bluuebunny/crossref_metadata_2025 huggingface dataset:
CSIG-24. BRAIN MICROENVIRONMENT-DEPENDENT NEURODEVELOPMENTAL LINEAGE PLASTICITY PROMOTES ADAPTATION TO ONCOGENE INHIBITION IN MALIGNANT GLIOMAS
Authors: Cadet Dimitri , Andrasz Cassidy , Bayley Nicholas , Fazzari Elisa , Fernandez Elizabeth , Okobi Quincy , Graeber Thomas , Bhaduri Aparna , Cloughesy Timothy , Nathanson David
Published: November 2024

Phenotypic plasticity drives non-genetic tumor adaptation in response to various microenvironmental and therapeutic pressures, consequently promoting tumor heterogeneity and progression. In malignant gliomas, the intrinsic and extrinsic mechanisms underlying phenotypic lineage plasticity and its contribution to drug resistance remain unclear. The epidermal growth factor receptor (EGFR) is frequently altered in glioma and serves as a critical regulator of normal radial glia (RG) cells – multipotent progenitors that give rise to cortical neurons and glia in the developing brain. Here, through interrogation of a large panel of diverse glioblastoma (GBM) patient-derived gliomaspheres and orthotopic xenografts, we find that enrichment of RG-like cells is significantly correlated with responses to pharmacological ablation of EGFR, highlighting EGFR as a crucial lineage survival factor for a population of malignant RG-like cells in GBM. Single-cell RNA sequencing and quantitative proteomics reveal that adaptation to EGFR inhibition is linked to a temporal contraction in RG-like cells and concomitant increase in lineage-restricted neuronal and oligodendrocyte progenitor (NPC/OPC)-like states exclusively in the orthotopic brain environment. This lineage transition is coupled to heightened RAS signaling gene expression programs and sustained activation of MAPK signaling, despite robust and durable inhibition of EGFR activation. Furthermore, constitutively active MEK – but not AKT – is sufficient to rescue tumor proliferation under EGFRi, suggesting that the brain microenvironment modulates RAS-MAPK oncogenic signaling to drive lineage transitions following EGFR blockade. Collectively, these results highlight a critical link between oncogenic signaling and neurodevelopmental lineage plasticity in malignant gliomas, presenting a compelling therapeutic opportunity to block tumor cell state transitions for more durable tumor responses in the native glioma tumor microenvironment.
CSIG-26. TARGETING EPIGENETIC DYSREGULATION AND ADAPTIVE RESISTANCE MECHANISMS IN DIPG/DMG
Authors: Xin Eric , Zhong Xiaowen , Huang Chris , Lu Richard
Published: November 2024

Diffuse intrinsic pontine gliomas (DIPG/DMG) are devastating pediatric brain tumors with very limited treatment options and a uniformly fatal prognosis. The recurrent histone H3K27M mutation in DIPG disrupts epigenetic regulation, leading to the hypothesis that this mutation-induced dysregulation creates a vulnerability to epigenetic targeting. We conducted a screening of compounds targeting epigenetic enzymes to identify potential inhibitors of patient-derived DIPG cell growth. High-throughput screening identified chaetocin, a fungal metabolite, as a potent inhibitor of DIPG cell growth. Chaetocin treatment selectively decreased proliferation and increased apoptosis in DIPG cells, significantly extending survival in DIPG xenograft models while restoring H3K27me3 levels. The loss of the H3K9 methyltransferase SUV39H1 also inhibited DIPG cell growth. Transcriptomic and epigenomic profiling showed that SUV39H1 loss or inhibition downregulated stemness and oncogenic networks, including growth factor receptor signaling. However, D2 dopamine receptor (DRD2) signaling adaptively upregulated, conferring resistance. Combining chaetocin with the DRD2 antagonist ONC201 or radiotherapy synergistically enhanced antitumor efficacy. This study reveals a therapeutic vulnerability in DIPG cells by targeting the SUV39H1-H3K9me3 pathway and compensatory signaling loops. Combining SUV39H1-targeting chaetocin with other agents, such as ONC201, may offer a new strategy for effective DIPG treatment. The findings suggest that chaetocin, by targeting and suppressing the H3K9me3 methyltransferase SUV39H1, inhibits DIPG tumor growth by downregulating stemness-related genes and growth factor signaling pathways. Overall, the study highlights a new therapeutic vulnerability in DIPG through the SUV39H1-H3K9me3 epigenetic pathway and compensatory signaling loops, suggesting an effective treatment strategy for DIPG.
CSIG-32. MODULATION OF HALLMARKS OF GLIOBLASTOMA MULTIFORME BY BIOACTIVE PHYTOCHEMICALS: A PRECLINICAL MECHANISTIC EVALUATION
Authors: Bobak Adam , Steves Michael , McMahon Emily , Spahiu Matea , Rahman Austin , Casarcia Nicolette , Bishayee Anupam
Published: November 2024

