scholarly journals ATIM-21. INTRAVENOUS DELIVERY OF TOCA 511 IN PATIENTS WITH HIGH GRADE GLIOMA RESULTS IN QUANTIFIABLE EXPRESSION OF CYTOSINE DEAMINASE IN TUMOR TISSUE

2017 ◽  
Vol 19 (suppl_6) ◽  
pp. vi30-vi31
Author(s):  
Tobias Walbert ◽  
Daniela Bota ◽  
Michael Vogelbaum ◽  
Steven Kalkanis ◽  
Linda Liau ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Cytosine Deaminase ◽  
High Grade Glioma ◽  
High Grade

scholarly journals Dichotomy in Growth and Invasion From Low to High Grade Glioma Cellular Variants 

2021 ◽  
Author(s):  
Krishnendu Ghosh ◽  
Samarandranath Ghosh ◽  
Uttara Chatterjee ◽  
Pritha Bhattacharjee ◽  
Anirban Ghosh
Keyword(s):  
Tumor Tissue ◽  
High Grade Glioma ◽  
High Grade ◽  
General Increase ◽  
Grade Transition ◽  
Median Survival Period ◽  
Neoplastic Lesion ◽  
Tightly Coupled ◽  
Glial Dysfunction ◽  
Environmental Milieu

Abstract Glial dysfunction outraging CNS plasticity and integrity results into one of the most dangerous cancer, namely glioma, featuring little median survival period and high recurrence. The hallmark properties of proliferation, invasion and angiogenesis with the infiltrated macrophages in glioma are expected to be tightly coupled or cross-linked, but not definitely related so far. Present study is aimed to find a relationship between this featured quadrangle from lower to higher grades of post-operative glioma tissues and their invading subsets. Elevated Ki67 associated proliferation in lower grades was supported with VEGF dependent angiogenic maintenance which found decrease unlikely in higher grades. In contrast, MMP-2 and 9 associated invasions augmented high in higher grades with dominant presence of CD204+ M2 polarized macrophages and a general increase in global DNMT1 associated methylation. Marked differences found in ECM invading cellular subsets of higher grades showing high proliferative capacity indicating rationally for recurrence, contrasting the nature of gross tumor tissue of same grade. Thus in lower grades the neoplastic lesion is more inclined for its growth while in higher grade more disposed towards tissue wreckage in support with cellular environmental milieu whereas the cellular variants and subsets of invaded cells showed different trends. Therefore, some operational dichotomy or coupling among cellular variants in glioma is active in determining its low to high grade transition and aggressive progression.

scholarly journals Pediatric high-grade glioma resources from the Children’s Brain Tumor Tissue Consortium

2019 ◽  
Vol 22 (1) ◽  
pp. 163-165 ◽  
Author(s):  
Heba Ijaz ◽  
Mateusz Koptyra ◽  
Krutika S Gaonkar ◽  
Jo Lynne Rokita ◽  
Valerie P Baubet ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Tissue ◽  
High Grade Glioma ◽  
High Grade ◽  
Pediatric High Grade Glioma

Durable complete responses observed in IDH1 mutated high grade glioma at first recurrence undergoing treatment with Toca 511 and Toca FC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13504-e13504 ◽  
Author(s):  
Timothy Francis Cloughesy ◽  
Derek Ostertag ◽  
Joseph C. Landolfi ◽  
Tobias Walbert ◽  
Michael A. Vogelbaum ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Phase 1 ◽  
Cytosine Deaminase ◽  
Suppressor Cells ◽  
High Grade Glioma ◽  
Initial Response ◽  
Idh1 Mutation ◽  
High Grade ◽  
Release Formulation ◽  
Extended Release Formulation

