bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSIG-31. MULTI-OMICS TO EDGE INTO PRECISION MEDICINE FOR DIPG
Authors: Tang Nanyun , Leskoske Kristin , Garcia-Mansfield Krystine , Sharma Ritin , Tolson Hannah , Pirrotte Patrick , Berens Michael 
Published: November 2021

Abstract
DIPG is an incurable pediatric brain tumor with 80% of patients harboring H3F3A (H3.3) mutation that substitutes methionine for lysine at position 27 (K27M), resulting in global depletion of H3.3K27 me3 (trimethylation). These histone mutations modify the epigenome and alter oncogenic transcription, causing oncogenic insults to progenitor cells in early neurodevelopment (1). To determine the reprogramming pathways in the cell context of H3.3K27M tumors, we conducted LC-MS based proteomic and phosphoproteomic analysis on seven patient-derived DIPG cell lines. Three normal neuronal stem cell lines were included as non-tumor brain cells for comparison. Pathway analysis identified 29 pathways that are significantly altered in DIPG compared to normal brain cells at both the protein abundance and phosphosite level. Notably, AKT and MAPK associated PI3K signaling, VEGF signaling, mTOR signaling, and HIF1a signaling were differentially active in H3.3K27M tumors compared to healthy control cell lines. We saw significantly higher activity of multiple kinases involved in axon guidance and cytoskeletal remodeling in DIPG, such as PTK2B, DYRK2, TTBK2 and MARK2. This is the first time to report an increased abundance and kinase activity of PYK2 protein (coded by PTK2B), a close homologue of FAK and its associated signaling in DIPG. PYK2 has been proposed to act in concert with Src to link Gi- or Gq-coupled receptors with the mitogen-activated protein (MAP) kinase signaling pathway (2). Because of the shared signaling across kinase pathways, targeting activated PYK2 in DIPG may complement inhibitors of other dysregulated signaling networks in DIPG such as MAPK2, VEGFR, PI3K and Src. Our data also found that IL13RA2 was upregulated in DIPG. We conclude that for H3 K27M DIPG tumors, campaigns to target PYK2, MAPK2, VEGFR, PI3K, Src and IL13Ra2 using small molecules that traverse the blood brain barrier loom as promising opportunities for drug development.
CSIG-32. microRNA 211, A POTENTIAL THERAPEUTIC AGENT FOR GROUP 3 MEDULLOBLASTOMA IN CHILDREN
Authors: Katsushima Keisuke , Lee Bongyong , Yuan Menglang , Kunhiraman Haritha , Stapleton Stacie , Jallo George , Raabe Eric , Eberhart Charles , Perera Ranjan 
Published: November 2021

Abstract
Medulloblastoma (MB) is a central nervous system (CNS) tumor that predominantly affects children and requires aggressive therapy. Affected individuals often suffer from treatment-related side-effects and treatment-resistant recurrences associated with high morbidity and mortality rates. There are four major molecular MB subgroups: wingless-type (Wnt)-activated, sonic hedgehog (Shh)-activated, group III (G3), and group IV (G4) MBs. While the molecular pathology of Wnt- and Shh-activated MBs is well defined, rather less is known about G3 and G4 MB's genetic basis, so their molecular diagnosis and consequent management have remained challenging. MBs develop through various genetic, epigenetic, and non-coding (nc)RNA-related mechanisms, with the role of ncRNAs, particularly microRNAs, in MB tumor growth is poorly defined. We addressed this knowledge gap with an exemplar of microRNA-211 (miR-211) implicated in G3 MB tumor growth. Compared to other MB subgroups, miR-211 is significantly downregulated in G3 MB cell lines, underscoring its important role as a therapeutic agent and a biomarker. miR-211 overexpression in G3 MB cells significantly reduced cell proliferation, invasion, 3D colony formation, and induced apoptosis. Oxygen consumption rates are higher in engineered cells, and we postulate that miR-211 is involved in G3 MB mitochondrial energy metabolism. miR-211 expressed G3 MB cells injected into mouse cerebella produce smaller tumors than those derived from parental cells. We applied single-cell RNA sequencing and immune histochemical assays to characterize tumors to identify the molecular mechanism of miR-211- driven tumor reduction in G3 MBs, and our preliminary results support that miR-211 is an attractive therapeutic agent to treat this aggressive MB subtype.
RADT-07. DETERMINATION OF THE OPTIMAL TIME INTERVAL BETWEEN POST-OPERATIVE MRI AND CT SIMULATION FOR STEREOTACTIC RADIOSURGERY PLANNING
Authors: Panse Drishti , Rogers Aubrey , Farhangi Edward , Péris-Celda Maria , Adil Khaled 
Published: November 2021