Glioblastoma multiforme (GBM) is an aggressive malignancy with extensive neovascularization, an immunosuppressive tumor microenvironment, and high recurrence rates. Bioactive plant secondary metabolites (phytochemicals), many from fruits and vegetables, have been extensively studied for GBM prevention and treatment. The objective of this study is to determine the effects of phytochemicals on GBM hallmarks and associated molecular mechanisms of action through evaluation of in vitro and in vivo studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to collect articles using PubMed, ScienceDirect and Scopus. While 1,344 articles were screened, 115 in vitro and 36 in vivo studies met our inclusion criteria. The Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) review of bias tool assessed in vivo study bias. In vitro, 49 alkaloids, 10 phenolics, 2 sulfur- compounds, and 5 terpenoids modulated GBM hallmarks of cell growth, invasion, cell cycle progression, neovascularization, and apoptosis. The PI3K/Akt/mTOR pathway was suppressed by 13 phytochemicals. Apoptosis was induced by 15 phytochemicals activating caspase-3, whereas 11 compounds inhibited Bcl-2. Cell cycle modulation occurred through decreased cyclin-dependent kinases and increased p53, p21, and p27. In vivo, 17 alkaloids, 5 phenolics, 2 sulfur-compounds, and 2 terpenoids had effects on GBM hallmarks. Invasion and neovascularization were inhibited through MMP, HIF-1α, and VEGF modulation. Six phytochemicals induced apoptosis in vivo through caspases and Bcl-2. Utilizing the SYRCLE review of bias tool, the average score quality of animal studies is 10% with many indicators of bias unclear. Various phytochemicals show promise to prevent and treat GBM due to their effects on numerous GBM hallmarks. Study limitations include the inclusion of literature reporting effects of single agents and lack of clinical studies. Future research is warranted to fill gaps in our analysis before recommending phytochemicals for prevention and treatment of GBM, a perilous malignancy.
RADT-07. HYPOFRACTIONATED RADIOTHERAPY IN BRAINSTEM GLIOMAS- EXPERIENCE FROM A TERTIARY CARE CENTRE IN INDIA
Authors: Dagar Abhilash , Ghosh Adrija , Aashita Aashita , Vivekananda Abiramasundari , Amritt Adhar , Raj Jaswin , Hazarika Sangeeta , Sharma Aman , Sharma D N , Mallick Supriya
Published: November 2024

Brainstem Gliomas have limited therapeutic options and poor outcomes. Radiation forms the cornerstone of management but data is lacking. We performed an audit of brainstem glioma patients treated with hypofractionated radiation between July 2021 to May 2024. Diagnostic MRI was co-registered with planning CT to delineate GTV with an isotropic 5 mm margin for CTV and 3mm for PTV. Baseline clinical and imaging details, radiation details, acute toxicities, steroid usage, progression, and overall survival data were recorded. PFS and OS were defined from the date of diagnosis to progression and death respectively. This study included 31 Brainstem glioma patients. The median age at presentation was 14 years (2–80 years). Majority of patients were male (67.7%). The baseline performance status assessed by ECOG/Lansky was 0-2 in 83.9%. The most common presenting complaint was motor weakness in 51.6% followed by cerebellar symptoms in 29%. Baseline neurological deficit was seen in 90.3%. The most common epicenter of the disease was pons (67.7%). Biopsy was available in only 9.7% (2 patients: Diffuse Midline Glioma H3k27 altered,1: High-Grade Glioma). VP shunting was done in 29%. All patients were planned via VMAT technique. Median GTV volume 34.3cc (4.9-109.5cc). Median PTV volume was 95.1 cc (7.9-363.1 cc). Most frequently used regimen was 40Gy/15#/3 weeks in 74.3% of patients. Median PTV coverage D95% was 98.7% (90.5-99%). Only one patient received concurrent Temozolamide. Median Radiation treatment time was 22.5 days (-46 days). Steroid usage during radiation was seen in 41.9% of the patients. Naso-gastric tube was required in 12.9% patients. During radiation, aspiration and raised ICT were seen in in 12.9% each. At a median follow-up of 6.42 months, the median PFS was 6.42 months (3-9.83 months) and OS was 7.18 months (3-11.37 months). Hypofractionation seems a feasible approach in brainstem gliomas. International collaborative efforts are required.
RADT-12. DERIVING IMAGING BIOMARKERS FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA USING DEEP LEARNING
Authors: Zhu Joshua , Hager Tommy , Chadha Saahil , Sritharan Durga , Weiss David , Hossain Sajid , Osenberg Klara , Moore Nicholas , Aneja Sanjay
Published: November 2024

PURPOSE

Primary central nervous system lymphoma (PCNSL) is typically treated with chemotherapy, steroids, and/or whole brain radiotherapy (WBRT). Determining which patients benefit from WBRT after chemotherapy and which are adequately treated with chemotherapy alone remains a clinical challenge. Although WBRT is associated with improved outcomes, it also carries a risk of neurocognitive side effects. This study aims to refine PCNSL patient phenotyping by leveraging deep learning (DL) extracted imaging biomarkers to enable personalized therapy.

METHODS

Our study included 71 patients treated between 2009-2021. The primary outcome of interest was overall survival (OS) assessed at one- and two-year cutoffs. The DL model leveraged an 8-layer 2D convolutional neural network analyzing individual slices of post-contrast T1-weighted pre-treatment MRI scans. Survival predictions utilized a weighted voting system related to tumor size. Model performance was assessed with accuracy, sensitivity, specificity, and F1 scores. Time-dependent AUCs were calculated and C-statistics were computed to summarize the results. Kaplan-Meier (KM) survival analysis assessed differences between low and high-risk groups and were evaluated using the log-rank test.

RESULTS

The cohort’s average age was 65.6 years with average OS of 2.80 years. For one-year OS, the model achieved an AUC of 0.73 (0.60-0.85), accuracy of 0.73 (0.61-0.82), sensitivity of 0.72 (0.54–0.85), and specificity of 0.73 (0.58–0.84). For two-year OS, the model achieved an AUC of 0.70 (0.58-0.82), accuracy of 0.70 (0.58-0.79), sensitivity of 0.68 (0.55–0.81), and specificity of 0.71 (0.55–0.84). Model performance is presented with respective 95% confidence intervals. KM curves showed the one and two-year models effectively discriminated between low- and high-risk group, reporting c-statistics of 0.73 (p<.001) and 0.71 (p<.001) respectively. A sub-analysis confirmed consistent model performance across different tumor volumes and focality.

CONCLUSION

DL classifiers of PCNSL MRIs can stratify patient phenotypes beyond traditional risk paradigms. Given dissensus surrounding PCNSL treatment, DL can augment risk stratification and treatment personalization, especially with regards to WBRT decision making.
RADT-13. REAL-WORLD DATA ON NEWLY DIAGNOSED WHO 4 GLIOMAS UNDERGOING TTFIELDS: SURVIVAL ANALYSIS AND RELAPSE PATTERNS FROM A SINGLE CENTER
Authors: Zhang Jing , Liu Yanwei , Qiu Xiaoguang , Zhang Wei
Published: November 2024

BACKGROUND

Tumor treating fields (TTFields) therapy is more and more widely used to treat patients with glioblastoma due to its effectiveness and low toxicity. In the 2023 V1 NCCN guidelines, TMZ combined with TTFields is the only preferred Class 1 recommended standard treatment for ndGBM patients aged ≤70 years.

