bluuebunny/crossref_metadata_2025 huggingface dataset:
NCMP-20. PRE-INFUSION NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS PREDICT THE DEVELOPMENT OF IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME (ICANS) – A MULTICENTER RETROSPECTIVE STUDY
Authors: Butt Omar , Zhou Alice , Lee Kenneth , Wu Gregory , Caimi Paolo , de Loma Marcos , Campian Jian , DiPersio John , Ghobadi Armin , Ances Beau
Published: November 2021

BACKGROUND

Neurological side effects after chimeric antigen receptor-modified (CAR) T cell therapy, termed immune effector cell-associated neurotoxicity syndrome (ICANS), are common and potentially devastating. We previously demonstrated that pre-infusion plasma neurofilament light chain (NfL), a well-established marker of neurodegeneration, may predict subsequent development of ICANS in a small, single-center cohort. This larger, retrospective multicenter study compares pre-infusion NfL to known post-infusion risk factors for developing ICANs including white blood cell (WBC) count, platelet count, C-reactive protein (CRP), fibrinogen, and ferritin levels.

METHODS

Inclusion criteria included available pre-infusion (up to 4 weeks prior to lymphodepletion) plasma from patients treated with a CAR T cell therapy (n = 30, 36% with ICANS, ASTCT consensus ICANS grade range 1-4). Exclusion criteria included confounding diagnoses known to elevate NfL levels (dementia, multiple sclerosis, recent stroke). Plasma NfL was assayed using a Simoa HD-1/HD-X kit (QuanterixTM). Post-infusion Day 3 or Day 5 WBC, Platelet, CRP, fibrinogen, and ferritin were obtained from the medical record. Group comparisons were done using log-rank tests with a Bonferroni-derived significance threshold, followed by receiver operating characteristic (ROC) curve classification.

RESULTS

Prior to infusion, individuals who ultimately developed ICANS had elevations in NfL ([87.6 v 29.4 pg/ml], p = 0.00004) with excellent classification (AUC 0.96), sensitivity (0.91) and specificity (0.95). Among known post-infusion risk factors, only post-infusion Day 3 ferritin (p = 0.004) and Day 5 ferritin (p = 0.003) differed between groups. Classification was inferior for both time points (Day 3 AUC = 0.87, specificity 0.71; Day 5 AUC 0.87, specificity 0.86).

CONCLUSION

Pre-infusion plasma NfL levels are a robust early marker for the development of ICANS that exceeds known post-infusion markers. Our findings suggest the risk of developing ICANS reflects pre-existing host-factors. Foreknowledge of ICANS development of may permit early, aggressive (preemptive or prophylaxis) ICANS-directed therapies, improving patient outcomes.
NCOG-04. THE IMPACT OF PROPHYLAXIS CHEMOTHERAPY ON CENTRAL NERVOUS SYSTEM (CNS) RELAPSES OF HIGH RISK DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL): A NETWORK META-ANALYSIS
Authors: Haddad Philip , Hammoud Dalia , Gallagher Kevin
Published: November 2021

BACKGROUND

CNS relapses with DLBCL tend to be uncommon. The risk increases with certain DLBCL types and certain identified risk features. There is no consensus regarding the optimal approach to CNS prophylaxis for high-risk DLBCL patients. While some favor prophylaxis with high-dose systemic therapy or intrathecal chemotherapy (IT), some experts advocate combining both approaches. In the absence of randomized trials, the role of chemotherapy prophylaxis remains controversial in DLBCL with contradictory comparative studies. The purpose of this meta-analysis is to evaluate the impact of CNS prophylaxis approaches on the clinical outcomes of high-risk DLBCL.

METHODS

A review of the medical literature was conducted using online databases. Inclusion criteria consisted of DLBCL diagnosis, English language, IT or high-dose systemic prophylactic chemotherapy, and comparative studies reporting CNS recurrence rates. A frequentist and Bayesian network meta-analysis were conducted using the netmeta package and random-effects model.

RESULTS

Twenty-one comparative studies with a total of 11,507 patients were included and analyzed. The relative risk (RR) of CNS recurrence was not statistically different between IT prophylaxis, high-dose chemotherapy, and no prophylaxis. However, the combination of IT prophylaxis and high-dose chemotherapy was found to be significantly associated with a reduced RR of CNS recurrence when compared to IT prophylaxis (RR 0.28, 95%CI 0.13-0.58), high-dose chemotherapy (RR 0.34, 95%CI 0.14-0.80), and no prophylaxis (RR 0.41, 95%CI 0.19-0.87).

CONCLUSIONS

This network meta-analysis is the first to compare the different CNS prophylactic approaches. It indicates that IT prophylaxis and high-dose chemotherapy each were not better than no prophylaxis. However, the combination of IT prophylaxis with high-dose chemotherapy was significantly superior to each approach alone as well as no prophylaxis. In the absence of randomized clinical trials, this network meta-analysis represents the most compelling data supporting the use of CNS prophylaxis in patients with high-risk DLBCL.
NCOG-11. ASSOCIATION OF HYPERGLYCEMIA AND TUMOR SUBCLASS ON SURVIVAL IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Liu Elisa , Vasudevaraja Varshini , Sviderskiy Vladislav , Feng Yang , Tran Ivy , Serrano Jonathan , Cordova Christine , Kurz Sylvia , Golfinos John , Sulman Erik , Placantonakis Dimitris , Possemato Richard , Snuderl Matija
Published: November 2021

BACKGROUND

RNA expression and DNA methylation studies have identified different subclasses of isocitrate dehydrogenase (IDH)-wildtype (wt) glioblastoma (GBM). However, the prognostic significance of molecular subclasses is unclear. Although hyperglycemia has been previously associated with worse survival, attempts to lower glucose have yielded mixed responses. The role of hyperglycemia may be confounded by molecular heterogeneity and have different impact in molecularly distinct GBM subclasses.

