bluuebunny/crossref_metadata_2025_split huggingface dataset:
BSCI-15 INVESTIGATING CD8 T CELL EXHAUSTION STATES WITHIN THE TME AND DRAINING LYMPH NODE OF PRIMARY BRAIN TUMORS AND BRAIN METASTASES
Authors: Waibl Polania Jessica , Hoyt-Miggelbrink Alexandra , Tomaszewski William , Fecci Peter 
Published: August 2022

Abstract
Brain metastases affect nearly 20% of all cancer patients. Likewise, glioblastoma (GBM) is the most common primary brain cancer in adults and remains universally lethal. Current immunotherapeutic efficacy is hindered by immunosuppression present in the brain tumor microenvironment (TME). T-cells, critical for tumor clearance, take on a functionally exhausted phenotype. Importantly, two exhaustion states, progenitor (Tpe) and terminal (Tte), have been identified in models of chronic infection and cancer. This distinction is particularly relevant, as Tpe can remain responsive to immune checkpoint blockade (ICB), while Tte cannot. To date, the dynamics and characteristics of these exhausted populations in primary tumors and brain metastases remain unclear. Using intracranially implanted murine models of GBM (CT2A) and metastatic melanoma (B16F10), Tpe and Tte were identified by flow cytometry as PD1+SLAMF6+ and PD1+TIM3+, respectively. Functional differences between subsets were evaluated via intracellular staining of IFNγ, TNFα, IL2, CD107a, and Ki67. To determine the role of antigen, we performed adoptive lymphocyte transfers of tumor-specific and non-tumor-specific transgenic T-cells into a TRP2 or OVA overexpressing intracranial CT2A or B16 tumor, respectively. Tte displayed higher cytotoxic molecule expression than Tte, consistent with chronic infection models. Key exhaustion-associated transcription factors were identified in exhaustion subsets, including Tox, Tcf7, T-bet, and Eomes. Tox and Tcf7 expression identified Tpe within tumor-draining lymph nodes, suggesting a potential origin outside of the tumor, and the capacity for rescued function. We observed a decline in the Tpe population over time, with an associated rise in Tte within both tumor types. Notably, the ratio of Tpe to Tte was higher at all time points in B16F10 compared to CT2A. Tte appeared only in tumor-specific T-cells of the TME, further confirming the tumor-antigen dependence of T cell exhaustion. Tpe may arise outside the TME in tumor-specific T-cells. Further study may reveal a means and time window for rescuing T-cell function with ICB for brain tumors.
BSCI-17 TOPIRAMATE DECREASES RADIATION-INDUCED CYTOTOXIC EDEMA IN HER2+ BRAIN METASTASES VIA AQUAPORIN 4 INHIBITION
Authors: Contreras-Zárate Maria J , Alvarez-Eraso Karen , Littrell Zachary , Kwak Gina , Ormond Ryan , Karam Sana D , Kabos Peter , Cittelly Diana 
Published: August 2022