METHOD

A total of 37 patients who were newly diagnosed as WHO 4 Gliomas in Tian Tan Hospital from 2020.8 to 2023.10 with TTFields were included in this retrospective analysis, and the median follow-up time was 449 days.

RESULT

The median age of the 37 patients was 50 years old, and 17 of them were male. Total resection was performed in 18 patients (48.6 %) and nearly total resection was performed in 14 patients (37.8%). The median time from diagnosis to first wearing of TTFields was 83 days(2.76 months). The median wearing time of TTFields was 9 months, and the median wearing compliance was 90%.The median PFS from diagnosis was 494 days (16.5 months). The 18 months OS rate was 86.7% from diagnosis to time of death after wearing TTFields. Among 37 patients receiving TTFields, 6 (16.2%) were found to have radiation damage. A total of 3 patients had non-radiological area and distal contralateral recurrence, and PFS were 7.2 months, 16.1 months, and 22.8 months, respectively.

CONCLUSION

PFS is associated with high total resection rate, early wearing of TTFields (median 2.76 months), and long wearing (median 9 months) with high compliance (median 90%). The recurrence pattern of patients with long-term wearing TTFields needs to be further explored. Currently, we are integrating clinical information and exploring the imaging characteristics of patients with distant metastases based on multimodality radiomics platform.
RADT-25. IMPACT OF SAME-DAY MASK CREATION ON GAMMA KNIFE TREATMENT
Authors: Mizrachi Mark , Hartley Benjamin , Hintz Eric , Goenka Anuj , Schulder Michael
Published: November 2024

OBJECTIVE

Technological advances have allowed stereotactic radiosurgery (SRS) to be administered using fixation with a noninvasive mask, rather than with a stereotactic frame. While the use of such masks offers advantages including the ability to hypofractionate SRS and improved patient comfort, there has been criticism that it eliminates the possibility of same-day, “wheels in to wheels out” SRS. Our study examines the feasibility of conducting mask fitting and SRS treatment on the same day versus the conventional different-day approach.

METHODS

Eligible participants had either underwent single-fraction-SRS (SF-SRS) or were in their initial session of hypofractionated-SRS (HF-SRS). 100 patients who underwent SRS from September 2020 to June 2021 were assessed. 52 patients underwent same-day fabrication and treatment, and 48 patients received treatment at least one day following mask fabrication. The Leksell Gamma Knife (LGK) console data was processed, and operator reports from each patient were extracted and analyzed.

RESULTS

The average number of pauses, pause time, and number of gates was greater for same-day patients. There was no significant difference in the number of positioning alarms between the groups. There were no significant differences in percent overestimation of treatment time or number of treatment alarms. Treatment gates occurred on average 19 minutes earlier for same-day patients then different-day patients, which likely corresponds to “mask fatigue,” due to spending 20 minutes longer on the treatment table, while the masks are being fabricated.

CONCLUSION

Mask-based SRS can be done safely and efficiently in a single day, mirroring the approach of frame-based treatments.
RADT-27. REPORT OF 9 CASES OF EMBRYONAL TUMORS OF THE CENTRAL NERVOUS SYSTEM WITH MULTILAYERED ROSETTES (ETMR)
Authors: Ai Ruyu , Li Juan , Lai Mingyao , Cai Linbo
Published: November 2024

OBJECTIVE

Embryonal Tumors of the Central Nervous System with Multilayered Rosettes (ETMR) are rare, and there’s no standard treatment protocol. This article reports on the current treatment status and prognosis of ETMR in our hospital.

METHODS

We retrospectively collected patients with ETMR who received treatment in the Oncology Department of Guangdong sanjiu Brain Hospital from January 2017 to January 2021, analyzed their clinical data.

RESULTS

Among 31 cases of central nervous system embryonic tumors (excluding medulloblastoma and ATRT), 9 (29.03%) were ETMR. The median age at diagnosis was 3 years old (1-15), and the male to female ratio was 4:5. Among them, 5 cases were accompanied by C19MC gene variation. Tumor location:6 was in supratentorial, 1 in the pineal region, 1 in the pons, 1 in the cerebellopontine. Eight patients underwent surgical resection at the first diagnosis, with 6 cases of total resection, 1 case of partial resection, and 1 case of biopsy. One case was misdiagnosed as a germinoma in the pineal region at the initial. After recurrence, surgical resection was performed to confirm the pathology as ETMR. One case was misdiagnosed as glioblastoma during the first surgery. The initial treatment for 4 patients after surgery was radiotherapy combined with concurrent chemotherapy. Recurrence patterns: 2 cases were intracranial dissemination, 2 cases were local recurrence, 1 was spinal cord dissemination. One patient did not receive treatment after surgery and tumor recurrence 3 months later. Survival analysis: The median survival time was 20 months. The 1-year progression-free survival rate (PFS) and overall survival rate (OS) were 22% and 61%, and the 2-year overall survival rate (OS) was 31%.

CONCLUSION

ETMR has a low incidence and poor prognosis. It is easy to misdiagnose and NGS is necessary to assist diagnosis when needed. More effective treatment methods need to be explored.
RADT-36. FUNCTION-ADAPTED RADIOTHERAPY PLANNING IN THE MANAGEMENT OF HIGH-GRADE GLIOMAS: A COMPARING STUDY FOR DOSE SPARING OF SPEECH-ELOQUENT BRAIN AREAS
Authors: Diehl Christian D , Troendle Malin L , Stefanowicz Sarah , Misslbeck Martin , Kram Leonie , Schwendner Maximilian , Ille Sebastian , Meyer Bernhard , Combs Stephanie E , Krieg Sandro M
Published: November 2024

BACKGROUND

Radiotherapy (RT) for brain tumors can induce injury of functional white matter tracts. In neurosurgery navigated transcranial magnetic stimulation (nTMS)- and diffusion tensor imaging (DTI)-based fiber tracts (FT) is an established tool to protect functional FT during tumor resection. We investigated it´s applicability in RT planning with the aim of dose reduction of language-associated fiber tracts.

