bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world experience with tumor treating fields (TTFields) in newly diagnosed glioblastoma: A survival meta-analysis with systematic review.
Authors: Ballo Matthew T. , Conlon Patrick , Lavy-Shahaf Gitit , Urman Noa , Kinzel Adrian , Vymazal Josef , Rulseh Aaron 
Published: June 2023

2059 Background: Tumor Treating Fields (TTFields) are electric fields that exert forces on cancer cells, disrupting processes critical for cancer cell viability and tumor progression. TTFields therapy became an FDA-approved treatment option for patients with newly diagnosed glioblastoma (GBM) in 2015 on the basis of the randomized controlled EF-14 study (NCT00916409). Subsequent approvals worldwide and increased adoption of TTFields has led to the question of whether or not a consistent survival benefit has been observed in the real-world setting, and whether device usage has played a role. Methods: A literature search was conducted using PubMed, Embase, and the Cochrane Library to identify clinical studies evaluating overall survival in adult patients with GBM treated with TTFields therapy. Comparative studies and single-cohort studies reporting on survival outcomes were included in the analysis. Inter-study heterogeneity was assessed using the Cochran Q test and quantified using the Higgins I2 statistic. Survival curves were pooled using a distribution-free random-effects method. Results: Our review identified 8 studies evaluating the clinical efficacy of TTFields therapy in newly diagnosed GBM, with patients spanning diverse geographic regions. Of these 8, 6 studies (reporting on a total of 1378 patients) compared the addition of TTFields therapy to standard of care (SOC) vs SOC alone, and were included in a pooled analysis for overall survival. Meta-analysis of comparative studies indicated a significant improvement in overall survival for patients treated with TTFields therapy vs those not receiving treatment (hazard ratio [HR]: 0.62; 95% CI, 0.52–0.73; P < 0.001). Inter-study heterogeneity was examined, and a sensitivity analysis indicated the pooled effect was robust and not dependent on any individual study. Among post-approval studies, the pooled median overall survival was 22.2 months (95% CI, 17.3–42.6) for TTFields-treated patients and 17.3 months (95% CI, 13.6–22.0) for the non-TTFields group. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields use. Furthermore, among studies reporting data on TTFields device usage, an average device usage rate of 75% or higher was found to consistently associate with prolonged survival when compared to an average usage rate below 75% (pooled HR: 0.63; 95% CI, 0.48–0.83; P = 0.001). Conclusions: Meta-analysis of comparative studies suggests a significant survival benefit with TTFields therapy added to standard radiochemotherapy for patients with newly diagnosed GBM, and that a 75% usage rate may be meaningful in the real-world setting.
Safety and feasibility of JAK inhibitor ruxolitinib in newly-diagnosed high-grade gliomas (CRUX): Final toxicity report.
Authors: Ahluwalia Manmeet Singh , Ozair Ahmad , Khosla Atulya Aman , Rauf Yasmeen , Wei Wei , Murphy Erin Sennett , Chao Samuel T. , Suh John H. , Stevens Glen , Peereboom David M. 
Published: June 2023

2060 Background: Dysregulation of the JAK/STAT pathway in newly-diagnosed high-grade gliomas (nHGG) is linked to enhanced survival and proliferation of tumor cells. Ruxolitinib, a small molecule inhibitor of JAK1, JAK2, and JAK3, limits glioma growth in preclinical models. This concept was explored in a phase I trial (NCT03514069), whose final report on toxicity is presented here. Methods: This non-randomized prospective study included 60 WHO Grade 3-4 nHGG patients who received standard of care (SOC) therapy along with ruxolitinib in a 3+3 dose-escalation design; level 1 of 10 mg BID, level 2 of 15 mg BID, level 3 of 20 mg BID, level -1 of 5 mg BID. The primary study objective was the determination of the maximum tolerated dose (MTD) of ruxolitinib in combination with chemoradiation. The secondary objective was the determination of safety, overall survival (OS), and progression-free survival (PFS). The exploratory aims were to investigate relationships between clinical outcomes and genomic signatures. Results: 60 patients were enrolled, with a median age of 60.5 years (range 22-78). 23 (38%) patients were female and 37 (62%) were male. 29 (48%) were MGMT unmethylated and received ruxolitinib with radiation of 60 Gy over 6 weeks. 31 (52%) patients were MGMT methylated and received ruxolitinib with 75 mg/m2 of temozolomide (TMZ) with radiation of 60 Gy over 6 weeks. The 1-year OS rate was 77% for all GBM patients; 62% for arm 1 (unmethylated MGMT) and 93% for arm 2 (methylated MGMT). Median OS for arm 1 was 18.1 months (10.1, NA) and was not reached for arm 2. MTD for both cohorts was 20 mg BID. No dose-limiting toxicities were observed. Toxicities attributable to study medications included four grade 4 AEs including seizure, respiratory distress, somnolence, and thromboembolic event along with 14 grade 3 adverse events (AEs), including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and meningitis. Conclusions: Ruxolitinib therapy is safe and feasible in combination with TMZ and radiation. Efficacy of ruxolitinib plus SOC appears promising compared to historical benchmarks for both MGMT methylated and MGMT unmethylated cohorts. A randomized phase 2 trial is planned. Clinical trial information: NCT03514069 .