Abstract
Brain metastasis (BM) occurs in 30-40 % of breast cancer patients with Her2+ tumors, and radiation is part of the standard treatment for BM. About 10% of BM patients treated with radiation develop brain edema. We have shown that combination of Ado-trastuzumab Emtansine (T-DM1)-the main targeted therapy for metastatic Her2+ Breast Cancer- and radiation increases the risk of developing radionecrosis by 13.5-fold (Stump et al., 2019). We also showed that T-DM1 enhances radiation-induced astrocytic toxicity and cytotoxic edema through upregulation of aquaporin-4 water-transporter (AQP4). Here, we determined whether blockage of AQP4 would prevent astrocytic swelling –cytotoxic edema- in vitro and in vivo models of Her2+ BM. Results: Electron microscopy of brain cortex from mice treated with 35 Gy (single dose), showed acute astrocytic end-feet swelling and a significant increase in AQP4 expression compared with non-irradiated mice. Consistent with prior findings in murine astrocytes, primary human astrocytes (huAST) also upregulated AQP4 levels 24 h post-radiation (8 Gy), and T-DM1 treatment exacerbated this effect. AQP4 upregulation was concomitant with 4.8 fold increase in the astrocytic area (indicative of cytotoxic edema). The FDA-approved anti-epileptic and migraine prevention drug, Topiramate (TPM), which works as an AQP4 inhibitor, blocked radiation-induced astrocytic swelling in huAST in vitro. Thus, we tested whether pre-treatment with TPM could prevent radiation-induced edema in a mouse model of HER2+BMs. Mice were injected intracardially JmT1BR3 brain metastatic cells and ten days later randomized based on the total head flux to (1) Radiation + vehicle, (2) Radiation + TPM (2 days prior to irradiation), (3) Non-Radiation + vehicle, and (4) Non-radiation + TPM. TPM decreased brain-water content (a marker of brain edema) in irradiated mice as compared with vehicle-treated mice, without alteration of metastatic burden 21 days post-injection. These results suggest TPM could be repurposed as a preventive agent of radiation-induced brain edema.
BSCI-18 ESTROGEN-DEPLETION DECREASES PROGRESSION OF ER¯ BRAIN METASTASES BY PROMOTING AN ANTI-TUMORAL LOCAL IMMUNE RESPONSE
Authors: Contreras-Zarate Maria , Alvarez-Eraso Karen , Littrell Zachary , Tsuji Nicole , Karam Sana , Ormond D Ryan , Kabos Peter , Cittelly Diana 
Published: August 2022

Abstract
We have shown that 17-β-Estradiol (E2) promotes brain metastasis (BM) of estrogen receptor negative (ER¯) BC cells by inducing neuroinflammatory ER+ astrocytes in the brain niche to secrete pro-metastatic factors critical for early brain colonization. E2-depletion prevented brain colonization of human xenografts (MDA231BR/NSG) and syngeneic (E0711/C57Bl6, 4T1/Balb-c) ER¯ models. Yet, whether E2-depletion can be used to decrease progression of established BM and how E2-dependent modulation of brain immune response contributes to the pro-metastatic effects of E2 remains unclear. To assess whether E2-depletion could decrease BM progression in a model that mimics standard of care for BM, E0771-GFP-luc cells were injected intracardially in syngeneic ovariectomized (OVX)-female C57Bl6 mice supplemented with E2. Seven days after injection (when micrometastases are established), mice received a single 15Gy dose brain irradiation and were randomized to continue receiving E2, E2 withdrawal (E2WD) or E2WD plus the aromatase-inhibitor letrozole (EWD+LET). Endpoint BM (but not systemic metastases) were significantly decreased in E2WD+Letrozole treated mice as compared to E2-treated mice. This effect was abolished when E0711 cells were injected in severely immunocompromised NSG mice or in the absence of brain irradiation, suggesting EWD+LET decreases BM progression through boosting radiation-induced anti-tumor immunity. Accordingly, there were no differences in BM progression in E2, EWD or E2WD+let treated mice in a xenograft model (F2-7 TNBC cells) in NSG mice, even in the presence of brain irradiation. Brain immune-profiling of brain irradiated E2, EWD and EWD+Let C57BL6 mice carrying E0771 BMs shows that brains of EWD+LET-treated mice had a significantly lower fraction of CD4 T cells and an increase in CD8 T cells, suggesting that EWD+letrozole decrease brain metastatic burden in part through modulation of T cells. These results suggest E2-depletion therapies could be used in combination with brain irradiation to decrease progression of BMs and promote an anti-tumoral immune response.
BSCI-21 COX4I1 EXPRESSION IN BRAIN METASTASES
Authors: Saad Mahak , Jones Karra , Loeffler Bradley , Mott Sarah , Griguer Corinne , Monga Varun 
Published: August 2022

Abstract

BACKGROUND
COX4I1 (Cytochrome C oxidase, subunit 4, isoform 1) is a mitochondrial enzyme involved in the process of switching from glycolysis to oxidative phosphorylation. A previously published prospective biomarker study in glioblastoma cells found that Cytochrome C oxidase (CcO) activity was associated with resistance to treatment with both radiation and temozolomide (TMZ). The current study was designed to retrospectively assess COX4I1 expression in brain metastases from various primary cancers.