METHODS

Clinical, laboratory, and molecular data on 89 IDH-wt GBMs profiled by clinical next-generation sequencing and treated with Stupp protocol were reviewed. IDH-wt GBMs were subclassified into RTKI (Proneural), RTKII (Classical) and Mesenchymal subtypes using DNA methylation. Average glucose was calculated by time-weighting plasma glucose measurements between diagnosis and last follow-up.

RESULTS

Patients were stratified into three groups using average glucose: tertile one (< 100mg/dL), tertile two (100-115mg/dL), and tertile three ( > 115mg/dL). Comparison across glucose tertiles revealed no significant differences in Karfnosky Performance Status (KPS), dexamethasone dose, MGMT methylation, or methylation subclass. Overall survival (OS) was not affected by methylation subclass (log-rank p=0.9) but decreased with higher glucose (log-rank p=0.015). Higher glucose tertiles were associated with poorer OS among RTK I (log-rank p=0.08) and mesenchymal tumors (log-rank p=0.05), but not RTK II (log-rank p=0.99). After controlling for age, KPS, dexamethasone dose, and MGMT status, glucose remained significantly associated with survival (adjusted hazard ratio=5.2, p=0.02). DNA methylation clustering did not identify a unique signature associated with high or low glucose levels. Metabolomic analysis of 23 tumors showed minimal variation across metabolites within the cohort with no differences across molecular subclasses.

CONCLUSION

Higher average glucose values were associated with poorer OS in RTKI and Mesenchymal IDH-wt GBM, but not RTKII. There were no discernible epigenetic or metabolomic differences between tumors in different glucose environments, suggesting a potential survival benefit with systemic glucose lowering in selected molecular subtype.
NCOG-15. THE EFFECTIVENESS OF ANTIEPILEPTIC DRUG DUOTHERAPIES IN GLIOMA PATIENTS: A MULTICENTER OBSERVATIONAL COHORT STUDY
Authors: van der Meer Pim , Dirven Linda , Fiocco Marta , Vos Maaike , Kouwenhoven Mathilde , van den Bent Martin , Taphoorn Martin , Koekkoek Johan
Published: November 2021

BACKGROUND

Uncontrolled seizures on antiepileptic drug (AED) monotherapy are common in glioma patients and about a third of patients need an add-on AED. The aim of this study was to determine whether levetiracetam combined with valproic acid (LEV+VPA), a commonly prescribed duotherapy, was more effective than other duotherapy combinations, which included either LEV or VPA, in glioma patients.

METHODS

In this multicenter observational cohort study, data of patients with a diffuse grade 2-4 glioma and having uncontrolled seizures on their first-line monotherapy LEV or VPA, was retrospectively analyzed. Primary outcome was treatment failure (i.e. replacement by or addition of a new AED, or withdrawal of an AED) for any reason. Secondary outcomes included: 1) treatment failure due to uncontrolled seizures; and 2) treatment failure due to adverse effects. Time to treatment failure was estimated with multivariable Cox proportional hazard models, from moment of AED duotherapy treatment initiation. The maximum duration of follow-up was 36 months.

RESULTS

A total of 355 patients received AED duotherapy after they showed treatment failure due to uncontrolled seizures on monotherapy. LEV+VPA was prescribed in 66% (236/355) and other AED duotherapy combinations including LEV or VPA in 34% (119/355) of patients. Patients using other duotherapy versus LEV+VPA had higher risk of treatment failure for any reason (cause-specific hazard ratio [csHR]=1.50 [95%CI=1.07-2.12], p=0.020), due to uncontrolled seizures (csHR=1.73 [95%CI=1.10-2.73], p=0.018), but not due to adverse effects (csHR=0.88 [95%CI=0.47-1.67]), p=0.703).

CONCLUSIONS

This observational cohort study showed that LEV+VPA has better efficacy than other AED combinations with either LEV or VPA, but toxicity was similar in the two groups.
NCOG-18. RELATIONSHIP BETWEEN RANO-PRO WORKING GROUP STANDARDIZED PRIORITY CONSTRUCTS AND DISEASE PROGRESSION AMONG MALIGNANT GLIOMA PATIENTS AS MEASURED THROUGH CLINICAL OUTCOMES ASSESSMENTS
Authors: Vera Elizabeth , Mendoza Tito , Acquaye Alvina , Briceno Nicole , Choi Anna , Christ Alexa , Grajkowska Ewa , Jammula Varna , Leeper Heather , Levine Jason , Lindsley Matthew , Reyes Jennifer , Roche Kayla , Rogers James , Timmer Michael , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Polskin Lily , Penas-Prado Marta , Pillai Valentina , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri
Published: November 2021