METHODS

Preoperative, nTMS-generated and DTI-based FT of the functional left hemispheric language network of patients with language-eloquent malignant gliomas (WHO III/IV) were imported into the planning software (ARIA®) according to the DICOM standard and contoured as a risk structure. Brain shift after tumor resection was compensated using elastic fusion (Brainlab®). The treatment plans were optimized or recalculated with the aim of reducing the dose to the fiber tracts outside the planning target volume (PTV). The dosimetric evaluation was performed according to dose volume histogram parameters.

RESULTS

RT plans of 27 patients were retrospectively evaluated in the study. The mean dose (Dmean) to the fiber tracts was 37.3+/-11.8 Gy, with plan optimization dose was 33.6 +/- 12.2 Gy (-10.9% p<0.01), within the 20 Gy isodose the dose reduction to be achieved was on average - 25.0% (range 0-48.5%). The V54Gy and V20Gy were on average 40.2 +/- 23.7% and 72.3 +/- 21.1% compared to 38.2 +/- 23.5% and 58.1 +/- 23.7% (both p<0.01) with optimization. The Dmean of the PTV did not change (59.8 Gy vs. 59.8 Gy (p=0.5)), nor did the dose homogeneity (HI, (D5-D95)/Dp)(p=0.63)). The dose exposure of the organs at risk was within the specified dose constraints.

CONCLUSION

This study showed that (nTMS)- and diffusion tensor imaging (DTI)-based fiber tractography could be used in radiotherapy planning to spare language-eloquent brain areas without having to accept dose reductions within the PTV. Whether the concept of tract-based sparing of language function brings clinical benefits to patients needs to be further investigated in prospective studies.
RADT-38. CLINICAL, MOLECULAR AND IMAGING FEATURES ASSOCIATED WITH LONG TERM SURVIVAL IN GLIOBLASTOMA PATIENTS
Authors: Sharif Muhammad , Andrews Carrie , Shah Sophia , Haldar Nilanjan , Cappelli Louis , Zhan Tingting , Alnahhas Iyad , Shi Wenyin
Published: November 2024

INTRODUCTION

Glioblastoma (GBM) is the most common malignant brain tumor in adults and has poor prognosis despite standard of care treatment. Nevertheless, certain patients surpass survival expectations. This study seeks to identify the clinical, molecular, and imaging characteristics of GBM associated with extended patient survival.

METHODS

In this retrospective cohort study, we examined records of adult GBM patients (WHO 2016 classification) treated at Thomas Jefferson University Hospital from 2010 to 2023. Exclusion criteria included a preoperative Karnofsky Performance Status (KPS) below 60 and treatment with hypo-fractionated radiation therapy. Patients were categorized into two groups: short-term survivors (STS), who survived less than 36 months from diagnosis, and long-term survivors (LTS), who survived more than 36 months. We reviewed patient charts and pathology reports for comprehensive clinical and molecular data. For radiomics analysis, tumor segmentation was performed using CaPTk software on the initial diagnostic MRI (T1 pre and post-contrast, FLAIR and T2 sequences). The relationship between overall survival of more than three years was analyzed with univariable logistic models for potential predictors using R statistical software.

RESULTS

Of the cohort of 210 patients, 37 (17.6%) survived beyond three years. The median age at diagnosis was 55 years (range; 29-79) Twenty-two patients were male and 15 were female. Twenty-two percent had IDH mutation and 65% had MGMT methylation. Factors associated with long-term survival included younger age at diagnosis (p =0.007), MGMT hypermethylation (p =0.019), IDH mutation (p=0.001), absence of TERT mutation (p = 0.002), higher average number of adjuvant temozolomide cycles (10 vs. 5; p = 0.005), and smaller volume of enhancing tumor on T1 post-contrast imaging segmentation (p=0.022). But there was no significant difference in FLAIR abnormality or necrotic core volumes between the groups.

CONCLUSION

In our cohort of GBM patients, patients diagnosed at a younger age, MGMT hypermethylation, IDH mutation, absence of TERT mutation, receiving more cycles of adjuvant temozolomide treatment, and smaller enhancing tumor volume on preoperative T1 post-contrast imaging were associated with longer survival. Future research involving larger cohorts and validation of our findings is needed.
RADT-46. RADIOSURGERY DOSE REDUCTION FOR BRAIN METASTASES ON IMMUNOTHERAPY (RADREMI):A PROSPECTIVE PILOT STUDY
Authors: Curtis Charles , Weisman Michael , McClelland Shearwood , Rhome Ryan , Anthony Paul , Agrawal Namita , Lautenschlaeger Tim , Zellars Richard , Kamer Aaron , Hanna Nasser , Zang Yong , Boyd LaKeisha , Shiue Kevin
Published: November 2024

BACKGROUND

The combination of immunotherapy and single-fraction stereotactic radiosurgery (SRS) for treatment of metastatic brain disease has yielded symptomatic radiation necrosis rates as high as 16%. The aim of this study was to evaluate the toxicity of dose reduced stereotactic radiosurgery (SRS) in patients receiving concurrent immune checkpoint inhibitors (ICI).

METHODS

RADREMI is a prospective, single arm, phase 1 pilot study evaluating adults with 1-10 brain metastases on MRI receiving ICI within 30 days of treatment. SRS was delivered using dose reduction: 18 Gy for lesions 0-2 cm, 14 Gy for lesions 2.1-3 cm, and 12 Gy for lesions 3.1-4 cm. Patients were evaluated at 6-months with regard to symptomatic radiation necrosis, defined as a 6-month rate of clinical symptomatology requiring steroid administration, bevacizumab, and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis.