METHODS
This single-institution, blinded, retrospective biomarker study evaluated 24 patients with paired brain metastases and primary cancers including lung cancer, malignant melanoma, breast cancer, colorectal cancer, renal cell carcinoma, and urothelial carcinoma. COX4I1 immunohistochemical expression in primary and metastatic samples was assessed using the H-score method. A paired t-test was used to assess the difference in total H-score between primary and brain metastasis tissue samples. Cox regression was used to assess the association between COX4I1 expression and overall survival (OS). For OS, time was calculated from metastatic tissue sample retrieval to death due to any cause.

RESULTS
Brain metastasis tissue samples were found to have a significantly lower total H-score, on average, when compared to primary cancer tissue samples (p=0.01, mean difference of -33.3). 83.3% of tissue samples from metastases were not radiated. 58.3% of patients were on systemic treatment 6 months prior to tumor resection of brain metastases. COX4I1 expression was not associated with overall survival.

CONCLUSIONS
There is significantly increased COX4I1 expression in primary cancers as compared to brain metastases. Anti-cytochrome C oxidase therapies may be beneficial for treatment of primary tumors. No patient or treatment variables were significantly associated with overall survival in paired patients.

KEYWORDS
COX4I1, cytochrome c oxidase, brain metastases
BSCI-22 DETERMINING THE EFFECT OF NOVEL SMALL MOLECULE DRUGS AGAINST THE MIGRATION OF BRAIN METASTASIS INITIATING CELLS (BMICS)
Authors: Mobilio Daniel , Kieliszek Agata , Chafe Shawn , Venugopal Chitra , Singh Sheila 
Published: August 2022

Abstract

BACKGROUND
Brain metastases are secondary tumors that predominantly arise from the spread of lung, skin, and breast cancers. The current standard of care for brain metastases is complete surgical resection, with a median survival of four months. Therefore, there is a dire need to discover new therapies that effectively target brain metastases. To do this, we have identified anti-brain metastasis drugs that specifically target brain metastasis initiating cells (BMICs), a cancer stem cell population that is thought to escape standard therapies and has the ability to leave their primary tumor, seed the brain, and form a secondary brain tumor. Since the migration of the BMICs is essential to the development of brain metastases in patients, the main goal of this study was to determine the effect our anti-brain metastasis drugs have against the migration of lung, skin, and breast BMICs.

METHODS
This migration assay utilizes a bi-well silicone structure which effectively establishes a ‘wound’ healing-like migration assay. BMICs are plated in optimized equal concentrations in each silicone bi-well structure to successfully form two cellular mono-layers that are separated by a middle silicone wall. Once cells adhere to the plate the silicone structure is removed and the area between the two cell populations is imaged over time with an in vitro imaging system.

RESULTS
This optimized assay has been used to screen our anti-brain metastasis drugs against the migration of lung, breast, and skin BMICs. Thus far our drugs have been tested against lung and skin BMICs which resulted in a significant decrease in BMIC migration.

