comprehensively characterize myeloid cell populations in pHGBT and investigate their functional phenotype.

METHODS
Spectral flow cytometry was performed on tumor tissue (biopsies or resections) and tumor fragments obtained by cavitron ultrasonic surgical aspiration (CUSA) in pHGBT patients (High-grade glioma n=2, Ependymoma n=1, Medulloblastoma n=6, Pilocytic Astrocytoma n=2) enrolled in the MIMIC program. This allowed quantification and comprehensive characterization of myeloid cell populations within the TME.

RESULTS
The pHGBT TME showed a low abundance of immune cells across different entities, with myeloid cells comprising the predominant proportion. CD49d was used to identify invading cells derived from bone marrow (CD49+) and resident microglia (CD49-). The total TAMs/microglia population was detected in both tumor tissue and CUSA tumor fragments in similar proportions, however resident CD49d- microglia were notably increased in CUSA tumor fragments. Additionally, invading TAMs displayed a mixed "M1" and "M2" polarization phenotype and exhibited higher expression of the chemokine receptor CCR2 and HLA-DR, and of the immune-checkpoint receptors SIRP1A/B, CD33, and TIM3, compared to resident microglia.

CONCLUSIONS
TAMs play a multifaceted role in pHGBT. The high expression of immune-checkpoint receptors by invading TAMs suggests an immunosuppressive phenotype, potentially facilitating tumor growth, infiltration and (immune)therapy escape. Although, differences between disease entities could not yet be analyzed, disparities were observed in the TME between tumor and CUSA samples, likely related to spatial cellular organization. Understanding TAM dynamics and functional differences between invading and resident subsets, as well as their underlying mechanisms, is crucial for advancing therapeutic efficacy in pHGBT.
INNV-02. USAGE TRENDS OF COLLAGEN TILE BRACHYTHERAPY FOR THE FIRST 1000 ORDERS
Authors: Garcia Michael , Turner Adam , Campbell Lisa , Brachman David 
Published: November 2023

Abstract

INTRODUCTION
Collagen tile brachytherapy (CTBT) was cleared by the FDA in 2018 for all recurrent intracranial neoplasms and in 2020 for newly diagnosed intracranial neoplasms. We sought to describe usage trends of CTBT by evaluating the first 1000 consecutive orders since CTBT became commercially available in 2019 with respect to tumor type (glioma, brain metastasis, meningioma) and CTBT treatment setting (newly diagnosed, recurrence with prior radiation, recurrence without prior radiation).

METHODS
Commercial data was accessed using Salesforce, Inc. Coefficient of correlation (r2) was estimated as a measure of orders over time. 1000 orders were divided into 4 time cohorts (Cohort 1 for 1st 250 orders, Cohort 2 for 2nd 250 orders, Cohort 3 for 3rd for 250 orders and Cohort 4 for 4th 250 orders). Order proportions were compared among time cohorts using X2 tests.

RESULTS
Time period for 1000 orders among 93 centers was 1/23/19–5/11/23. Over these 17 completed yearly quarters there was a positive trend in ordering frequency (r2=0.97). Tumor type was known for 917 orders, of which 52.2% were glioma, 37.4% metastases, and 10.4% meningioma. Proportions of orders for tumor type did not change over time cohorts (p=0.26). Treatment setting was known for 816 orders, of which 80.3% were in recurrence with previous radiation, 14.3% newly diagnosed, and 5.4% recurrence without previous radiation. For glioma and meningioma, treatment setting did not change over time cohorts (p=0.5, p=0.3, respectively). However, for metastases, the proportion of orders for use in the newly diagnosed setting increased over time: 6.4% in Cohort 1, 19.2% in Cohort 2, 21.6% in Cohort 3, 34.7% in Cohort 4 (p&lt; 0.001).

CONCLUSION
CTBT usage is increasing over time. Proportions of orders among tumor types (glioma, meningioma, metastases) has not changed. However, use of CTBT is increasing in the newly diagnosed setting for brain metastases.
INNV-05. OUTCOMES OF RECURRENT GLIOBLASTOMA PATIENTS WITH RADIATION NECROSIS FOLLOWING GAMMATILE BRACHYTHERAPY IMPLANTATION
Authors: McCracken D Jay , McCracken Courtney , Kenning Tyler , Nowlan Adam , Dunbar Erin 
Published: November 2023