RESULTS

Between 2019 and 2023, 18 eligible patents were entered with 12 evaluated. All patients were treated within the 18 Gy cohort. The median follow up was 13.82 months. The median number of brain metastases treated was 1.5 (inner quartiles 1, 3) with up to 7 lesions treated. The proportion of patients who experienced symptomatic radiation necrosis by 6 months was calculated with the 95% confidence interval tested against a historical proportion of 16%. The incidence of symptomatic radiation necrosis at 6 months was 1 of 12 (0.083; 95% CI: 0.002, 0.385; p-value 0.234) following SRS.

CONCLUSIONS

Our findings of dose reduced SRS with concurrent ICI unfortunately did not have statistical significance regarding symptomatic radiation necrosis. This was likely due to the small number of evaluable patients. The secondary endpoint of local control is currently under review. Dose reduced SRS with concurrent ICI warrants further studies to evaluate toxicity and local control.
CTIM-02. PIONEERING QUAD-TARGETING CAR T CELL THERAPY IN PEDIATRIC CNS TUMORS – ANALYSIS FROM THE INITIAL PATIENTS TREATED ON THE FIRST-IN-HUMAN PHASE 1 TRIAL BRAINCHILD-04
Authors: Ronsley Rebecca , Seidel Kristy , Narayanaswamy Prabha , Pattabhi Sowmya , Wendler Jason , Ho On , Rawlings-Rhea Stephanie , Gust Juliane , Huang Wenjun , Crotty Erin , Leary Sarah , Runco Daniel , Hauptman Jason , Gardner Rebecca , Park Julie , Annesley Colleen , Jensen Michael , Vitanza Nicholas
Published: November 2024

BACKGROUND

BrainChild-04 is a first-in-human clinical trial of quad-chimeric antigen receptor (CAR) T cell therapy for children and young adults with central nervous system (CNS) tumors. This trial administers repeated locoregional CAR T cells targeting B7-H3, EGFR, HER2, and IL-13Ralpha2 (“quad-CAR T cells”), leveraging multi-antigen targeting to address the tumor heterogeneity of high-grade CNS tumors.

METHODS

The primary endpoints are feasibility and safety, and secondary endpoints are disease response and correlative studies of CAR T cell activity. The trial utilized a Bayesian Optimal Interval (BOIN) statistical design with three planned dose regimens(DR). There are 2 arms with weekly delivery for 3 weeks of a 4-week cycle:(A) –diffuse intrinsic pontine glioma (DIPG), (B) –non-pontine diffuse midline glioma (DMG) or other relapsed CNS tumors.

RESULTS

Enrolled patients include DMG N=6, DIPG N=5, other CNS tumors N=4. Of the 15 enrolled patients, 7 have been infused with 8 awaiting infusions. A total of 33 intracranial CAR T doses have been delivered, including Arm A DR 1 (N=1), Arm B DR 1 (N=3), DR2 (N=3). The most common adverse events have been grade 1-2 fever (7/7 patients), grade 1-3 headache (6/7), and grade 1-2 nausea/vomiting (6/7). There have been no DLTs and no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity (ICANS). CTCAE and tumor inflammation-associated neurotoxicity are both being captured. All treated patients are alive with median follow up time post-initial infusion of 93(14-198) days. CAR T cells were detected by flow cytometric analysis of CSF post-infusion in 14/24 CSF samples. Radiographic response, CSF circulating tumor DNA, targeted mass spectrometry, and cytokine analysis will be presented.

CONCLUSIONS

Our preliminary experience suggests tolerability of locoregional delivery of quad-CAR T cells at doses currently evaluated. The trial remains ongoing and these data support continued evaluation of this product to better assess anti-tumor activity in patients with CNS tumors, including DIPG/DMG.
CTIM-06. OUTCOME OF PATIENTS WITH RECURRENT MEDULLOBLASTOMA AND EPENDYMOMA TREATED WITH PEMBROLIZUMAB, AN IMMUNE CHECKPOINT INHIBITOR: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC045)
Authors: Hwang Eugene , Kilburn Lindsey , Mitchell Duane , Lin Tong , Poussaint T Y , Robinson Giles , Gajjar Amar , Lenzen Alicia , Dorris Kathleen , Robison Nathan , Fangusaro Jason , Fouladi Maryam , Onar-Thomas Arzu , Dunkel Ira
Published: November 2024

BACKGROUND

Children with recurrent medulloblastoma and ependymoma typically have a dismal prognosis. Immune checkpoint blockade has revolutionized treatment of some resistant cancers. PBTC045 is a safety and preliminary efficacy study of pembrolizumab, a PD-1 inhibitor, in children with recurrent/progressive brain tumors. Here we present the strata that included children with recurrent/progressive ependymoma and medulloblastoma.

METHODS

Eligibility included patients aged 1-21 years old with recurrent/progressive ependymoma or medulloblastoma and with functional scores ≥70, no greater than physiologic steroid usage and standard washout periods, among other eligibility criteria. Pembrolizumab was administered at 2mg/kg IV every three weeks. Tumor tissue (if available) and serum were collected for correlative studies. Primary endpoints included toxicity and response, and two stages were planned requiring objective responses for potential expansion.

RESULTS

Patients with progressive ependymoma (Stratum D, n=13) or medulloblastoma (Stratum E, n=14, one ineligible) were enrolled. The median age at diagnosis was 3.37 years (range, 1-12.7) and 7 years (range, 2.2-13.1), respectively. The median age at study entry was 8.5 years and 11.4 years, respectively. There were no first-stage objective responses in either stratum, and thus the expansion arms were not initiated. Grade 3 or greater treatment-related adverse events included rash (n=1), anemia (n=1) and neutropenia (n=2), with no dose-limiting toxicities. The median progression-free survival (PFS) for ependymoma and medulloblastoma were 1.38 months (range, 1.08-1.51) and 1.41 months (range, 1.22-3.45), respectively. Immune correlative analyses are ongoing.