SIGNIFICANCE
Since brain metastasis arises from the migration of cancer cells to a secondary organ, it is crucial to discover the effect of anti-brain metastasis drugs on BMIC migration prior to the initiation of preclinical animal trials.
CLRM-08 TARGETING IMMUNE-PAYLOAD TO THE GLIOBLASTOMA TUMOR MICROENVIRONMENT USING A MACROPHAGE-BASED TREATMENT RELYING ON AUTOLOGOUS, GENETICALLY MODIFIED, HEMATOPOIETIC STEM CELL-BASED THERAPY: THE TEM-GBM STUDY (NCT03866109)
Authors: Eoli Marica , Farina Francesca , Gentner Bernhard , Capotondo Alessia , Anghileri Elena , Barcella Matteo , Brambilla Valentina , Bruzzone Maria Grazia , Carrabba Matteo , Cuccarini Valeria , d’Alessandris Giorgio , Meco Francesco Di , Ferla Valeria , Franzin Alberto , Ferroli Paolo , Gagliardi Filippo , Legnani Federico , Mazzoleni Stefania , Mortini Pietro , Naldini Matteo Maria , Olivi Alessandro , Pallini Roberto , Patanè Monica , Paterra Rosina , Pollo Bianca , Saini Massimo , Snider Silvia , Naldini Luigi , Russo Carlo , Finocchiaro Gaetano , Ciceri Fabio 
Published: August 2022

Abstract
We developed an autologous hematopoietic stem cell-based platform designed to deliver IFNa, by a transcriptional and post-transcriptional control mechanism mediated by miRNA target sequences, specifically into the tumor microenvironment (TME) via Tie-2 expressing monocytes (Temferon). As of Feb 2022, 3 escalating doses of Temferon (0.5-2.0x106/kg) were tested across 15 newly diagnosed, unmethylated MGMT GBM patients assigned to 5 cohorts. Follow-up from surgery is 6–28mo (2–25mo after Temferon). To date, no DLTs have been identified. As expected, 1mo after the administration of the highest tested dose, the hematopoietic system of Temferon-treated patients was composed of up to 30% of CD14+ modified cells. Temferon-derived progeny persisted, albeit at lower levels, up to 18mo (longest time of analysis). Despite the substantial proportion of engineered cells, very low concentrations of IFNα were detected in the plasma and in the CSF, indicating tight regulation of transgene expression. SAEs were mostly attributed to conditioning chemotherapy (infections) or disease progression (seizures). 1SUSAR (persistent GGT elevation) occurred. Median OS is 15mo from surgery. Homing of transduced cells to the tumor was demonstrated by the presence of gene-marked cells in the 2nd surgery specimens of 3 out 4 pts belonging to low dose cohorts. Single-cell RNA seq of the TME highlighted a Temferon signature associated with the induction IFNa responsive genes and macrophage repolarization. Potential long-term benefit with Temferon was identified in a patient from cohort 3, who had PD at D+120 with two distant enhancing lesions, and increased tumor necrosis. 1y following Temferon, with no 2nd-line therapy added, there was approximately 40% reduction in enhancing tumor volume compared to D+180 with a stable clinical and imaging picture thereafter. The results provide initial evidence of Temferon’s potential to modulate the TME of GBM patients, and anecdotal evidence for long lasting effects of Temferon in prevention of disease progression.
CLRM-14 INTRATUMORAL EXTRACELLULAR METABOLIC IMPACT OF DFMO AND AMXT 1501 IN LIVE HUMAN GLIOMAS
Authors: Riviere-Cazaux Cecile , Neth Bryan , Rahman Masum , Kizilbash Sani , Burns Terry 
Published: August 2022