Abstract

BACKGROUND
The incidence of brain metastasis is approximately 200,000 worldwide annually. Stereotactic radiation therapy of post-operative cavity reduces local recurrence. Surgical cavity size changes significantly with 96.5% demonstrating volumetric change during post-operative period. We sought to define the optimal time interval that preserved the volumetric dimensions between the post-surgical MRI and the CT simulation used for stereotactic radiosurgery planning.

METHODS
Seven patients with brain metastasis that underwent surgical resection and stereotactic radiation treatment at Albany Medical Center from February 2019 to April 2020 were included in the study. A total of 8 target lesions were included. Brain lab planning system was used for contouring the target volume. A postoperative MRI within 24-48 hours after surgery was obtained. 3 patients required an additional interim MRI 16-50 days after surgery. The planning CT simulation was performed 2 days prior and up to 15 days after the post-operative/interim MRI and target volumes were compared.

RESULTS
The average volume of the post-surgical cavity contoured by the neurosurgeons on the post-operative/interim MRI was 15.96 cc (± 7.79 cc, range of 6.54 -24.9 cc). The average volume of the post-surgical cavity contoured by the radiation oncologists on the planning CT was 15.71 (± 7.49 cc, range of 6.53 -24.31 cc). There was no noticeable change in volume size between post-operative/interim MRI and planning CT up to the period of 15 days.

LIMITATION
This was a retrospective pilot study with a small sample size and patients recruited from a single center.

CONCLUSION
There is no change in size of the cavity volume for up to 15 days between post-operative/interim MRI and planning CT. This knowledge will help understand the optimal time interval between post-operative MRI and CT simulation for the stereotactic radiation therapy planning.
RADT-26. PROTON VERSUS PHOTON CRANIOSPINAL IRRADIATION FOR ADULT MEDULLOBLASTOMA: A DOSIMETRIC AND TOXICITY ANALYSIS
Authors: Breen William , Geno Connie , Harmsen William , Brown Paul , Waddle Mark , Qian Jing , Burns Terence , Ruff Michael , Neth Bryan , Yan Elizabeth , Laack Nadia , Mahajan Anita 
Published: November 2021

Abstract
Medulloblastoma is a posterior fossa tumor rarely diagnosed in adults. Treatment includes craniospinal irradiation (CSI). Proton CSI is increasingly utilized to decrease radiation dose to normal tissues, despite the lack of randomized data demonstrating decreased toxicity compared to photon CSI. This single institution retrospective study of 39 adult medulloblastoma patients includes nineteen patients treated with photon CSI prior to 2015, and twenty treated with proton CSI thereafter. Median age was 28 years (range 18-66). Molecular subtype was most commonly sonic hedgehog (68%). The most common fractionation schedule was 36 Gy CSI in 20 fractions (85% of photon and 58% of proton patients) with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to the cochleae (median 32 Gy vs. 44 Gy), lacrimal glands (8 vs. 36 Gy), lens (2 vs. 28 Gy), parotid glands (3 vs. 26 Gy), pharyngeal constrictors (6 vs. 15 Gy), esophagus (2 vs. 29 Gy), heart (0 vs. 14 Gy), lungs (1 vs. 7 Gy), liver (0.1 vs. 7 Gy), and skin (38 vs. 51 Gy) (all p&lt; 0.001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% vs. 35%, p= 0.044) and decreased median weight loss during radiation (+1.0 vs. -2.8 kg, p= 0.011). Acute hospitalization was associated with increased weight loss (p= 0.009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At last follow-up five photon patients had died (two of progressive disease, three without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. In conclusion, this study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.
RADT-30. MULTISESSION RADIOSURGERY ALONE FOR TREATMENT OF PRESUMED MENINGIOMAS: AN INTERIM REPORT FROM A SINGLE INSTITUTION PROTOCOL
Authors: Carrasquilla Michael , Tai Alexander , Forsthoefel Matthew , Wang Edina , Lei Siyuan , Campbell Lloyd , Suy Simeng , Harris Breant , Azumi Norio , Berkowitz Frank , Voyadzis Jean-Marc , Kalhorn Christopher , Jean Walter , McGrail Kevin , Collins Sean , Collins Brian 
Published: November 2021