Recognizing the importance of clinical outcomes assessments (COA), the RANO-PRO Working Group recommends inclusion of core symptoms/functions in clinical care/research for malignant glioma patients. This study evaluated the association between the recommended symptoms (pain, perceived cognition, seizures, aphasia, treatment-specific symptoms) and functions (physical: weakness, walking; and role/social: work, usual activities) and disease progression in these patients. MDASI-Brain Tumor and EQ-5D-3L scores, Karnofsky Performance Status (KPS), and Neurologic Function Score (NFS) were evaluated in relation to disease progression by chi-square tests, independent- and paired-samples t-tests, adjusted for multiple comparisons. Our sample included 336 patients with malignant glioma; 82% white, 64% male, median age=52 (21-79). Imaging study revealed disease progression for 46% of patients. All symptoms except seizures and difficulty concentrating were worse in the group whose imaging showed disease progression versus stable disease, as well as the functions of walking, work, activity, and self-care (0.8 < difference < 1.8). Patients with disease progression were 4 times more likely to have a poor KPS (≤ 80) and worse NFS. Among patients with disease progression (n=112), all symptoms, except seizures, worsened from first assessment to time of progression. Up to 22% of patients reported worsening mobility, self-care, and usual activity; 46% and 35% had worsened KPS and NFS, respectively. Seven symptoms and functions were each individually reported by at least 10% of patients as having worsened the most. Worsening of symptoms and functions was not observed among patients with stable disease, except in difficulty understanding. Identified core symptoms/functions worsen at the time of progression demonstrating the relationship between priority constructs and a traditional tumor response measure while highlighting the importance of longitudinal collection of COA. The pattern of worsening was observed via both patient- and clinician-reported outcomes, emphasizing the utility of COA in clinical care and clinical trials.
NCOG-19. PROGNOSTIC FACTORS IN ELDERLY PATIENTS WITH GLIOBLASTOMA: A RETROSPECTIVE INSTITUTIONAL SERIES OF 160 PATIENTS
Authors: Pellerino Alessia , Bruno Francesco , Pronello Edoardo , Mo Francesca , Franchino Federica , Rudà Roberta , Soffietti Riccardo
Published: November 2021

INTRODUCTION

Glioblastoma (GBM) prevails in elderly patients, who often suffer from other comorbidities that may affect the outcome. The aim of the study was to investigate clinical characteristics, comorbidities, and treatment-related complications that may impact the outcome of elderly patients with GBM.

PATIENTS AND METHODS

In this institutional retrospective study, we included GBM patients ≥ 65 years diagnosed with glioblastoma from 2015 to 2020. We retained information about comorbidities according to Charlson Comorbidity Index (CCI), Karnofsky prognostic score (KPS), MGMTp methylation, and clinical complications during treatment or follow-up.

RESULTS

We included 160 patients. Median age was 72 years (65-88). Median time of follow-up was 9.25 months. Median progression-free survival (mPFS) and overall survival (mOS) were 5.84 and 9.67 months. In a multivariate analysis, factors affecting survival were: KPS after surgery ≥ 70 (mPFS: HR 0.24, 0.13-0.44; mOS: HR 0.43, 0.24–0.76. 95% CI), partial vs gross total resection (mPFS: HR 2.15, 1.23–3.77; mOS: HR 2.61, 1.34–5.07. 95% CI), MGMTp methylation (mPFS: HR 0.35, 0.22–0.55; mOS: HR 0.37, 0.24–0.76. 95% CI), and complications after surgery (mPFS: HR 2.52, 1.39–4.55; mOS: HR 2.96, 1.63–5.40. 95% CI). Conversely, age and CCI were not significantly correlated with prognosis.

CONCLUSIONS

For elderly patients with GBM, CCI does not seem to predict the outcome. Other factors such as extent of surgery, MGMTp methylaton, postoperative KPS, and clinical complications after surgery retain a significant prognostic importance. Further studies are needed to standardize clinical prognostic scales specific for elderly GBM patients.
NCOG-20. LONGITUDINAL ASSESSMENT OF SUBJECTIVE COGNITIVE FUNCTION IN ADULTS WITH LOW GRADE GLIOMA TREATED WITH PROTON RADIATION THERAPY
Authors: Zarrella Giuliana , Parsons Michael , Sherman Janet , Dietrich Jorg , Shih Helen
Published: November 2021

INTRODUCTION

Our group previously demonstrated stability in neurocognitive function (NCF) over a 5-year period after proton radiation therapy (PRT) in low grade glioma (LGG) patients. Subjective cognitive function (SCF) had not been previously explored, nor had individual analyses of cognition, which can detect variability in trajectory. We used the newly derived Functional Assessment of Cancer Therapy-Brain Cognitive-Index (FACT-Br-CI) to examine SCF in LGG patients after PRT and compare longitudinal changes in SCF and NCF.

METHODS

20 LGG patients (M age =37.5) treated with PRT completed NCF tests and self-report measures annually for 5 years or until tumor progression. Group change in SCF was examined with paired t-test (baseline vs final FACT-Br-CI). Individual change scores were calculated for FACT-Br-CI and NCF tests (clinical trials battery composite; CTBC). Individual deterioration in NCF was defined by reliable change index (RCI) on CTBC, and in SCF was defined as decline of >/=1 SD in FACT-Br-CI. Relationships between change in SCF and NCF were explored with correlations.

RESULTS

At the group level, no change was observed in FACT-Br-CI between baseline and last follow-up (t(19)=-.91;p=ns). Individual SCF analyses at last follow-up found the number of patients reporting decline=3 (15%), improvement=5 (25%), and no change=12 (60%). Individual changes were observed in SCF in 20% of patients at 3 months, 5.9% at 6 months, 12.5% at 12 months, 13.3% at 24 months, and 11.1% at 36 months. Median time to any deterioration in SCF was 36 months and for NCF was not reached. Correlation between CTBC and FACT-Br-CI change scores did not reach statistical significance (r=.41;p=ns).

CONCLUSION

Consistent with previous research, group analyses of LGG patients did not show cognitive decline after PRT. However individual analyses of SCF showed variability within the group: some patients experienced cognitive decline during follow up. Consideration of individual differences may yield additional information.
NCOG-22. RETROSPECTIVE ANALYSIS OF VISUAL OUTCOMES AFTER BEVACIZUMAB-BASED THERAPY IN OPTIC PATHWAY GLIOMA
Authors: Siegel Benjamin , MacDonald Tobey , Wolf David
Published: November 2021

BACKGROUND

Patients with optic pathway glioma (OPG) are vulnerable to debilitating visual impairment. Consequently, vision stabilization is a primary treatment goal. Bevacizumab has demonstrated promising effects on radiographic tumor burden, but less is known about its impact on vision. Our objective was to characterize visual outcomes associated with bevacizumab-based therapy (BBT) in OPG.