Phase I and pharmacodynamic study of arsenic trioxide plus radiotherapy for newly diagnosed glioblastoma.
Authors: Ryu Samuel , Ye Xiaobu , Olson Jeffrey J. , Mikkelsen Tom , Bangiyev Lev , Lesser Glenn Jay , Batchelor Tracy , Nabors Louis B. , Desideri Serena , Walbert Tobias , Grossman Stuart A. 
Published: June 2023

2061 Background: Arsenic Trioxide (ATO) demonstrated prolonged survival in a transplanted rodent glioblastoma (GBM) model. Given the lack of effective therapies before temozolomide was available, the NCI funded NABTT Brain Tumor Consortium initiated a Phase I study of ATO with radiation in patients with newly diagnosed glioblastoma. Dose escalations using two different schedules of ATO were studied. Methods: Patients with newly diagnosed GBM (MGMT and IDH mutation status unknown) were assigned to receive ATO once or twice weekly during the 6-week course of radiation. The starting ATO dose was 0.25 mg/kg. This was escalated by 0.05 mg/kg until an MTD was reached. Patients did not receive ATO or other adjuvant therapy once the radiation was completed. As ATO affected tumor vasculature and blood flow in experimental imaging studies, perfusion MRIs were obtained before ATO administration and one and six weeks later. Survival was a secondary endpoint. Results: Thirty-one patients were enrolled: median age 54.9 years, 68% male, 77% patients KPS >90, 77% had tumor resection. The MTD was determined to be 0.4mg/kg on the weekly schedule and 0.3mg/kg on the biweekly schedule. ATO was well tolerated with 81% of patients completing the 6 weeks combined treatment. Major dose limiting toxicities were increased aspartate and alanine aminotransferases and one case of hyperkalemia. For all patients the median overall survival (mOS) was 17.7 months and the median progression-free survival (mPFS) was 5.4 months. However, there was a significant survival difference between the two ATO dose schedules across all doses with a mOS of 22.8 months in the biweekly schedule, vs 12.1 months in the weekly schedule (P = 0.039). There was a similar difference in mPFS (10.2 months vs 3.2 months, respectively, P = 0.004). Similarly, there were significant differences in perfusion imaging between the two ATO dose schedules with relative cerebral blood flow showing a significant decrease after one week of ATO treatment on the biweekly schedule (p = 0.007). Conclusions: TheMTDs of ATO in patients with GBM administered once or twice weekly for six weeks with standard radiation were determined. This regimen was well tolerated. Survival in patients on the biweekly schedule was much better (22.8 months) than expected in patients not receiving temozolomide. In addition, patients on biweekly ATO also had significant changes on MRI perfusion studies suggesting a pharmacodynamic effect of this agent. These finding should be explored further in patients with newly diagnosed MGMT unmethylated GBM where temozolomide has very limited activity. Clinical trial information: NCT00045565 .
Efficacy of function-enhanced, re-activatable, dual-specific CAR T cells pre-loaded with oncolytic virus for immunotherapy of high-grade glioma.