e13504 Background: Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to cell division requirements for virus integration into the genome and defects in innate and adaptive immune responses found in cancers that support virus replication. Toca 511 spreads through cancer cells and stably delivers the gene for an optimized yeast cytosine deaminase that converts the prodrug Toca FC (an investigational, extended-release formulation of 5-fluorocytosine) into 5-fluorouracil (5-FU). 5-FU kills infected cancer cells that are dividing, diffuses and kills surrounding cancer cells as well as myeloid derived suppressor cells and tumor associated macrophages, thus reestablishing immunity to tumor. Methods: In this phase 1 trial (NCT01470794), ascending doses of Toca 511 were injected into the resection bed of patients with recurrent high grade glioma undergoing resection, followed by oral administration of courses of Toca FC 5-7 weeks after Toca 511 injection. Additional cohorts included combination of Toca 511 & Toca FC with bevacizumab or lomustine. Results: Objective responses (ORs) are observed in IDH1 wildtype (wt) and mutant (mt) phenotypes, including 3 complete responses (CRs) (2 IDH1 mt and 1 IDH1 wt) and 2 partial responses (2 IDH1 wt) for patients treated with Toca 511 & Toca FC, and 1 CR (1 IDH1 mt) for a patient treated with Toca 511 & Toca FC and bevacizumab. ORs are observed 6-19 months after Toca 511 injection and are consistent with an immunologic mechanism. Median time to initial response is 9.2 months; median duration of response (mDOR) is 25.2 months. Excluding the combination cohorts, mDOR is 26.7 months. All responders are alive 21.2+ to 42.6+ months, suggesting a correlation of OR and OS. An additional radiologic CR is observed in 1 IDH1 mt patient at 1st recurrence who received intravenous Toca 511 plus injection into the resection bed. All 4 IDH1 mt patients treated at 1st recurrence had CRs. Conclusions: There may be an association between ORs and IDH1 mutation with Toca 511 & Toca FC treatment. Updated clinical benefit, molecular profiles and tumor mutational load are reported. Clinical trial information: NCT01470794.

A first-in-human study of neural stem cells (NSCs) expressing cytosine deaminase (CD) in combination with 5-fluorocytosine (5-FC) in patients with recurrent high-grade glioma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2018-2018 ◽  
Author(s):  
Jana Portnow ◽  
Behnam Badie ◽  
Timothy W. Synold ◽  
Alexander Annala ◽  
Bihong Chen ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Human Study ◽  
Tumor Resection ◽  
Cytosine Deaminase ◽  
High Grade Glioma ◽  
Intracerebral Microdialysis ◽  
High Grade ◽  
Drug Concentrations ◽  
Average Maximum ◽  
The Brain

2018 Background: Human NSCs are inherently tumor-tropic, making them attractive drug delivery vehicles. This pilot-feasibility study assessed the safety of using genetically-modified NSCs for tumor selective enzyme/prodrug therapy. An immortalized, clonal NSC line was retrovirally-transduced to stably express CD, which converts the prodrug 5-FC to 5-fluorouracil (5-FU), producing chemotherapy locally at sites of tumor in the brain. Methods: Patients 18 years or older with recurrent high-grade glioma underwent intracranial administration of NSCs during tumor resection or biopsy. Four days later, 5-FC was administered orally every 6 hours for 7 days. Study treatment was given only once. A standard 3+3 dose escalation schema was used to increase doses of NSCs from 1 x 107 to 5 x 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU; serial blood samples were obtained to assess systemic drug concentrations. Three patients received iron-labeled NSCs for MRI tracking. Brain autopsies were done on 2 patients. Results: Fifteen patients received study treatment. Three were inevaluable for toxicity and replaced. All patients tolerated the NSCs well. There was 1 dose-limiting toxicity (grade 3 transaminitis) possibly related to 5-FC. At the highest dose level of NSCs, the average steady-state concentration of 5-FU in the brain was 63.9±7.9 nM. The average maximum 5-FU level in brain was 104±88 nM compared to 24±36 nM in plasma, indicating local production of 5-FU in the brain by the NSCs. MR imaging of iron-labeled NSCs showed preliminary evidence of NSC migration. Autopsy data documented (by IHC, FISH, and PCR) NSCs at distant sites of tumor in the brain and no development of secondary tumors. Conclusions: This first-in-human study has demonstrated safety and proof-of-concept regarding NSC-mediated conversion of 5-FC to 5-FU and NSC tumor-tropism. NSCs have the potential to overcome obstacles of drug delivery that limit current gene therapy strategies. Results of this pilot study will serve as the foundation for future NSC studies. (Supported by NCI 1R21 CA137639-01A1, CIRM DR-01421). Clinical trial information: NCT01172964.