METHODS

This is a single-institution, retrospective review of patients treated with BBT for OPG from 2011 to 2020. Ophthalmologic and radiographic data were abstracted before and after treatment. Clinically significant visual acuity (VA) impairment was defined as logMAR > 0.5 and change in VA was defined as change from baseline of logMAR ≥ 0.2.

RESULTS

Sixteen patients (13 sporadic OPG, 3 NF1-associated OPG) with evaluable vision outcomes were identified. Treatment indications were radiographic progression (N=15) and vision deterioration (N=4). Prior to BBT, 15 (94%) had failed at least one chemotherapy regimen. BBT regimens included bevacizumab/irinotecan (N=12), bevacizumab monotherapy (N=3) and bevacizumab/vinblastine (N=1). Nine patients (56%) had baseline VA impairment. Thirteen patients (81%) had stable or improved vision after BBT, including 8 of 9 with baseline VA impairment and all 4 patients with vision deterioration as a treatment indication. Eleven patients (69%) had radiographic progression following BBT (Median time-to-progression 66 weeks, IQR 27 weeks), 9 of whom had stable vision at time of progression. There were no associations between VA and age at treatment, NF1-status, histology, or BBT regimen.

CONCLUSIONS

BBT was associated with favorable visual outcomes for most patients with OPG in this modest retrospective cohort. Consistent with prior research, radiographic and ophthalmologic outcomes were discordant; a majority of patients experienced progressive disease despite stable vision. Next steps include (1) assessing visual field and optical coherence tomography outcomes in the same cohort and (2) comparing outcomes for BBT with other common therapies including carboplatin/vincristine and vinblastine.
NCOG-26. SOCIOECONOMIC FACTORS AFFECTING SURVIVORSHIP OF GLIOBLASTOMA PATIENTS IN THE PHILIPPINES: A RETROSPECTIVE COHORT STUDY
Authors: Hong Manilyn , Omar Abdelsimar , Khu Kathleen Joy
Published: November 2021

BACKGROUND

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults worldwide. However, data on the survivorship of glioblastoma for low-middle income countries is sparse. We studied the clinical features, treatment, and survivorship of surgically managed GBM patients at a tertiary referral center in the Philippines over a 5-year period. We determined whether socioeconomic factors such as income level, employment status, marital status and educational attainment affected survival.

METHODS

A retrospective cohort study within a 5-year period (2015 to 2019) of surgically managed GBM patients in a single center was conducted using chart review and telephone interview.

RESULTS

A total of 48 cases met the inclusion criteria. Mean age of the cohort was 41 years, with a male predilection (62%). Mean duration of symptoms was 2.8 months. Majority of the tumors were were >5 cm at the time surgery (90%), and involved more than one lobe (40%). Majority (73%) had preoperative KPS ≥70, and underwent subtotal resection (56%). Only 15% (n=7) had adjuvant chemoradiatherapy while another 23% (n=11) had radiotherapy alone. Median overall survival (OS) was 7.6 months (228 days). Most patients had rural residence (56%), low-income (83%), full time employment (79%), married status (73%) and secondary education (44%). Multi-variate analysis showed that only extent of resection (GTR p=0.0297 and STR p=0.0400) were associated with improved survival while widower status (p=0.0116) were significantly more at risk.

CONCLUSION

Many glioblastoma patients managed at our center in the Philippines presented at an advanced stage in their natural history, with larger tumors and more extensive distribution at time of presentation. After surgery, majority did not receive adjuvant treatment. As such, the median overall survival was less than that reported in published cohorts in developed countries. Extent of resection and marital status were significantly associated with survivorship.
NCOG-30. AWAKE CRANIOTOMY FOR MENINGIOMA RESECTION: A STUDY ON THE SAFETY AND TOLERABILITY
Authors: Bakhshi Saqib Kamran , Jawed Noyan , Shafiq Faraz , Enam Syed Ather
Published: November 2021

Resection of intra-axial brain tumors under scalp block improves safety of surgery, permitting preservation of neurological function and early recovery. However, limited data is available on employing this anesthesia technique for extra-axial tumors particularly meningioma, raising concerns that it may not be feasible due to dural attachment of tumor causing intractable pain and discomfort. We retrospectively analyzed 17 patients who underwent AC for resection of meningioma at our hospital during last 5 years, employing non-probability consecutive sampling. Variables for demographics, and details of diagnosis and surgical procedure were recorded. Eleven of these cases had grade I meningioma, and 6 had grade II meningioma. The mean age of these patients was 45.8 ± 10.5 years. Seizures were the most common presenting complain (n = 7; 41.2%). Eleven patients (58.3%) had convexity meningioma, 4 (33.3%) had parasagittal meningioma and 1 each had a parafalcine and anterior skull-base meningioma. The mean duration of surgery was 180.8 ± 36.2 minutes and the median estimated blood loss was 450 ml (IQR: 225 ml – 737.5 ml). The mean length of stay in the hospital was 3.1 ± 1.3 days. Only 1 patient had a prolonged hospital stay of 7 days because of post-operative seizures. Simpson grade I resection was performed in 6 (41.7%) patients, and grade II resection in 10 (50%) patients. Deterioration in pre-operative neurological exam was not seen in any patient, and no one required emergency intubation, conversion of surgery to general anesthesia, or re-operations. We propose that AC does not pose any significant risk of intra-operative or post-operative pain during meningioma resection, particularly convexity and parasagittal meningioma, and can make surgery possible for patients who are high risk for, or are not willing to undergo general anesthesia.
EXTH-23. PRECLINICAL EFFICACY OF A TARGETED, BRAIN PENETRANT INHIBITOR OF FATTY ACID DESATURATION IN GLIOBLASTOMA
Authors: Eyme Katharina , Sammarco Alessandro , Neustadt Rudolph , Mnatsakanyan Hayk , Tardiff Daniel , Chung Chee Yeun , Badr Christian
Published: November 2021

There is increasing evidence that targeting de novo fatty acid synthesis could be effective for the treatment of primary and metastatic brain tumors, but brain penetrant inhibitors of this pathway are still lacking. We have previously reported that Stearoyl CoA Desaturase (SCD), a desaturase enzyme which converts saturated fatty acids into their unsaturated counterparts is a therapeutic target in glioblastoma (GBM). We showed that SCD exerts a cytoprotective role by protecting GBM cells against lipotoxicity and is essential for maintaining self-renewal and tumor initiating properties in GBM stem cells (GSCs).