Authors: Webb Mason , Tonne Jason , Thompson Jill , Pulido Jose , Coffey Matthew C. , Loghmani Houra , Harrington Kevin Joseph , Pandha Hardev S. , Melcher Alan , Diaz Rosa Maria , Parney Ian F. , Vile Richard 
Published: June 2023

2062 Background: While cancer therapeutics have made tremendous progress within the past several decades, this benefit has not been seen in many primary cancers of the brain. Particularly confounding have been high-grade gliomas (HGG), which retain a dismal prognosis. Currently, novel therapies are being explored to rise to this unmet, critical need. One such therapy are CAR T cells, immune cells which have been engineered to target malignancy-specific antigens. Unfortunately, the efficacy of CAR T cell therapies against solid tumors is significantly limited, in large part due to impaired expansion/persistence in the immune suppressive tumor microenvironment (TME). Here we show that in vivo reactivation of CAR T cells through their native T Cell Receptor (TCR) by an oncolytic virus (OV) has therapeutic benefit in HGG. Methods: An EGFRvIII third-generation MSGV1 retroviral CAR construct containing the CD28, 4-1BB, and CD3z moieties, in tandem with the scFv derived from the human monoclonal antibody 139 and the marker Thy1.1 (38) was used to generate our CAR T cells. C57Bl/6 mice were used for in vivo experiments and both B16- and CT2A-EGFRvIII murine glioma cell lines were injected in the brain to model HGG. OVs and CAR T cells were given systemically by tail vein. OVs used include reovirus, vesicular stomatitis virus, and adenovirus. Results: By using OV in combination with EGFRvIII CAR T cells, we were able to generate a CD8 CAR population with TCR specificity for both the EGFRvIII and OV epitopes. These dual-specific (DS) CAR T expressed a memory phenotype and persisted for much longer than conventional CAR T cells. Further, we showed that these DS CAR T cells are more cytotoxic and can respond more rapidly than their conventional counterparts. We created a novel delivery mechanism for this combination OV + CAR T therapy using virus-loaded CAR T cells to bypass initial antiviral clearance from the immune system. Treatment with these OV-loaded CAR T cells lead to significant benefit in mice with HGG tumors which could be further enhanced by a systemic boost with OV, which rapidly re-activated DS CAR T cells against tumor and resulted in long-term cures of greater than 80% of treated animals. Conclusions: These promising results show that DS CAR T cells can overcome the critical therapeutic challenge of CAR T as a treatment for solid tumors. Given these promising results, we will go on to develop a clinical trial in which CAR T cells will be pre-loaded with OV and administered intravenously to patients with HGG, followed by systemic boosting with virus to re-activate DS CAR T cells against their tumor.
Ultrasensitive detection and monitoring of central nervous system tumors from plasma using personalized whole-genome ctDNA profiling.
Authors: Tran Ivy , Galbraith Kristyn , Gardner Sharon L. , Allen Jeffrey C. , Harter David , Wisoff Jeffrey , Hidalgo Eveline Teresa , Afterman Danielle , Gonzalez Santiago , Smadbeck James , Lauterman Tomer , Alon Ury , Kandasamy Ravi , Tavassoly Iman , Polak Paz , Oklander Boris , Raju Praveen , Zviran Asaf , Snuderl Matija 
Published: June 2023

2064 Background: Patients with the central nervous system (CNS) tumors are largely followed up by imaging. Current plasma-based liquid biopsy techniques have limited utility in neuro-oncology due to a low circulating cell-free tumor DNA (ctDNA) burden, blood-brain barrier, and low number of mutations in coding regions. Whole genome sequencing (WGS)-derived patient specific mutational signature from a matched tumor-normal WGS can provide a personalized, highly sensitive and specific approach to detect mutations in ctDNA and provide blood-based monitoring in brain tumor patients. Furthermore, it can be performed on lower amount of peripheral blood since WGS requires less sequencing depth compared to targeted ctDNA panels. Methods: We have profiled a cohort of 28 extra- and intra-axial adult and pediatric brain tumors including adult and pediatric low- and high-grade glioma (9), meningiomas (11), medulloblastomas (5), ependymomas (2), neurocytoma (1). Tumor DNA was extracted from archival pathology tissue, normal DNA from unsorted white blood cells, and ctDNA from 1-2 mL of post-surgery plasma. WGS was performed with 40x coverage for Tumor-Normal DNA and 20x for ctDNA. Using WGS of matched Tumor-Normal and plasma samples, we derived a personalized mutational pattern using SNVs, indels, and copy numbers for quantification and ultra-sensitive detection of ctDNA in plasma samples. An AI-based error suppression model was implemented to filter out the noise in the cell-free DNA (cfDNA) while the personalized mutational signature was used to detect the ctDNA in the cfDNA and to amplify the somatic signal to determine the Tumor Fraction at the time of diagnosis, during the therapy or surveillance period. The ctDNA Tumor Fraction (TF) was compared to the clinical status and MRI-based imaging. Results: All subtypes of brain tumors contained enough mutations to derive personalized mutational signatures. Most mutations were distributed in the noncoding DNA. TF correlated with clinical status and with the disease course on imaging at given time points reaching a 10-4 minimal residual disease detection sensitivity. We were able to detect ctDNA across all WHO grades ranging from WHO 1 meningioma to WHO 4 glioblastoma and medulloblastoma. Furthermore, we were able to detect tumor-specific copy number aberrations such as MYCN amplification in plasma samples and mutational signatures. Conclusions: Here we demonstrate that patient-specific WGS tumor signature in ctDNA from plasma can be used for sensitive monitoring of adults and children with primary low- and high-grade CNS tumors.