Abstract

PURPOSE
Meningiomas are the most commonly diagnosed primary intracranial tumor. Resection and single-fraction radiosurgery are treatment options with well-established long-term outcomes data. Multisession radiosurgery is an alternative treatment option with promising early results. However, mature outcomes literature does not yet exist. In this study, we report our institution’s interim results on the efficacy and safety of 5-fraction radiosurgery alone for radiographically diagnosed meningiomas.

MATERIALS AND METHODS
Between 2005-2015 all patients who completed treatment on a single institution protocol utilizing 5-fraction robotic radiosurgery alone for the treatment of progressing radiographically diagnosed meningiomas were eligible for inclusion. Local control was calculated using the Kaplan-Meier Method.

RESULTS
Forty-four consecutive predominately female patients (84%) ranging in age from 33-85 (median: 59) were included in the present study. Median tumor volume was 4.05mm3 (range: 0.94-15.4mm3) and the majority of tumors were located at the base of skull (66%). A median dose of 25Gy (range: 25Gy-35Gy), was delivered to a median isodose line of 82%, (range: 70%-90%) over a median of 7 days (range: 5-11 days). Acute toxicity was minimal with 7 patients (15%) requiring a short course of steroids for symptomatic edema during treatment. Of 16 patients who presented with a cranial nerve deficit, symptom improvement was noted in 11 patients (69%). No permanent treatment related toxicity was noted in our cohort. The median radiographic follow-up was 6.9 years (range: 0.5-14.8 years). The 5 and 8-year local control rates were 100% and 95%. The median time to local failure (n=2) in our cohort was 8.2 years.

CONCLUSIONS
The treatment of radiographically diagnosed meningiomas with 5-fraction robotic radiosurgery provides excellent local control to date, with low rates of acute and late toxicity. However, with late failures noted in our series, continued follow-up is needed to determine the optimal dose required for long-term tumor control.
CTIM-03. AUTOLOGOUS ADOPTIVE IMMUNE-CELL THERAPY ELICITED A DURABLE RESPONSE WITH ENHANCED IMMUNE REACTION SIGNATURES IN PATIENTS WITH RECURRENT GLIOBLASTOMA: AN OPEN LABEL, PHASE I/IIA TRIAL
Authors: Lim Jaejoon , Park Young Joon , Ahn Ju Won , Sim Jeong Min , Kim Suwan , Hwang Sojung , Sung Kyungsu , Cho Kyunggi 
Published: November 2021

Abstract
Glioblastoma multiforme (GBM) is an aggressive malignancy classified by the World Health Organization as a grade IV glioma. Despite the availability of aggressive standard therapies, most patients experience recurrence, for which there are currently no effective treatments. We aimed to conduct a phase I/IIa clinical trial to investigate the safety and efficacy of adoptive, ex-vivo-expanded, and activated natural killer cells and T lymphocytes from peripheral blood mononuclear cells of patients with recurrent GBM. This study was a single-arm, open-label, investigator-initiated trial on 14 patients recruited between 2013 and 2017. The immune cells were administered via intravenous injection 24 times at 2-week intervals after surgical resection or biopsy. The safety and clinical efficacy of this therapy was examined by assessing adverse events and comparing 2-year overall survival (OS). Transcriptomic analysis of tumor tissues was performed using NanoString to identify the mechanism of therapeutic efficacy. No grade 4 or 5 severe adverse events were observed. The most common treatment-related adverse events were grade 1 or 2 in severity. The most severe adverse event was grade 3 fever. Median OS was 22.5 months, and the median progression-free survival was 10 months. Five patients were alive for over 2 years and showed durable response with enhanced immune reaction transcriptomic signatures without clinical decline until the last follow-up after completion of the therapy. In conclusion, autologous adoptive immune-cell therapy was safe and showed durable response in patients with enhanced immune reaction signatures. This therapy may be effective for recurrent GBM patients with high immune response in their tumor microenvironments. Trial registration: The Korea Clinical Research Information Service database: KCT0003815, Registered 18 April 2019, retrospectively registered.
CTIM-10. REPRODUCIBILITY OF CLINICAL TRIALS USING CMV-TARGETED DENDRITIC CELL VACCINES IN PATIENTS WITH GLIOBLASTOMA
Authors: Batich Kristen , Mitchell Duane , Healy Patrick , Herndon James , Broadwater Gloria , Michael Gunn , Huang Min-Nung , Hotchkiss Kelly , Sanchez-Perez Luis , Nair Smita , Congdon Kendra , Norberg Pam , Weinhold Kent , Archer Gary , Reap Elizabeth , Xie Weihua , Shipes Steven , Albrecht Emily , Peters Katherine , Randazzo Dina , Johnson Margaret , Landi Daniel , Desjardins Annick , Friedman Henry , Vlahovic Gordana , Reardon David , Vredenburgh James , Bigner Darell , Khasraw Mustafa , McLendon Roger , Thompson Eric , Cook Steven , Fecci Peter , Codd Patrick , Floyd Scott , Reitman Zachary , Kirkpatrick John , Friedman Allan , Ashley David M , Sampson John 
Published: November 2021