Using a panel of patient derived GSCs, mouse orthotopic GSC models, isogenic astrocytes models of gliomagenesis as well as in silico analysis, we report that in addition to SCD1, a second SCD isoform is also essential for GSCs maintenance. Further we demonstrate that while EGFR/PI3K/AKT signaling promotes lipogenesis, the activation of RAS/MEK/ERK signaling creates a metabolic vulnerability and sensitizes to SCD inhibitors. We tested a first-in-class, clinically relevant SCD inhibitor and showed that this compound effectively inhibits fatty acid desaturation in GSCs in a mouse orthotopic GSC model. Importantly, using different GSCs mouse models, we demonstrate that this SCD inhibitor can effectively increase overall survival as a monotherapy. Further, SCD inhibition impairs DNA-damage repair via homologous recombination thereby sensitizing to the standard of care therapeutics for GBM, ionizing radiation and temozolomide (TMZ). Consequently, combining this inhibitor with TMZ in mouse orthotopic GSC models leads to a significantly increased overall survival.

Altogether, our results provide a deeper understanding of de novo fatty acid dynamics in GBM and support the clinical testing of a new SCD inhibitor, with favorable pharmacokinetic and pharmacodynamic properties, in patients diagnosed with GBM.
EXTH-26. LAYER-BY-LAYER NANOPARTICLES DESIGNED FOR DUAL BLOOD-BRAIN BARRIER AND GLIOMA TARGETING
Authors: Straehla Joelle , Hajal Cynthia , Safford Hannah , Offeddu Giovanni , Wyckoff Jeffrey , Kamm Roger , Hammond Paula
Published: November 2021

BACKGROUND

While biologically diverse, high grade gliomas (HGGs) have a dismal prognosis in both adults and children. Promising therapeutics have been identified for HGGs based on common genomic alterations and aberrant signaling pathways, but achieving effective drug exposure at the tumor site remains a challenge largely due to the blood-brain barrier (BBB). HYPOTHESIS: A tunable nanocarrier platform can improve nanoparticle delivery across the (BBB) and into glioma cells.

METHODS

We synthesized layer-by-layer nanoparticles by coating anionic, fluorescent liposomes with nanometers-thick layers of oppositely charged polyelectrolytes, creating a library of organic, nontoxic drug carriers with varied surface chemistries. We characterized the library using dynamic light scattering and quantified interactions with a range of pediatric and adult glioma cell lines using flow cytometry. We used intravital two-photon microscopy to quantify nanoparticle trafficking across the intact BBB through a cranial window in anesthetized mice.

RESULTS

Nanoparticle surface chemistry strongly influences cellular trafficking in vitro, with two polymers identified as particularly high-performing across brain tumors lines: poly-L-aspartic acid (semi-synthetic) and hyaluronic acid (natural polysaccharide). The addition of the angiopep-2 targeting moiety onto these polymers improved nanoparticle uptake into brain microvascular endothelial cells in vitro without abrogating tumor affinity. We developed a new algorithm to quantify permeability of fluorescent compounds across the BBB in vivo and validated our method by measuring dextran permeability at varied molecular weights. In our initial study in non-tumor-bearing mice (n=12), we successfully quantified nanoparticle permeability across the BBB. In this study, surface functionalization did not increase BBB permeability above the control nanoparticle, though it did improve nanoparticle half-life in circulation and may still impart a therapeutic benefit when loaded with drug. Additional investigations in orthotopic tumor-bearing mice are ongoing. In summary, we report the development of layer-by-layer nanocarriers as a modular drug delivery platform with therapeutic potential for gliomas.
EXTH-44. SYSTEMIC CCL3 TREATMENT ENHANCES IMMUNOTHERAPY EFFICACY THROUGH IMPROVED DENDRITIC CELL MIGRATION
Authors: Hotchkiss Kelly , Batich Kristen , Janampalli Mrinaj , Norberg Pam , Sampson John
Published: November 2021

INTRODUCTION

Dendritic cell (DC) vaccines have shown marginal success in treating glioblastoma (GBM), with inefficient vaccine migration a major limitation. Prior evidence from our clinical trials demonstrated that tetanus diphtheria (Td) preconditioning produced greater DC migration to vaccine draining lymph nodes (VDLNs) and long-term survival. Greater DC numbers reaching VDLNs was also associated with long-term survival. We found from preclinical studies and our patients that increased DC migration was dependent upon the chemokine (C-C motif) ligand 3 (CCL3).

METHODS

The effect of systemic CCL3 treatment on DC vaccine migration (n=5), antigen-specific T cell responses (n=5) and efficacy against orthotopic GL261-OVA and SMA560 tumors (n=10) was studied in C57Bl/6 and VMdK mice. DCs were electroporated with OVA-mRNA or pulsed with ODC1 neoantigen peptide. Median overall survival (mOS) was measure in days (d) post-intracranial implantation.