Vulnerability to immune therapy in BRAF- and MYB-altered pediatric gliomas.
Authors: DeCuypere Michael , LoPresti Melissa , Najem Hinda , Tripathi Shashwat , Xiu Joanne , Seifert Hilary , Brown Valerie I. , López Giselle Y. , Nicolaides Theodore , Horbinski Craig M. , Heimberger Amy B. 
Published: June 2023

2066 Background: The frequency and expression of predictive immune biomarkers in pediatric gliomas is relatively unknown. Here, we sought to define predictive signatures of immunotherapy responders by examining immune checkpoint expression, immune cell population signatures, and gene amplifications in a variety of pediatric gliomas. Methods: We profiled a cohort of pediatric, adolescent, and young adult glioma samples submitted to Caris Life Sciences (Phoenix, AZ) for analysis (N = 207). The cohort was further stratified by driver mutations: IDH mutant (N = 103), H3-3A mutant (N = 36), MYB-altered (N = 4), BRAF-altered (N = 39), and IDH wild type [IDH WT] (N = 25). De-identified next generation DNA sequencing (592-gene or whole exome) and RNA (whole transcriptome) sequencing were used to determine tumor-infiltrating immune cell signatures and immune checkpoint protein expression. Transcriptomic signatures predictive of response to immunotherapy (T cell inflamed score) and replication stress response defect (RSRD) score were calculated on transcripts per million (TPM) values. Immune cell fractions were estimated using RNA deconvolution (quanTIseq). Results: BRAF-altered tumors showed the highest IFN gamma signature (a clinically relevant inflammatory biomarker), a high pro-inflammatory M1 macrophage signature, and very high CD4+/CD8+ T cell signatures compared to other tumor groups. IDH mutant, but not WT gliomas, were relatively deficient in T cell infiltration but revealed an increase in dendritic cell signatures. IDH WT gliomas showed more T cell enrichment but higher immune suppressive checkpoint expression. H3-3A mutant tumors showed relatively low immune cell infiltration and immune checkpoint expression. Pro-inflammatory M1 macrophages were lower in the high-grade glioma microenvironment compared to low-grade. Immune suppressive M2 macrophages were elevated in the IDH WT microenvironment relative to other gliomas. There was no apparent difference in the frequency of PD-1+ T cells and tumor-expressed PD-L1 among the various molecularly defined pediatric glioma groups. Conclusions: In general, BRAF- and MYB-altered gliomas displayed high immune activation relative to other tumors. IDH WT tumors have an immune suppressive microenvironment with relatively high immune checkpoint expression. Based on predictive markers, BRAF- and MYB-driven gliomas show signatures suggesting the possibility of a greater response to immunotherapies than IDH WT/mutant gliomas or H3-3A gliomas.
Phase I study of BTK inhibitor ibrutinib with temozolomide and radiation in newly-diagnosed glioblastoma (EQUILIBRIUM): Final trial report.
Authors: Ahluwalia Manmeet Singh , Ozair Ahmad , Khosla Atulya Aman , Patel Neha , Elson Paul , Murphy Erin Sennett , Yu Jennifer S. , Chao Samuel T. , Suh John H. , Stevens Glen , Peereboom David M. 