Abstract

INTRODUCTION
Vaccination with dendritic cells (DCs) fares poorly in primary and recurrent glioblastoma (GBM). Moreover, GBM vaccine trials are often underpowered due to limited sample size.

METHODS
To address these limitations, we conducted three sequential clinical trials utilizing Cytomegalovirus (CMV)-specific DC vaccines in patients with primary GBM. Autologous DCs were generated and electroporated with mRNA encoding for the CMV protein pp65. Serial vaccination was given throughout adjuvant temozolomide cycles, and 111Indium radiolabeling was implemented to assess migration efficiency of DC vaccines. Patients were followed for median overall survival (mOS) and OS.

RESULTS
Our initial study was the phase II ATTAC study (NCT00639639; total n=12) with 6 patients randomized to vaccine site preconditioning with tetanus-diphtheria (Td) toxoid. This led to an expanded cohort trial (ATTAC-GM; NCT00639639) of 11 patients receiving CMV DC vaccines containing granulocyte-macrophage colony-stimulating factor (GM-CSF). Follow-up data from ATTAC and ATTAC-GM revealed 5-year OS rates of 33.3% (mOS 38.3 months; CI95 17.5-undefined) and 36.4% (mOS 37.7 months; CI95 18.2-109.1), respectively. ATTAC additionally revealed a significant increase in DC migration to draining lymph nodes following Td preconditioning (P=0.049). Increased DC migration was associated with OS (Cox proportional hazards model, HR=0.820, P=0.023). Td-mediated increased migration has been recapitulated in our larger confirmatory trial ELEVATE (NCT02366728) of 43 patients randomized to preconditioning (Wilcoxon rank sum, Td n=24, unpulsed DC n=19; 24h, P=0.031 and 48h, P=0.0195). In ELEVATE, median follow-up of 42.2 months revealed significantly longer OS in patients randomized to Td (P=0.026). The 3-year OS for Td-treated patients in ELEVATE was 34% (CI95 19-63%) compared to 6% given unpulsed DCs (CI95 1-42%).

CONCLUSION
We report reproducibility of our findings across three sequential clinical trials using CMV pp65 DCs. Despite their small numbers, these successive trials demonstrate consistent survival outcomes, thus supporting the efficacy of CMV DC vaccine therapy in GBM.
CTIM-11. PHASE 2 STUDY OF SL-701, A NOVEL IMMUNOTHERAPY, IN ADULTS WITH RECURRENT GBM: A HIGH PARAMETER FLOW CYTOMETRY ANALYSIS OF CD8+ T CELLS AND POTENTIAL IMPLICATIONS FOR PATIENT ENRICHMENT STRATEGIES
Authors: Peereboom David , Lindsay Ross , Badruddoja Michael , Nabors L Burt , Kumthekar Priya , Lieberman Frank , Tran David , Phuphanich Surasak , Schiff David , Sherman Jonathan , Butowski Nicholas , Dunbar Erin , Fink Karen , Iwamoto Fabio , Moertel Christopher , Schulder Michael , Walbert Tobias , Habboubi Nassir , Grzegorzewski Krzysztof , Brooks Christopher , Reardon David 
Published: November 2021