Abstract
Implantation of collagen tile brachytherapy GammaTile (GT Medical Technologies Tempe, AZ) allows for targeting of radiation to residual malignancy following surgical resection of gross disease. Radiation necrosis (RN) can develop after radiotherapy or brachytherapy. We sought to determine outcomes in recurrent glioblastoma patients with RN after treatment with Gammatile. All patients were previously treated with surgical resection followed Stupp protocol chemoradiation. At recurrence, patients underwent repeat surgical resection and implantation of GammaTile. Subsequent MRIs were assessed for stability, presumed RN or progression. Symptomatic RN patients were treated with corticosteroids or bevacizumab. From December 2020 to February 2023, 19 patients were treated. Median time from initial radiation to GammaTile therapy was 270 days. A total of 8 patients (42%) developed RN at a median time of 81 days from GammaTile. In RN patients vs those that did not develop RN, pathological tumor viability was lower (20% vs 50%, p=0.3), age was lower (54 vs 63, p=0.06), tumor volume was lower (10.8 cc vs 51.9 cc, p=0.02), time from initial surgery was longer (470 days vs 299 days, p=0.46), number of GammaTiles placed was lower (5 vs 8, p=0.045), rate of gross total resection (GTR) was higher (100% vs 64%, p=0.04), and MGMT methylation rate was higher (63% vs 11%, p=0.03). No patients in the RN group experienced radiographic progression (0% vs 45%, p=0.009) and 3 (38%) required bevacizumab therapy. Median overall survival from GammaTile surgery in the RN group was 325 days vs 188 days (p=0.03). Our series demonstrates a significant survival benefit in patients who develop RN following GammaTile implantation after glioblastoma recurrence. RN developed in younger patients with smaller tumor volumes, lower pathological tumor viability, and higher rates of GTR and MGMT methylation status.
INNV-06. SIGNIFICANCE OF MOLECULAR DIAGNOSTICS FOR THERAPEUTIC DECISION-MAKING IN RECURRENT GLIOMA
Authors: Blobner Jens , Dengler Laura , Blobner Sven , Eberle Constantin , Weller Jonathan , Teske Nico , Karschnia Philipp , Ruehlmann Katharina , Heinrich Kathrin , Ziemann Frank , Greif Philipp , Jeremias Irmela , Wuerstlein Rachel , Hasselmann Korbinian , Dorostkar Mario , Harter Patrick , Quach Stefanie , Stoecklein Veit , Albert Nathalie , Niyazi Maximilian , Tonn Joerg-Christian , Thon Niklas , Westphalen Benedikt , von Baumgarten Louisa 
Published: November 2023

Abstract

BACKGROUND
Targeted therapies have substantially improved survival in cancer patients with malignancies outside the brain. Whether in-depth analysis for molecular alterations may also offer therapeutic avenues in primary brain tumors remains unclear. We herein present our institutional experience for glioma patients discussed in our interdisciplinary Molecular Tumor Board (MTB) implemented at the Comprehensive Cancer Center Munich (LMU).

METHODS
We retrospectively searched the database of the MTB for all recurrent glioma patients after previous therapy. Recommendations were based upon next-generation sequencing results of individual patient’s tumor tissue. Clinical and molecular information, previous therapy regimens and outcome parameters were collected.

RESULTS
Overall, 73 consecutive recurrent glioma patients were identified. In the median, advanced molecular testing was initiated with the third tumor recurrence. The median turnaround time between initiation of molecular profiling and MTB case discussion was 48 ± 75 days (range: 32 - 536 days). Targetable mutations were found for 50 recurrent glioma patients (68.5%). IDH1 mutation (27/73; 37%), EGFR amplification (19/73; 26%) and NF1 mutation (8/73; 11%) were the most detected alterations and a molecular-based treatment recommendation could be made for all of them. Therapeutic recommendations were implemented in 12 cases (24%) and one third of these heavily pretreated patients experienced clinical benefit with at least disease stabilization.

CONCLUSION
In-depth molecular analysis of tumor tissue may guide targeted therapy also in brain tumor patients and considerable anti-tumor effects might be observed in selected cases. However, future studies to corroborate our results are needed.
INNV-07. ADJUVANT POST-SURGERY TREATMENT OF RECURRENT IDH2 MUTANT ANAPLASTIC OLIGODENTROGLIOMA (AO) WITH IDH2 INHIBITOR, ENASIDENIB: A CASE REPORT
Authors: Kong Xiao-Tang , Fu Beverly Dan , Myung Joon , Bota Daniela 
Published: November 2023

Abstract

INTRODUCTION
Recent phase III trial presented by Mellinghoff at 2023 ASCO demonstrated successful treatment of Isocitrate dehydrogenase (IDH)–mutant grade 2 gliomas with Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes. Ivosidenib and enasidenib are separate inhibitors of mutant IDH1 and IDH2, which have shown single-agent activity for the treatment of IDH1- or IDH2-mutant acute myeloid leukemia but the effect in the treatment of glioma is uncertain. Here we report a case of IDH2 mutant AO, who was treated with enasidenib for about two years with fair tolerance and was postponed the next intervention.