Abstract
Gliomas may leverage alternate metabolic pathways in response to metabolism-targeted therapeutic intervention, all of which remain unexplored in the live human glioma, in situ. Defining emergent mechanisms of metabolic resistance in response to therapeutic challenge can help guide rational combinatorial therapies. To date, the metabolic response of gliomas in response to therapeutic intervention has remained poorly understood due to the relative inaccessibility of the live human tumor, in situ. Microdialysis is an underutilized tool that could be leveraged to overcome this longstanding challenge. Data from our ongoing intraoperative microdialysis trial have revealed an upregulation of polyamine metabolism and a novel glioma-associated metabolite, guanidinoacetate (GAA) -- a metabolite co-produced with ornithine, which is required for polyamine synthesis. In a Phase 0 trial, we will evaluate in situ glioma responses to polyamine depletion (difluoromethylornithine, DFMO) with or without blockade of polyamine uptake (AMXT 1501) to identify candidate extracellular biomarkers of target engagement and cytotoxicity in fifteen post-operative patients who have undergone a standard-of-care planned subtotal resection for high-grade glioma. Intraoperatively, high-molecular-weight catheters will be implanted into the residual tumor and brain adjacent to the resection cavity for post-operative longitudinal monitoring of extracellular metabolites via microdialysis. Polyamines and guanidinoacetate, a candidate biomarker of glioma-upregulated polyamine synthesis, will be monitored throughout therapeutic intervention from post-operative day (POD) 1 to POD5 via longitudinal microdialysis to determine live in situ glioma pharmacodynamic responses to polyamine depletion. Catheters will be removed on post-operative day five prior to discharge. We hypothesize that GAA will reflect local tumor production of polyamine metabolism. Additionally, in situ microdialysis in Phase 0 trials will allow for pharmacodynamic and pharmacokinetic, in addition to metabolic, monitoring, an opportunity which is rarely afforded in most clinical trials due to lack of access to the CNS.
CLRM-15 TRIAL IN PROGRESS: A PHASE 1B/2 STUDY OF GB5121, A NOVEL, HIGHLY SELECTIVE, POTENT, AND CNS-PENETRANT INHIBITOR OF BRUTON’S TYROSINE KINASE (BTKI) FOR RELAPSED/REFRACTORY PRIMARY/SECONDARY CNS LYMPHOMA (R/R PCNSL/SCNSL) AND PRIMARY VITREORETINAL LYMPHOMA (PVRL)
Authors: Soussain Carole , Grommes Christian , Issa Samar , Ward Renee , Peterson Caryn , Cravets Matt , Mathias Anita , Sosa Judith , Kirby Brian , Ding Zhaoqing , Yusuf Isharat , Rose Mark , Steinberg Marcos , Tun Han W 
Published: August 2022

Abstract
BTK plays an important role in B cell receptor and Toll-like receptor signaling pathways, which are constitutively active in primary CNS lymphomas, and hence represents an excellent therapeutic target. Ibrutinib, a first-generation BTKi, was evaluated in phase 1/2 trials for R/R PCNSL, SCNSL, and PVRL, showing limited survival benefit. GB5121 is a novel, orally available, covalent BTKi with superior specificity, CNS penetration, and CNS target occupancy in preclinical testing versus other BTKis including ibrutinib. GB5121 is well-suited for evaluation in CNS lymphoma. This is a phase 1b/2 open-label study of GB5121 in adults with R/R PCNSL, isolated SCNSL or PVRL and will be conducted in three parts: phase 1b dose-escalation, expansion, and phase 2. Eligibility criteria for phase 1b dose-escalation and expansion (N≈30 for each) include age ≥18 years, ECOG≤2, R/R PCNSL, R/R SCNSL with CNS-only relapse, or R/R PVRL. Patients with newly diagnosed PCNSL who cannot tolerate standard high-dose methotrexate-based therapies are also eligible. Patients with prior allogeneic stem cell transplant are excluded. A Bayesian optimal interval design will be employed to perform dose escalation to determine the recommended phase 2 dose (RP2D). In the absence of dose-limiting toxicity (DLT), dose levels will increase sequentially according to a modified Fibonacci approach. Safety, tolerability, PK/PD, DLT, maximum tolerated dose, and preliminary therapeutic activity will be assessed to determine the optimal biological dose informing the RP2D. Phase 1b expansion will further explore therapeutic activity and characterize safety and tolerability of GB5121 at the RP2D. Phase 2 will initiate following RP2D determination. This is a single-arm, open-label study to investigate GB5121 safety and efficacy in patients with R/R PCNSL. Adverse events will be graded per CTCAE v5.0. Clinical response will be determined using International Primary CNS Lymphoma Collaborative Group criteria. Progression-free and overall survival will be evaluated. Enrollment begins May 2022 (NCT05242146).
CLRM-16 PATIENT-FOCUSED DRUG DEVELOPMENT IN NEURO-ONCOLOGY: A PILOT STUDY OF QUALITATIVE PATIENT INTERVIEWS EMBEDDED WITHIN A NEUROFIBROMATOSIS 2 CLINICAL TRIAL
Authors: Merker Vanessa , Von Imhof Liesel , Park Elyse , Babovic-Vuksanovic Dusica , NghiemPhu PhiOanh [Leia] , Yohay Kaleb , Plotkin Scott 
Published: August 2022