scholarly journals HGG-40. HIGH GRADE GLIOMA CELL LINE COHORT AS AN EXAMPLE OF CHILDREN’S BRAIN TUMOR TISSUE CONSORTIUM TUMOR SPECIMEN PROCESSING PIPELINE

2018 ◽  
Vol 20 (suppl_2) ◽  
pp. i97-i97
Author(s):  
Mateusz Koptyra ◽  
Valerie Baubet ◽  
Lamiya Tauhid ◽  
Namrata Choudhari ◽  
Tiffany Smith ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Cell Line ◽  
Glioma Cell ◽  
Tumor Tissue ◽  
High Grade Glioma ◽  
Glioma Cell Line ◽  
High Grade ◽  
Processing Pipeline ◽  
Tumor Specimen ◽  
Specimen Processing

scholarly journals BIOM-56. THE INTEGRATION OF A LIQUID BIOPSY PROGRAM INTO THE CARE OF PEDIATRIC BRAIN TUMOR PATIENTS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii13-ii14
Author(s):  
Alexandra Miller ◽  
Luca Szalontay ◽  
Hamza Ahmad ◽  
Nancy Bouvier ◽  
Irene Rodriguez-Sanchez ◽  
...  
Keyword(s):  
Liquid Biopsy ◽  
Tumor Tissue ◽  
Clinical Care ◽  
High Grade Glioma ◽  
Response To Therapy ◽  
Low Grade ◽  
High Grade ◽  
Cell Free Dna ◽  
Free Dna ◽  
Minimal Residual

Abstract Pediatric CNS tumors remain the leading cause of cancer-related death in children and adolescents. Safe sampling of tumor tissue for diagnostic purposes may be difficult if not impossible. Detection of minimal residual or recurrent disease prior to definitive clinical or radiographic progression may allow earlier initiation of novel therapies and ultimately improve overall survival. Given the rarity of serial sampling of tumor tissue, our understanding of molecular evolution in response to therapy remains limited. Recent technological advances have led to the development of “liquid biopsy” assays, which detect cell-free DNA (cfDNA) in blood, cerebrospinal fluid (CSF) or other bodily fluids. Here, we report our initial clinical experience with the recently established MSK Kids pediatric neuro-oncology liquid-biopsy program at Memorial Sloan Kettering Cancer Center (MSKCC) using MSK-IMPACT, which is clinically validated by the New York State Department of Health for CSF cell-free DNA (cfDNA)vprofiling. All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families. Samples from 29 unique patients were sequenced. Histopathology included high-grade glioma (5); low-grade glioma (2); medulloblastoma (8); pineoblastoma (3); retinoblastoma (4); other (7). CSF cfDNA could be detected in 18/42 samples (43%) and 12/29 patients (34%). CSF cfDNA was more commonly detected in higher-grade, disseminated tumors such as high-grade glioma (60%), medulloblastoma (38%), and pineoblastoma (100%). Low-grade lesions without leptomeningeal involvement did not result in detectable CSF cfDNA shedding (86% were negative). In a subset of patients, MSK-IMPACT identified previously unrecognized molecular actionable targets (e.g. BRAF-KIAA1549 fusion); or the detection of “minimal residual disease” prior to the detection of tumor recurrence by conventional diagnostics, impacting clinical care decisions. Future directions include integration of CSF cfDNA into prospective clinical trials as a correlative biomarker.

scholarly journals INNV-26. IN VITRO CHEMO RESISTANCE PROFILES OF CIRCULATING GLIAL CELLS REPLICATE CHEMO CHARACTERISTICS OF TUMOR TISSUE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi135-vi135
Author(s):  
Dadasaheb Akolkar ◽  
Sanket Patil ◽  
Vishakha Mhase ◽  
Pradip Devhare ◽  
Pooja Fulmali ◽  
...  
Keyword(s):  
Glial Cells ◽  
Peripheral Blood ◽  
Drug Response ◽  
Tumor Tissue ◽  
High Grade Glioma ◽  
Cytotoxic Drugs ◽  
High Grade ◽  
Label Free ◽  
Chemotherapy Drugs