CONCLUSIONS

Immune checkpoint inhibition holds potential for CNS cancer treatment, and as a single agent, is well tolerated. However, in the current study, checkpoint inhibition monotherapy does not appear to significantly prolong survival or induce radiographic responses in children with recurrent/progressive ependymoma or medulloblastoma. Potential incorporation of checkpoint inhibitors into treatment for these patients will likely require combinatorial approaches that may be informed by the correlative science.
CTIM-08. FIRST IN HUMAN STUDY OF THE MRNA-BASED CANCER VACCINE CVGBM IN PATIENTS (PTS) WITH NEWLY-DIAGNOSED AND SURGICALLY RESECTED MGMT-UNMETHYLATED GLIOBLASTOMA (GBM): FIRST RESULTS FROM THE DOSE ESCALATION PHASE
Authors: Tabatabai Ghazaleh , Freres Pierre , Glas Martin , Hau Peter , von Baumgarten Louisa , van Den Bent Martin , Burger Michael C , Seidel Clemens , Herrlinger Ulrich , Mildenberger Iris , Neyns Bart , Schafer Henning , Wick Antje , Falk Martin , de Chama Laura Leticia Freitas , Kelemen Peter , Schwenke Frauke , Koch Sven D , Roche Paula Romer , Gnad-Vogt Ulrike
Published: November 2024

INTRODUCTION

CVGBM is an investigational therapeutic mRNA-based vaccine encoding 8 epitopes derived from tumor associated antigens with potential relevance in GBM. This is an ongoing, first-in-human study evaluating the safety of CVGBM in pts with newly-diagnosed MGMT-unmethylated GBM.

METHODS

HLA-A*02:01-positive pts with newly-diagnosed MGMT-unmethylated GBM (CNS WHO Grade [Gr] 4) who had a gross total or partial resection and completed radiotherapy ± concomitant temozolomide received CVGBM on Days 1, 8, 15, 29, 43, 57 and 71 + 6 optional doses at 6-week intervals. Primary endpoints are safety, tolerability and dose-limiting toxicities (DLTs). Immunogenicity is an exploratory endpoint.

RESULTS

As of 29/2/2024, 16 pts were enrolled in the dose-escalation part (Part A); 3 each in DL 1 (12 µg), DL 2 (25 µg), and DL 3 (50 µg), and 7 in DL 4 (100 µg). For all cohorts, mean time on study from 1st dose to last visit was 4.5 months (min: 1.5; max: 8). 109 doses were administered (mean: 6.8 doses per pt). All pts completed the 2-week DLT evaluation period without DLTs. Of 156 treatment-emergent adverse events (TEAEs), the majority (73%) were CTCAE Gr 1 (21% Gr 2, 6% Gr 3). The most common related TEAEs were chills (n=13), pyrexia (n=12), headache (n=12), fatigue (n=11) and malaise (n=5), mostly of mild to moderate severity. 7 pts had 9 ≥ Gr 3 AEs assessed as potentially related to CVGBM by the investigators outside the DLT period (cerebral edema [n=2], leukoencephalopathy, pseudoprogression with cerebral edema, structural epilepsy, ataxia, hypertension, malaise and fever [1 of each]), evenly distributed across cohorts. First immunogenicity data are planned to be presented.

CONCLUSIONS

CVGBM was generally well tolerated with an acceptable safety profile. The highest tolerated dose was not reached. Based on all available safety data, the selected dose for trial expansion was 100 µg. Previously presented at ESMO 2024, “FPN (Final Publication Number): 4400, Ghazaleh Tabatabai et al. - Reused with permission.
CTIM-18. HIGH LEVEL OF MUTATIONAL LOAD AND DIVERSITY OF TUMOR INFILTRATING T LYMPHOCYTES ARE FAVORABLE PROGNOSTIC MARKERS FOR CANCER SURVIVAL IN CHILDREN WITH RECURRENT MEDULLOBLASTOMA DURING ADOPTIVE CELLULAR THERAPY
Authors: Yegorov Oleg , Yang Changlin , Stratford Yanina , Mitchell Duane
Published: November 2024

BACKGROUND

Adoptive cellular therapy (ACT) has shown remarkable efficacy in some patients with solid tumors, resulting in durable complete responses. A key mechanism behind this success is the targeting of neoantigens by T cells. There is culminating evidence that tumor-infiltrating lymphocytes (TILs) have a major effect on the clinical attributes of human cancer and can influence the tumor response to various therapy regimens. We have been sequencing RNA isolated from patient’s tumors to evaluate their mutational burden and identify tumor-specific neoantigens. Additionally, we have identified the entire repertoire of tumor-infiltrating lymphocytes in patients with recurrent medulloblastoma.

METHODS

Total tumor RNA was extracted from resected brain tumor specimens and after we applied in-house bulk RNA-Seq and TCR-Seq techniques using rapid amplification of cDNA ends (RACE) technology with the addition of a common adapter at the 5’ end.

RESULTS & CONCLUSIONS

Analysis of the 22 tumor tissues revealed that the frequency of non-synonymous mutations varied dramatically more than 10-fold among patients with recurrent medulloblastoma undergoing adoptive cellular therapy (Re-MATCH protocol, FDA IND BB-14058). Patients with shorter overall survival exhibited non-synonymous mutation frequencies between 0.113 and 0.335 mutations per megabase (Mb). Children with prolonged overall survival had higher mutation frequencies, ranging from 0.6 to 1.1 mutations per Mb. These findings highlight the potential of using mutational burden as a biomarker for patient selection and treatment customization, ultimately aiming to improve outcomes in ACT for recurrent medulloblastoma. Up to 2000 unique TCR clones were found among TIL populations in patients who responded well to ACT. Patients with poor outcomes had significantly lower TCR diversity, with only 10-40 unique TCR clones among TILs. The correlation between TCR diversity among TILs and clinical outcomes in pediatric brain tumors underscores the importance of a diverse T cell repertoire for the success of ACT.
CTIM-20. IDENTIFYING CANDIDATE ANTIGEN TARGETS FOR PEDIATRIC BRAIN TUMOR IMMUNOTHERAPIES THROUGH COMPREHENSIVE IMMUNOGENOMIC ANALYSIS
Authors: Yang Changlin , Trivedi Vrunda , Yegorov Oleg , Mitchell Duane
Published: November 2024

BACKGROUND

Identifying tumor rejection antigens continues to be a significant challenge in the development of effective immunotherapies and their application to pediatric brain tumors.