Abstract

BACKGROUND
The Food and Drug Administration recently issued guidance on conducting qualitative research to support patient-focused drug development. In prior FDA submissions, qualitative data has been critical to demonstrate the content validity of and meaningfulness of change in quantitative trial endpoints. Qualitative patient interviews embedded within neuro-oncology trials can supplement traditional quantitative measures by providing nuanced information on patients’ treatment priorities, benefit/risk assessments, and quality of life.

METHODS
We interviewed people with neurofibromatosis 2 (NF2) in stage one of the brigatinib arm of a multicenter, phase II, adaptive platform-basket trial for progressive NF2-related tumors (NCT04374305). Transcripts were coded by two analysts using a hybrid inductive/deductive framework; cross-cutting themes were generated using the Framework Method.

RESULTS
16/20 trial enrollees participated in interviews May 2021-March 2022. The radiographic response rate (volume shrinkage ≥20% from baseline) at 6 months for target and non-target tumors was 5% and 22%, respectively. However, most participants rated their change in overall status as minimally (10/16) or much (3/16) improved. Several participants acknowledged their tumor size had not changed significantly but felt tumor stability was an improvement over previously accelerated growth rates; this importantly allowed them to avoid or postpone future surgery. Participants also valued prevention of symptomatic decline, minimal impact of side effects on social roles and activities, the convenience of oral medication, and the sense of hope and agency gained from participating in a trial.

CONCLUSIONS
Virtual, in-depth qualitative interviews were feasible across multiple sites and provided unique information on NF2 patients’ conceptualization of clinical benefit. Qualitative interviews embedded within neuro-oncology trials can reveal 1) whether trial design and choice of outcome measures align with patient priorities; 2) whether and how new treatments improve patients’ quality of life; and 3) what degree of change in quantitative measures such as radiographic progression are clinically meaningful.
CLRM-17 USE OF EXTERNAL CONTROL DATA FOR PLANNING AND ANALYZING GBM TRIALS: READY FOR PRIME TIME?
Authors: Polley Mei-Yin , Schwartz Daniel , Dignam James 
Published: August 2022

Abstract
Randomized controlled trials (RCT) have been the gold standard for evaluating medical treatments for many decades. Randomization reduces systematic biases resulting from treatment or patient selection, whereby the improvement in clinical outcomes may be attributed to the experimental therapy under study. However, RCTs are often criticized for requiring large sample sizes and taking a long time to complete. For newly diagnosed glioblastoma (GBM), the clinical trial landscape has seen little progress since the establishment of the standard of care (SOC) by Stupp. Given the urgent need for better therapies, it has been argued that data collected from patients treated with the SOC from past GBM trials can provide high-quality external control data to supplement concurrent control arm in future trials, thereby increasing drug development efficiency by reducing the number of patients treated with SOC. Herein we consider a new design approach that leverages historical control data in the design and analysis of phase 3 GBM trials. At the first stage, patients are randomized with an equal probability to standard (concurrent control) arm and experimental arm. An interim analysis entails an outcome comparison between the concurrent and external control arms. If comparability is established, the external control data are carried forward to be combined with concurrent control data at the second stage where the randomization ratio is adapted to favor the experimental therapy, thereby reducing the number of patients treated in the concurrent control arm. Using completed phase 3 GBM trials, we elucidate the potential gain in design efficiency and draw caution to scenarios where it may fall short on meeting statistical criteria. We highlight practical challenges in its implementation and conclude that the new method is not ready for definitive phase 3 GBM studies at the current time. This work represents a critical appraisal of this new concept in GBM.