RESULTS

Intravenous CCL3 at the time of intradermal DC vaccination resulted in a dose-dependent increase in migration to VDLN (10ug p=0.036, 20ug p< 0.0001, 50ug p< 0.0001). Mean migration levels following CCL3 treatment were similar to Td-preconditioning (p=0.52) but showed significantly less variability between mice. Combined CCL3 and DC vaccination generated more tumor antigen-specific CD8+IFNγ+ T cells 7 days compared to DC vaccine alone (p=0.0045). CCL3+OVA-DC treatment resulted in significantly greater survival compared to OVA-DC alone (mOS 37 vs 19.5 d; p=0.0174) in established GL261-OVA. CCL3 treatment increased survival in mice with established SMA560 tumors treated with neoantigen ODC1 peptide-pulsed DCs (Tumor alone mOS: 21d, DCvac: 25d, CCL3+DCvac: 48d, p=0.002).

CONCLUSIONS

These data combined with previous success of our DC vaccine clinical trials reflect the potency of CCL3 to enhance DC vaccine-specific migration, immune responses and survival. CCL3 is a novel and safe adjuvant to overcome prior limitations in DC vaccine therapy and may be translatable to increase heterogeneous tumor antigen presentation following vaccine-targeted tumor killing.
EXTH-66. ENHANCEMENT OF ANTI-PD-1 THERAPY WITH EXTENDED HALF-LIFE IL-2 IS INDEPENDENT OF MHC CLASS I RESTRICTED ANTIGEN RECOGNITION FOR TREATMENT OF EXPERIMENTAL GLIOMA
Authors: Tritz Zachariah , Ayasoufi Katayoun , Malo Courtney , Himes Benjamin , Khadka Roman , Fain Cori , Goddery Emma , Yokanovich Lila , Jin Fang , Hansen Michael , Parney Ian , Wang Chensu , Moynihan Kelly , Irvine Darrell , Wittrup Dane , Johnson Aaron
Published: November 2021

Glioblastoma (GBM) is the most common malignant brain tumor in adults, responsible for approximately 225,000 deaths per year. Despite pre-clinical successes, therapeutic interventions have failed to extend patient survival by more than a few months. Anti-PD-1 checkpoint inhibition monotherapy has had efficacy against some tumor types but not GBM. The aim of this study was to determine whether supplementing anti-PD-1 checkpoint blockade with an engineered extended half-life IL-2 could improve outcomes in a preclinical model of disease. Our enhanced checkpoint blockade (ECB) strategy reliably cures approximately50% of C57BL/6 mice bearing orthotopic GL261 gliomas and extended median survival even in the mice that eventually succumbed. This therapy generates robust immunologic responses, features of which include secondary lymphoid organ enlargement and increased activation status of both CD4 and CD8 T cells. Further, many of the characteristics of brain-tumor mediated peripheral immunosuppression, including MHC class II downregulation on APCs, are prevented by ECB combination therapy. This immunity is durable, with long-term ECB survivors able to resist GL261 rechallenge. Notably, ECB’s efficacy is independent of host MHC class I restricted antigen presentation, being equally efficacious in MHC class I and CD8 T cell deficient mice. Conversely, ECB combination therapy is reliant on CD4 T cells and their depletion abrogates the therapy’s survival benefit. Our data shows ECB combination immunotherapy to be efficacious against the GL261 glioma model through an MHC class I independent mechanism, enhancing its off-the-shelf translational appeal relative to strategies requiring extensive knowledge of tumor-specific antigens.
EXTH-68. DUAL METABOLIC REPROGRAMMING BY ONC201/TIC10 AND 2-DEOXYGLUCOSE HAS A STRONG ANTIPROLIFERATIVE EFFECT ON MEDULLOBLASTOMA CELLS
Authors: Dwucet Annika , Cao Qiyu , Pruss Maximilian , Westhoff Mike-Andrew , Wirtz Christian Rainer , Siegelin Markus D , Karpel-Massler Georg
Published: November 2021

BACKGROUND

Medulloblastoma represents one of the most common brain tumors in children. While the understanding of the molecular characteristics of this disease has very much advanced, more efficient and less toxic therapeutics are still in high demand. In this study we examined whether the imipridone ONC201/TIC10 affects the metabolic and proliferative activity of medulloblastoma cells alone and in combination with 2-Deoxyglucose in vitro.

METHODS

Extracellular flux (agilent seahorse) and Western blot analyses were performed to assess effects on tumor cell metabolism and the expression of proteins of the respiratory chain in established medulloblastoma cells. MTT assays and spheroid assays were performed to examine anti-proliferative effects in a 2-D and 3-D setting.

RESULTS

Treatment with ONC201/TIC10 has a strong inihibitory effect on the cellular viability of different medulloblastoma cells independent of c-Myc expression. While ONC201/TIC10 decreases the oxidative consumption rates in D458 (c-Myc high) and DAOY (c-Myc low) cells, extracellular acidification rates experienced an increase in D458 and a decrease in DAOY cells. Treatment with ONC201/TIC10 in combination with the glycolysis inhibitor 2-Deoxyglucose synergistically inhibited the cellular viability of medulloblastoma cells and impaired the growth of spheroids.

CONCLUSION

Overall, ONC201/TIC10 profoundly inhibits the proliferative activity of medulloblastoma cells in a c-Myc-independent manner. Additional treatment with the glycolysis inhibitor 2-Deoxyglucose synergistically enhances the anti-medulloblastoma activity of ONC201/TIC10. This promising approach warrants further investigations.
EXTH-69. FUNCTIONAL GENOMICS UNCOVER GENETIC DEPENDENCIES IN ATRTS
Authors: Merk Daniel , Hirsch Sophie , Tsiami Foteini , Walter Bianca , Haeusser Lara , Babaei Sepideh , Admard Jakob , Casadei Nicolas , Roggia Cristiana , Spohn Michael , Schittenhelm Jens , Singer Stephan , Schüller Ulrich , Piccioni Federica , Persky Nicole , Root David , Claassen Manfred , Tatagiba Marcos , Tabatabai Ghazaleh
Published: November 2021