CASE REPORT
A 36 yo female was diagnosed anaplastic ogligodentroglioma in 2006, 17 yrs ago. The patient underwent surgery resection, radiation and Temozolomide (TMZ), and 4 cycles of adjuvant TMZ. In 2021, fifteen years later, she was found tumor recurrence. She had a second surgery with near gross total resection. Pathology confirmed anaplastic oligodentraglioma with negative IDH1 mutation but positive IDH2 R172K mutation. To avoid re-radiation nor re-challenge with TMZ, the patient opted IDH2 inhibitor therapy after surgery. The patient tolerated the treatment, and her brain MRI demonstrated no tumor recurrence until one year later when her brain MRI showed vague sub-centimeter nodular non-enhancing lesion at surgical area. Enasidenib was continued for additional 6 months until recent MRI showed small and slow growth. Total therapy is 20 months. Clinically, the patient has no symptoms from tumor.

DISCUSSION
Our case review found post-surgery therapy with IDH2 inhibitor Enasidenib for IDH2 mutant recurrent AO is tolerated and could postpone next intervention such as re-radiation or re-challenge with TMZ.
INNV-14. INTERIM REPORT OF A PHASE 1/2 STUDY OF SONODYNAMIC THERAPY (SDT) USING AMINOLEVULINIC ACID (ALA) AND LOW-INTENSITY FOCUSED ULTRASOUND IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Syed Hasan , Kilburn Lindsay , Packer Roger , Keating Robert , Mueller Sabine , Patel Nirali , Fenn Peter , Clanton Ryan , Andresen Corina , Marcus Stuart , Benaim Ely 
Published: November 2023

Abstract

BACKGROUND
DIPGs are devastating pediatric brain tumors with limited treatment options, poor prognosis, and survival of 9-11 months. Preclinical studies demonstrate that performing SDT through MR-guided focused ultrasound (MRgFUS) activates ALA metabolite, protoporphyrin IX (PpIX), leading to tumor cell death and prolonging survival in rodent glioma models through generation of reactive oxygen species and lipoperoxidation, without affecting normal tissue. MEDTHODS: Herein we report preliminary data from an ongoing first-in-child dose-escalation trial of ALA-SDT post-radiation therapy in children ≥ 5 years with DIPG. The trial aims to evaluate the safety and tolerability of ALA-SDT, determine the recommended-phase-2-dose and assess preliminary efficacy and pharmacokinetics (PK) of ALA administered intravenously.

RESULTS
The first study cohort completed enrollment of 3 subjects. Six hours prior to SDT, patients received an infusion of ALA (SONALA-001) at a dose of 5 mg/kg, followed by sonication with 200J. The first subject was treated in 2 sessions: each to half of the pons 30 days apart. Two subsequent subjects had the entire pons treated in a single session. No dose-limiting toxicity (DLT) or related adverse event grade ≥ 3 were observed. For SONALA-001, the Cmax occurred at the end of infusion, followed by rapid clearance (15.7 mL/min/kg), with a plasma half-life of &lt; 1 hour, indicating rapid distribution (5530 ml/kg). For PpIX, the Cmax occurred 6 hours post-dose and declined with a longer mean half-life of 3.8 hours. Both Cmax and AUCall demonstrate circulating PpIX and systemic exposure were significantly lower than for ALA.