METHODS

To identify candidate antigen targets for Medulloblastoma (primary MB, n=170; recurrent MB, n=21), Diffuse Intrinsic Pontine Glioma (DIPG, n=10), and Pediatric High-Grade Astrocytoma (HGA, n=12) for adoptive cellular therapy, we conducted a comprehensive immunogenomic analysis of the transcription profiles of the most aggressive pediatric brain tumors and performed in silico antigen prediction across a wide range of antigen classes.

IMPORTANCE OF THE STUDY

Pediatric brain tumors are heterogeneous diseases, and current standard treatments do not adequately address this variability. Newer and safer patient-specific treatment approaches are needed for high-risk patients who do not respond to standard therapies. Cellular immunotherapy could be crucial for improving survival and reducing morbidity. For an effective immune response against these brain tumors, appropriate tumor antigens must be targeted. While subgroup-specific genetic mutations in medulloblastoma patients have been reported, the immunogenicity of these genetic alterations remains unknown. Using a custom antigen prediction pipeline, we identified potential tumor rejection antigens with significant implications for the development of cellular therapies for MB, DIPG, and HGA.

RESULTS

Antigen prediction analysis revealed that most patients express few candidate neoantigen targets that pass all filtering criteria. Overall, the proportion of predicted tumor-associated antigens (TAAs) was higher than that of neoantigens and gene fusions for all molecular subtypes, except for SHH, which exhibited a higher neoantigen burden. Notably, cancer-testis antigens and previously unrecognized neurodevelopmental antigens were found to be expressed in most patients across all medulloblastoma subgroups. Although the absolute immune cell content is predicted to be low, immune gene-signature analysis revealed subgroup-specific differences.
CTIM-22. MEDIAN AND 2 YEARS SURVIVAL OF NEWLY DIAGNOSED UNMETHYLATED MGMT GLIOBLASTOMA PATIENTS TREATED WITH TEMFERON IMMUNO-GENE THERAPY
Authors: Eoli Marica , Farina Francesca , Cuccarini Valeria , Gentner Bernhard , Barcella Matteo , Anghileri Elena , Bruzzone Maria Grazia , Carrabba Matteo , D’Alessandris Quintino Giorgio , DiMeco Francesco , Ferla Valeria , Franzin Alberto , Ferroli Paolo , Gagliardi Filippo , Legnani Francesco , Capotondo Alessia , Mazzoleni Stefania , Mortini Pietro , Olivi Alessandro , Pallini Roberto , Patanè Monica , Paterra Rosina , Pollo Bianca , Saini Marco , Snider Silvia , Naldini Luigi , Russo Carlo , Ciceri Fabio , Finocchiaro Gaetano
Published: November 2024

TEM-GBM is an open-label, Phase 1/2a dose-escalation study aimed to evaluate the safety and efficacy of a myeloid cell-targeted therapy (Temferon) in up to 27 newly diagnosed GBM patients with unmethylated MGMT (uMGMT). Temferon, consists of autologous Hematopoietic Stem Progenitor Cells (HSPCs) genetically modified with a lentiviral vector to deliver IFN-α2 within the tumor microenvironment by Tie-2 expressing macrophages. As of 21st May 2024, 24 GBM patients in 8 cohorts received incremental doses of Temferon and 6 are still alive. For all patients, median overall survival (OS) and median progression free survival reach 17 months and 8.3 months from first surgery, respectively. The interim survival rate at 2 years in Temferon-treated patients is 30% (6 of 20 patients; 3 patients excluded as follow-up is below 1 year). The mOS and the % of patients surviving up to 2 years are currently higher than previously reported for uMGMT patients treated as per standard practice (12.7 months and 14,8%, respectively). Two out of the six patients did not receive any additional treatment lines up to two years after 1st surgery. The other four patients instead received a 2nd treatment line (bevacizumab, regorafenib, Gamma-Knife, metronomic Temozolomide, Lomustine) as per the PI judgment, on average after 443 days from 1st surgery (333 days from Temefron - range 223-1030 days from first surgery). Specifically, Bevacizumab administration started 12 months after 1st surgery for one patient and 19 months for the other 2 patients at 5 mg/kg. The data further confirms the initial evidence on safety and tolerability of Temferon and highlight the potential to prolong the survival of patients affected by uMGMT GBM.
CTIM-27. DOC1021 CELL-BASED VACCINATION AS ADJUVANT THERAPY FOR GLIOBLASTOMA: PHASE I CLINICAL TRIAL ANALYSIS
Authors: Esquenazi Yoshua , Zhu Jay , Hsu Sigmund , Zvavanjanja Rodrick , Vu Mia , Highberg Eva , Akshar Trivedi , Liu Wei , Namekar Madhuri , Hofferek Colby , Ernste James , Mossop Corey , Christina Clay , Amin Sabina , Benjamin Musher , Ravi Vinod , Jan Kemnade , Aguilar Laura , Turtz Alan , Tandon Nitin , Konduri Vanaja , Georges Joseph , Decker William
Published: November 2024