Brain tumors are the leading cause of cancer-related deaths in children. Embryonal brain tumors including medulloblastoma and atypical teratoid rhabdoid tumors (ATRTs) account for 15% of all primary brain and CNS tumors under the age of 14 years, with ATRTs being most prevalent in infants. Despite intensive research efforts, survival estimates for ATRT patients stay relatively low as compared to other tumor entities with a median survival of around 17 months. We here describe genome-wide CRISPR/Cas9 knockout screens in combination with small-molecule drug assays to identify targetable vulnerabilities in ATRTs. Based on functional genomic screening revealing ATRT context-specific genetic vulnerabilities (n = 671 genes), we successfully generated a small-molecule library that shows preferential activity in ATRT cells as compared to a broad selection of other human cancer cell lines. Of note, none of these drugs differentially affect ATRT cells from distinct molecular subgroups, suggesting that top candidate inhibitors might serve as pan-ATRT therapeutic avenues. CDK4/6 inhibitors, among the most potent drugs in our library, are capable of inhibiting tumor growth due to mutual exclusive dependency of ATRTs on either CDK4 or CDK6. Our approach might serve as a blueprint for fostering the identification of functionally-instructed therapeutic strategies in other incurable diseases beyond ATRT, whose genomic profiles also lack actionable alterations so far.
EXTH-79. TRIAL WORKING GROUPS TO EXPEDITE PRECLINICAL TRANSLATION FOR PAEDIATRIC BRAIN TUMOURS
Authors: Rahman Ruman , Walker David , Campbell Emma , Aquilina Kristian
Published: November 2021

INTRODUCTION

Children's brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children, including intra-CSF chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate these. The science and technology underlying these developments is not traditionally embedded within the paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures, and the testing and licensing of implantable devices, add difficulty at the regulatory level.

METHODS

In early 2021, we launched the ‘Clinical Trials Working Group for Central Nervous System Drug Delivery’. This aims to accelerate clinical trials to assess the safety and effectiveness of drug delivery devices for treating paediatric brain tumours. On March 1st, we hosted the first virtual meeting of this group, involving 38 leading brain tumour scientists and clinicians from the UK, EU and US.

RESULTS

A pre-meeting survey identified the main challenges to acceleration of this preclinical to clinical research pathway as: (1) a lack of specific funding for prototype development and/or scale up for clinical trials; (2) difficulties in navigation of the regulatory landscape; (3) lack of accurate preclinical models; and (4) increased need for multicentric working. Discussion at the meeting echoed the survey responses, and there was agreed consensus that a ‘Roadmap’ document for preclinical to clinical translation should be created. Following the meeting, we launched a pump prime funding call for projects that will address challenges along the preclinical to clinical pathway to move trial proposals into an ‘advanced state of readiness’.

CONCLUSION

The ideas generated during the initial meeting will help form the basis of a ‘Clinical Trials’ workshop in the autumn of 2021.
EXTH-82. T CELL HITCHHIKING AS A MECHANISM OF DRUG DELIVERY TO THE BRAIN
Authors: Singh Kirit , Gedeon Patrick , Schaller Teilo , Snyder David , Khasraw Mustafa , Sampson John
Published: November 2021

INTRODUCTION

The blood-brain barrier (BBB) restricts access to the central nervous system (CNS). Our brain bispecific T cell engager (hEGFRvIII:CD3 BRiTE) treats subcutaneous syngeneic tumor (CT2AvIII) but not intracranial CT2AvIII. CD3 engaging molecules such as nanoparticles can be carried into the brain by binding to activated T cells. We therefore sought to determine if co-administration of larger molecules (BRiTE, approx. 55kDa) with activated T cells could cross the BBB, enhancing survival.

METHODS

We implanted 8–10-week-old transgenic hCD3 mice (n=7-8 per group) with 30,000 CT2AvIII cells. Tumors were established for 6 days. Mice were administered either (1) autologous lymphocyte transfer (ALT) alone (single intravenous (IV) injection, 1 x 107 activated T cells), (2) serial IV BRiTE doses (50ug, 10 days) (3) BRiTE and ALT or (4) no treatment. Mice were followed for survival using Kaplan-Meier curves and compared via log rank test. Targeted mass spectroscopy analysis as well as PET/CT imaging of mice administered Iodine-124 radiolabelled BRiTE was performed to assess for intracranial accumulation.

RESULTS

Mice who received BRiTE and ALT demonstrated significantly enhanced survival compared to controls (median survival 29 vs 21 days, p=0.0135). Mice who received only BRiTE or ALT exhibited median survival comparable to controls (p=0.192, p=0.944 respectively). Mass spectroscopy analysis revealed that mice had a 7-fold increased peak area ratio of BRiTE in the CNS when co-treated with activated T cells compared to BRiTE alone (0.14, 0.02 respectively) while PET/CT imaging demonstrated increased radioactive signal over background localized to coordinates within the brain where tumors were injected.

CONCLUSIONS

Giving activated T cells alongside BRiTE allows better access to the intracranial compartment and is required to achieve efficacy in mice with syngeneic orthotopic glioma. Future work will determine the optimal dose and schedule for this approach, as well as defining the precise mechanism by which this occurs.
QOLP-26. ANALYSIS OF REDDIT USERS' PERSPECTIVES OF BRAIN TUMORS
Authors: Tripathi Sanidhya , Prabhu Arpan , Thomas Kevin , Parker Pearman , Rodriguez Analiz
Published: November 2021

BACKGROUND

Reddit, ranking 6th in worldwide Internet site traffic, is a commonly used forum among patients and caregivers affected by brain tumors to discuss diagnoses, treatment, and self-care management. The use of the online forum may suggest patients and caregivers have unmet needs and are seeking further support outside of the clinical setting. We aimed to examine trends from Reddit discussion treads on brain tumors to identify areas of need in patient care.