CONCLUSION
SDT signals an innovative and well-tolerated approach for patients with DIPG in our first study cohort. As expected, the PK for SONALA-001 demonstrate rapid infusion and clearance, whereas for PpIX, the PK are consistent with formation of a metabolite. Clinical trial enrollment is ongoing and dose-escalation cohorts will provide additional PK and safety data.
INNV-17. TREATMENT DECISION AND QUALITY OF LIFE OF PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA RECEIVING TUMOR TREATING FIELDS (TTFIELDS) THERAPY IN ROUTINE CLINICAL CARE: RESULTS FROM THE TIGER STUDY
Authors: Bähr Oliver , Tabatabai Ghazaleh , Fietkau Rainer , Goldbrunner Roland , Glas Martin 
Published: November 2023

Abstract

BACKGROUND
TTFields therapy, concurrent with temozolomide, is approved for treatment of newly diagnosed glioblastoma (ndGBM), following results from the pivotal EF-14 study. The multicenter, prospective TIGER study (NCT03258021) investigated real-world use of TTFields therapy in patients with ndGBM during routine clinical care in Germany. Data on patient treatment decisions and health-related quality of life (HRQoL) are reported.

METHODS
Reasons for patient decision to receive TTFields therapy were evaluated via questionnaire (scoring scale: 1 [not at all] to 5 [strongly]) at baseline. In patients who decided to receive TTFields therapy, HRQoL was assessed via the EORTCQLQC30/BN20 questionnaire at baseline, and 2 and 4 months after initiating therapy. HRQoL parameters included: global health status and functioning, insomnia, headaches, fatigue, nausea/vomiting, pain, itchy skin, hair loss, seizures, dyspnea, appetite loss, constipation, diarrhea, visual disorder, leg weakness, drowsiness, bladder control, motor dysfunction, communication deficit, future uncertainty, and financial difficulties.

RESULTS
Overall, 710 patients (259 female; 451 male) were enrolled (Aug 2017–Nov 2019). Mean age was 59 years (range: 19–85). In total, 582 (82%) patients decided to start TTFields therapy, while 128 (18%) declined; the proportion of women was similar in each group (36% and 38%, respectively). Predominant reasons for deciding to start TTFields therapy were the prospect of treatment success (mean score: 4.5) and doing something to fight their disease (4.2). Predominant reason for deciding against TTFields therapy was carrying the device (4.4). During 4-month study follow-up, there was no decline or improvement in any HRQoL parameter, except for more itchy skin, consistent with EF-14 data.

CONCLUSION
TIGER is the largest non-interventional study to date on TTFields therapy use in routine clinical care. Most patients opted to receive TTFields therapy, with fighting their disease and hope for treatment success as major motivators. HRQoL was not impaired during follow-up, except for skin itchiness.
INNV-18. MULTIPHASE COMBINED TREATMENT, INCLUDING INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY FOR ADULTS WITH GBM: SINGLE INSTITUTE REAL WORLD MEDICAL DATA IN THE LIGHT OF CLINICAL TRIAL RESEARCH DATA
Authors: Van Gool Stefaan , Van de Vliet Peter , Kampers Linde , Makalowski Jennifer , Sprenger Tobias , Schirrmacher Volker , Stuecker Wilfried 
Published: November 2023

Abstract
A phase III prospective externally controlled cohort trial recently demonstrated beneficial effects of DCVax®-L for adults with GBM. The beneficial effect of TTF was demonstrated in a RCT. We designed a multiphase combined treatment using subsequentially 1/ modulated electrohyperthermia and Newcastle Disease Virus therapy to induce immunogenic cell death (ICD) during temozolomide maintenance chemotherapy, 2/ two autologous DC vaccinations (IO-Vac®), and 3/ ICD immunotherapy, long-peptide vaccines and one boost IO-Vac® vaccine. During phase 2 + 3, individualized modulatory immunotherapy was provided. Fifty adults with first-line IDH1wt GBM were retrospectively analysed: MGMT promoter-unmethylated (unmeth, 10 f, 18 m); -methylated (meth, 12 f, 10 m). Median age was 48y, median Karnofsky performance index was 80. More than half of the patients had less than complete resection. Dynamics in tumor biology and immune response were demonstrated during treatment (e.g. mRNA expression for PDL1 in circulating tumor cells), and required treatment adaptations (checkpoint inhibitors). The median OS of unmeth and meth patients were 22m (2y-OS: 42%) resp. 38m (2y-OS: 81%, p=0.0414). There were no considerable treatment-related adverse reactions. The (external) control arms in the DCVax®-L and TTF trials, which reflect the current standard-of-care clinical results, showed median OS and 2y-OS of 15m/21% in unmeth and 21m/42% in meth patients. TTF improved the OS in both unmeth and meth patients (17m/27% and 32m/59%), while DCvax®-L improved OS only in meth patients (15m/19% and 30m/58%). These real world data support to prospectively explore the addition of individualized multimodal immunotherapy during and after standard of care, and the role of treatment adaptations during treatment.