Abstract Survival of high-grade glioma patients remains dismal due to onset of resistance to even the limited systemic treatment option currently available. Except for indirect prediction of alkylating agent Temozolomide response through MGMT promotor methylation and NTRK fusions for larotrectinib, there are no biomarkers available for drug response prediction. Cell based, in vitro chemosensitivity assays can interrogate the efficacy of an array of cytotoxic drugs. However, the unavailability of live tumor cells for such assays pose challenges in clinical practice. Repeat biopsies are neither advisable nor feasible. Access to Circulating Glial Cells (CGCs) can provide real time insight into the chemo dynamics of the tumor. In this study, we show for the first time that CGCs can be harvested from peripheral blood of glioma patients for chemo response and resistance profiles (CRR) of cytotoxic drugs. CGCs were harvested from 15 ml of peripheral blood from high grade GBM patients (n=9) out of whom cells derived from surgically excised tumor tissue were also available for comparison in 2 patients. CellWizard™ process was adopted for enrichment of CGCs which is based upon epigenetically active media with paradoxical chemo-toxicity that selectively induces lethality in normal cells. This paradoxical cytotoxicity of the medium leads to selective elimination of most leukocytes thus facilitating a label free negative enrichment of CGCs. In vitro chemo sensitivity assay performed on live CGCs and cell death events were determined to evaluate response to different class of chemotherapy drugs. Evaluation of drug response showed very high concordance between tumor derived cells and CGCs in both patients where live tissue was available. In 7 patients where CGCs alone could be evaluated, the response showed replication between in vitro profile compared to treatment antecedents in 5 patients. 2 patients were treatment naïve and the response reflected high sensitivity to Temozolomide.

scholarly journals Pediatric High Grade Glioma Resources From the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pediatric Brain Tumor Atlas (PBTA)

2019 ◽  
Author(s):  
Heba Ijaz ◽  
Mateusz Koptyra ◽  
Krutika S. Gaonkar ◽  
Jo Lynne Rokita ◽  
Valerie P. Baubet ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Cell Lines ◽  
Glioma Cell ◽  
Tumor Tissue ◽  
Pediatric Brain Tumor ◽  
High Grade Glioma ◽  
High Grade ◽  
Primary Tumors ◽  
Pediatric Brain ◽  
Pediatric High Grade Glioma

ABSTRACTBackgroundPediatric high grade glioma (pHGG) remains a fatal disease. Increased access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Children’s Brain Tumor Tissue Consortium (CBTTC) from the first release (October 2018) of the Pediatric Brain Tumor Atlas (PBTA).MethodspHGG tumors with associated clinical data and imaging were prospectively collected through the CBTTC and analyzed as the Pediatric Brain Tumor Atlas (PBTA) with processed genomic data deposited into PedcBioPortal for broad access and visualization. Matched tumor was cultured to create high grade glioma cell lines analyzed by targeted and WGS and RNA-seq. A tissue microarray (TMA) of primary pHGG tumors was also created.ResultsThe pHGG set included 87 collection events (73 patients, 60% at diagnosis, median age of 9 yrs, 55% female, 46% hemispheric). Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36% H3.3, 47% TP53, 24% ATRX and 7% BRAF V600E variants). A pHGG TMA (n=77), includes 36 (53%) patient tumors with matched sequencing. At least one established glioma cell line was generated from 23 patients (32%). Unique reagents include those derived from a H3.3 G34R glioma and from tumors with mismatch repair deficiency.ConclusionThe CBTTC and PBTA have created an openly available integrated resource of over 2,000 tumors, including a rich set of pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.IMPORTANCE OF STUDYHigh-grade gliomas (HGG) remain the leading cause of cancer death in children. Since molecularly heterogeneous, preclinical studies of pediatric HGG will be most informative if able to compare across groups. Given their relatively rarity, there are few readily available biospecimens and cellular models to inform preclinical laboratory and genomic translational research. Therefore, the aim of this CBTTC study was to highlight the panel of pediatric HGG cases whose primary tumors have undergone extensive genomic analysis, have clinical data, available imaging and additional biospecimens, including tumor, nucleic acids, cell lines and FFPE tissue on a tissue microarray (TMA).

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