METHODS

We used a qualitative, descriptive design to understand patient and caregivers unmet and met needs. We analyzed the top 100 posts and accompanying 271 comments from the ‘braincancer’ subreddit to identify common themes.

RESULTS

The qualitative content analysis revealed three major topic areas: (1) moving through the grief process; (2) processing diagnostic pathway; and (3) expressing gratitude toward other Reddit users. Most of the authors of the posts were patients with brain tumors (n = 32; 38.5%) who used Reddit as a reflective journaling tool to move through the grief process for themselves or loved ones. About 47% of theses posts discussed the diagnostic process of glioblastoma multiforme (GBM) brain tumors, where users requested an inclusive/welcoming environment in the clinic by their healthcare professionals (HPs). Users also solicited and gave support for other members in the online community.

CONCLUSIONS

This study highlights the need of implementing social media as a part of HPs’ repertoire for patient outreach/needs. Furthermore, social media outlets like Reddit can help HPs understand the level of support they can give to their patients. Plans of action for physicians seeking to meet the needs of brain tumor patients include monitoring the concerns of patients, becoming verified on the platform/openly identifying themselves online, or conducting ‘Ask Me Anything’ discussions to educate patients.
RBIO-01. DEVELOPING THE FRAMEWORK FOR TUMOR TREATING FIELDS (TTFIELDS) TREATMENT PLANNING FOR A PATIENT WITH ASTROCYTOMA IN THE SPINAL CORD
Authors: de Los Santos Jennifer , Arvatz Smadar , Zeevi Oshrit , Levi Shay , Urman Noa , Naveh Ariel , Marciano Tal
Published: November 2021

The use of Tumor Treating Fields (TTFields) following resection and chemoradiation has increased survival in patients with Glioblastoma. Patient-specific planning for TTFields transducer array placement has been demonstrated to maximize TTFields dose at the tumor: providing higher TTFields intensity (≥ 1.0 V/cm) and power density (≥ 1.1 mW/cm3) which are associated with improved overall survival. Treatment planning was performed for a 48 year old patient following T10-L1 laminectomy, gross total resection, and postoperative chemoradiation for an anaplastic astrocytoma of the spinal cord. An MRI at 3 weeks following chemoradiation showed tumor recurrence. Based on the post-chemoradiation MRI, a patient-specific model was created. The model was created by modifying a realistic computational phantom of a healthy female. To mimic the laminectomy, the lamina in T10-L1 was removed, and the region assigned electric conductivity similar to that of muscle. A virtual mass was introduced into the spinal cord. Virtual transducer arrays were placed on the model at multiple positions, and delivery of TTFields simulated. The dose delivered by different transducer array layouts was calculated, and the layouts that yielded maximal dose to the tumor and spine identified. Transducer array layouts, in which the arrays were placed on the back of the patient with one array above the tumor and one array below the tumor, yielded the highest doses at the tumor site. Such layouts yielded TTFields doses of over 3.4mW/cm3 which is well above the threshold dose of 1.1 mW/cm3 reported previously [Ballo et al. Red Jour 2019]. The framework developed for TTFields dosimetry and treatment planning for this spinal tumor will have the potential to increase dose delivery to the tumor bed while optimizing placement that may enhance comfort and encourage device usage.
RTID-01. PHASE III MULTICENTER RCT OF POST-SURGICAL STEREOTACTIC RADIOTHERAPY VERSUS SURGICALLY TARGETED RADIATION THERAPY FOR THE TREATMENT OF LARGE NEWLY DIAGNOSED BRAIN METASTASES – TRIAL IN PROGRESS
Authors: Weinberg Jeffrey , Beckham Thomas , McAleer Mary Frances , Johnson Jason Michael , Yuan Ying , Lin Heather , Kudchadker Rajat , Schwartz Theodore , Knisely Jonathan , Dunbar Erin , McCracken David , Wefel Jeffrey
Published: November 2021

BACKGROUND

Resection (R) followed by single- or multi-fraction stereotactic radiosurgery (SRT) of brain metastases (BMs) lowers resection bed recurrence compared to R alone. Nevertheless, for larger BMs, 12-month recurrence rates after R+SRT can exceed 20–30%. Aiming to improve outcomes, a permanently implanted collagen tile brachytherapy device (GammaTile, GT Medical Technologies, Tempe, AZ) utilizing Cs-131 seeds embedded within a bioresorbable collagen tile was developed and is described as Surgically Targeted Radiation Therapy (STaRT) to distinguish it from external beam radiotherapy. STaRT allows rapid, intense localized radiation dose delivery directly to the tumor bed with predictable dosimetry immediately at the time of R, which may confer reduced risk for radiation necrosis compared to other therapies. It is hypothesized that R+ STaRT will increase surgical bed recurrence-free survival (SB-RFS), while reducing impact on functional and neurocognitive status compared to R+SRT.

METHODS

Multicenter, randomized, comparison trial of patients with resectable, previously untreated “index” BMs (≥ 2.5–5cm), and 0–3 other tumors, will be preoperatively randomized 1:1 to undergo R+SRT or R+STaRT to the index lesion; unresected tumors in both groups will receive SRT. Planned sample size is 180 from 14 sites. Enrollment opened 03/31/2021. First subject was enrolled 04/07/2021. Primary endpoint is SB-RFS. Secondary endpoints include overall survival, quality of life, neurocognition, functional status, imaging findings and adverse events. Follow-up will be through 24 months. This will be the first randomized trial comparing R+SRT versus R+STaRT delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. Primary and secondary outcome measures captured will elucidate the potential risks and benefits of these two RT delivery methods in the setting of newly diagnosed BMs. We will present trial accrual progress, available data, experience and lessons learned.