Published: June 2023

2067 Background: Novel therapeutic strategies are urgently needed in newly-diagnosed glioblastoma (GBM). Ibrutinib, an oral small molecule inhibitor of BTK, is currently being investigated for several B-cell malignancies and solid tumors. Preclinical evidence suggests ibrutinib in inhibiting cancer stem cell in glioblastoma. We sought to investigate the safety and tolerability of ibrutinib in nGBM. Methods: A non-randomized, prospective phase I trial was conducted in nGBM patients with Karnofsky performance status ≥70% and normal organ function, who received standard of care chemoradiation plus ibrutinib in a 3+3 dose-escalation design (level 1: 420 mg daily, level 2: 560 mg daily, level -1: 280 mg daily). Primary study objective was to determine maximum tolerated dose (MTD) of ibrutinib in combination with radiotherapy (RT) of 60 Gy over 6 weeks with/without 75 mg/m2 of temozolomide (TMZ). Secondary objective was to determine safety, overall survival (OS), and progression-free survival. Results: 26 patients were enrolled, with 12 (46%) females. Median age was 61.5 years (range 76-22). 15 (58%) patients were MGMT methylated and 11 (42%) were unmethylated. Dose-limiting toxicities (DLTs) were observed at all dose levels of ibrutinib plus RT (ibru+RT) cohort. MTD of ibrutinib was noted to be 420 mg daily with RT+TMZ. All MGMT methylated and 2 unmethylated patients received ibrutinib+RT+TMZ. Remaining 9 unmethylated received ibru+RT. In ibru+RT+TMZ, median cycles of TMZ were 4 (range 0-6) and of ibrutinib were 3 (range 0-26). EGFR amplification status was available for 22 patients, of which 8 (36%) were amplified. Survival outcomes are described, stratified using log-rank test. Conclusions: 420 mg of Ibrutinib daily is safe and feasible in combination with TMZ and radiation in nGBM. Outcomes of ibrutinib appears promising compared to historical survival data in the MGMT methylated cohorts. Further trials are planned. Clinical trial information: NCT03535350 . [Table: see text]
Interrogating drug action and immune response in organotypic glioma microenvironment.
Authors: Liang Jiyong , Huo Longfei , Xu Jihong , Sharma Pratibha , Chen Xiaohua , Puduvalli Vinay K. 
Published: June 2023

2068 Background: The glioma tumor microenvironment is characteristic of a high level of heterogeneity and a profoundly immune suppressive phenotype as driven by the presence of glioma stem cells and abundant innate immune cells of the myeloid lineages, rendering glioblastomas (GBM) recalcitrant to conventional treatments and immunotherapies. To address the full complexity of the brain tumor with its diverse components, we have developed an organotypic slice culture system to overcome several limitations of the other preclinical models and allow interrogation of drug action and immunomodulatory agents in human GBM ex vivo. Methods: We performed extensive characterization of the organotypic glioma slice system and optimization of the ex vivo tissue culture conditions, and determined the longitudinal dynamics of slice cell viability, relative tumor versus immune cellularity, and responses to a selection of therapeutic agents and cytokines by multiplexed flow cytometry and single cell transcriptome (scRNA seq) profiling. Results: Single cell transcriptomic analysis showed that both tumor and immune cell heterogeneity were preserved ex vivo for the two-week observation time, which exhibited tumor-type specific gene expression profiles suggesting cooperative interactions among cell populations. Consistent with the findings in fresh tumor specimens and an immune suppressive microenvironment, we found a scarcity of T lymphocytes in IDH mutant gliomas, whereas abundant T cells were found in recurrent GBM slices that persisted ex vivo. Additional analyses revealed that T cell infiltration in GBM was associated with the mesenchymal-like molecular phenotype, which exhibited remarkable intratumor heterogeneity highlighting the presence of stem-like cells and a unique cell population expressing aberrant cancer genes and antigen presenting molecules. We further found that T cells in organotypic GBM slices acquired a potent effector phenotype in response to cytokine-induced reprogramming of microglia and tumor-associated macrophages. In addition, scRNA seq also revealed a population of cancer-associated fibroblast-like cells that are present in all tumors sequenced, which may function to mediate the interactions between immune and tumor cells as our data suggested. Conclusions: We demonstrated that the organotypic slice culture system we developed is compatible with genomic, pharmacological, and immunotherapeutic manipulations and provided data showing that organotypic slice culture preserves glioma microenvironment ex vivo allowing acquisition of crucial information of response of heterogeneous patient tumor tissue to the agent tested. This method represents a unique mechanism by which therapy development can be facilitated in an ex vivo setting.