Glioblastoma is an aggressive tumor for which median survival remains 14-18 months despite aggressive standard of care. Cellular immunotherapy approaches have recently shown promise. Homologous antigenic loading is an ex-vivo technique that leverages p38MAPK and mTORC1 signaling cascades to initiate powerful cDC1-like skewing in monocyte-derived dendritic cells, leading to downstream induction of tissue-infiltrating, cytolytic effector memory T-cells. This open-label phase I clinical trial evaluated the autologous dendritic cell vaccine DOC1021 prepared through homologous antigenic loading and administered bilaterally near the deep cervical lymph nodes. Three courses of vaccine were administered every 2 weeks after completion of chemoradiation, adjuvanted concurrently with six weeks of weekly type I interferon. Four dose levels from 3.5x106 to 3.6x107 total vaccine cells were tested. Tumor progression prior to vaccination was not an exclusion criterion. Sixteen newly diagnosed IDH-WT patients completed treatment, median age 63 years and 94% MGMTp unmethylated. The most common related AEs were grade 1 injection-site reactions and grade 1-3 fatigue and urticaria. No DLTs were observed. Immunohistochemistry of tumors derived from early post-vaccination second resections showed enhanced CD8+ T-cell infiltration and pathologic findings consistent with residual rather than relapsed GBM in 2/3 patients. Analysis of post-vaccination PBMC in dose level cohorts 2-4 indicated expansion of both CD4+ (13/13) and CD8+ (11/13) central memory T-cell compartments (p<0.002 and p<0.05, respectively) as well as expansion of CD8+CD127+ T-cells (12/13; p<0.001). Among three patients for whom tissue was obtained pre- and post-vaccination, clinical outcomes correlated with Visium spatial transcriptomic analysis. Median survival for the MGMTp unmethylated cohort (n=15) has not yet been reached but is statistically greater (p<0.05) than that of matched historic controls. The results indicate that DOC1021 is safe, can be effectively integrated within existing standards of care and is potentially efficacious in a challenging patient population.
CTIM-29. TUMOR RESPONSES IN A RANDOMIZED PHASE IIB TRIAL OF A CMV VACCINE IMMUNOTHERAPEUTIC CANDIDATE (VBI-1901) IN RECURRENT GLIOBLASTOMAS
Authors: Merrell Ryan , Wen Patrick , Forst Deborah , Schulte Jessica , Odia Yazmin , Bota Daniela , Nagpal Seema , Bonm Alipi , Diaz-Mitoma Francisco , Anderson David , Lassman Andrew , Iwamoto Fabio
Published: November 2024

Cytomegalovirus (CMV) antigens have been reported in over 90% of GBMs. CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens, respectively, which are immunogenic targets in a CMV-based GBM immunotherapeutic. First-recurrent GBM patients were enrolled, with Karnofsky Performance Status of at least 70, to receive VBI-1901 (a gB/pp65 enveloped virus-like particle [eVLP]) adjuvanted with GM-CSF and given intradermally (NCT03382977). Patients were vaccinated with VBI-1901 every 4 weeks, with surveillance brain MRI scans every 6 weeks. Among 16 subjects receiving the highest dose of VBI-1901 in the Phase I/IIa portion of the study, the disease control rate was 44%, including 2 durable partial responses, which translated into a mOS of 12.9 months. Based on these results, the study was amended into a randomized study. Approximately 60 adult subjects (18 years or older) with first recurrence of WHO 2016 grade IV Glioblastoma, IDH-wildtype will be randomized at a 1:1 ratio to two open-label cohorts to receive: VBI-1901 or standard of care (SOC) treatment with lomustine or carmustine. Only subjects with a CD4/CD8 ratio ≥1 or a CD4 count of ≥ 400/uL at screening are eligible, as people with a preserved immune system are more likely to respond to immunization with VBI-1901 based on the initial phases of the study. As of May 15, 2024, 23 patients have been randomized across 6 sites. Among evaluable patients (n=13), disease control rates of 43% and 0% have been observed in the VBI-1901 and SOC arms, respectively, including 1 partial response in the VBI-1901 arm. Full enrollment (n=60) is anticipated by the end of the year across 11 sites, and updated tumor response data and select biomarkers associated previously with tumor responses will be presented.
CTIM-31. PRELIMINARY RESULTS OF A PHASE II STUDY OF STEREOTACTIC RADIOSURGERY IN CONJUNCTION WITH THE PD-1 INHIBITOR PEMBROLIZUMAB FOR THE TREATMENT OF RECURRENT HIGH-GRADE MENINGIOMA
Authors: Oberheim Bush Nancy Ann , Kumar Karishma , Rabbitt Jane , Daras Mariza , Sneed Penny , Boreta Lauren , Nakamura Jean , Butowski Nicolas , DeGroot John , Raleigh David , Braunstein Steve
Published: November 2024

Recurrence of higher-grade meningioma after initial resection and radiotherapy is frequent and associated with high rates of morbidity and mortality. Salvage therapies have limited efficacy and average survival after recurrence is approximately 5-10 years. We report here preliminary data from a phase 2 study combining immunotherapy with checkpoint inhibition with stereotactic radiosurgery for treatment of recurrent high-grade meningioma (NCT04659811). Adult patients with either grade 2 or 3 meningioma who have recurred despite treatment with surgery and radiation and who meet eligibility criteria received stereotactic radiosurgery, in 1 to 5 fractions, in conjunction with pembrolizumab 200mg on the first day of radiation and then every 3 weeks until progression, unacceptable toxicity or for 2 years. Primary objective is PFS12, and secondary objectives include safety of the combined treatment in recurrent meningioma, mOS, mPFS, and neurocognitive function and QOL metrics. To date we have enrolled 18 of planned 37 patients, 33% female, 39% grade 2 and 61% grade 3. Safety lead in was completed without any dose limiting toxicity. There have been 4 SAEs, only one of which was related to study treatment (cerebral edema). 29% of patients had at least one AE, the most common were GI disorders (23%), skin disorders (23%) and headache (17%). Preliminary data from 12 patients shows PFS12 to be 50%, which suggests that the combination of stereotactic radiosurgery may be more beneficial than treatment of Pembrolizumab alone (mPFS 7.6 months). One patient was found to have a homozygous focal deletion of the MLH1 gene and had a dramatic reduction in size of her meningioma with a durable response for over one year. These preliminary data suggest that the combination of stereotactic radiosurgery and pembrolizumab is safe, well tolerated and may be beneficial to patients with recurrent higher-grade meningioma.