Abstract
Treatment of glioblastoma (GBM) remains a critical challenge and unmet medical need due to limited treatment options. SL-701 is a novel immunotherapy comprised of synthetic peptides designed to elicit a target-specific anti-tumor immune response against the GBM antigens IL-13Rα2, ephrinA2, and survivin. A multicenter, 2-stage, phase 2 clinical trial (NCT02078648) that evaluated the safety and efficacy of SL-701 in 74 adults with recurrent GBM was previously reported. This report describes preliminary data to suggest a correlation of immunocompetence to clinical outcome. In stage 2 (SL-701 + bevacizumab + poly-ICLC) the overall survival at 12 months was 50%. Two of 28 patients enrolled in stage 2 achieved CR (duration of response: 7.8 and 8.8 months) and 2 achieved PR (duration of response: 7.9 and 8.8 months). In a preliminary analysis to assess CD8+ T-cell responses, long-term survivors were comprised largely of subjects with an SL-701-induced target-specific CD8+ T-cell response, indicating a potential correlation of immunocompetence to clinical outcome. By week 24, SL-701-induced target-specific CD8+ T cells expressing IFNg were detected in 8 of 27 patients (30%) who had sufficient samples, with co-expression of PD-1, TIM3, and LAG3 detected in 4 patients. To further understand the T-cell response to SL-701, deep sequencing of target-specific CD8+ T cells using whole transcriptome-based molecular cytometry and high parameter (25+ color) flow cytometry is currently underway and updated data will be reported.
CTIM-15. FIRST-IN-HUMAN PHASE 1 STUDY OF CD200 ACTIVATION RECEPTOR-LIGAND (CD200AR-L) AND ALLOGENEIC TUMOR LYSATE VACCINE IMMUNOTHERAPY FOR RECURRENT GLIOBLASTOMA: INITIAL RESULTS FROM AN ONGOING CLINICAL TRIAL
Authors: Neil Elizabeth , Eaton Anne , Lunn Shannon , Nelson Kristen , Greengard Emily , Moertel Christopher , Olin Michael 
Published: November 2021

Abstract

BACKGROUND
Poor efficacy and adverse events limit the use of immunotherapy in the treatment of glioblastoma. CD200AR-L, a novel immunotherapy targeting multiple checkpoints with a single peptide inhibitory ligand, activates the immune system by downregulating CD200-inhibitory receptor, PD-1/PD-L1, and CTLA-4.

METHODS
Single-center, first-in-human, dose-escalation phase 1 clinical trial (NCT04642937) utilizing a 3 + 3 design initiated accrual in 12/2020 at dose level-1; CD200AR-L 3.75micrograms/kg/dose administered on days 1 and 2 by intradermal injection after topical imiquimod. On day 2, a fixed dose of an allogeneic vaccine is also injected intradermally. Induction Phase consists of this injection series weekly for 4 weeks with monitoring for dose-limiting toxicity through day 28.

RESULTS
Between 12/2020 to 3/2021, 6 patients were enrolled on dose level-1; aged 37-65 years, 4 men, all with KPS &gt;/= 80, and 3 patients on daily dexamethasone (4mg (n=2), 2mg (n=1)). Five were at first recurrence, 1 at second and 5 had cancers MGMT-promoter unmethylated. All completed the 4 weeks of induction. One dose-limiting toxicity of a grade-III encephalopathy was observed. Non-dose-limiting grade-III toxicities included, lymphopenia (n=1) and immunotherapy-related intracranial edema (IrICE) (n=2). IrICE symptoms were temporarily mitigated with ‘bevacizumab rescue protocol.’ No patients had local injection site reactions. Three patients are off study for radiographic disease progression confirmed on pathology (n=1) and radiographic disease progression with progressive neurological decline (n=2). Completed investigational hematologic immune monitoring for 4/6 patients revealed, that between weeks 2 and 4 post-vaccination, evidence of immune stimulation with an increase in CD4/8 T-cells, natural killer, and natural killer T-cells. There was also a reduction in immunosuppressants noted by a decrease in PD-1/PD-L1 and CTLA-4 expression on CD4/8 T-cells, CD14, CD11c, and myeloid-derived suppressor cells.

CONCLUSION
Initial dosing of CD200AR-L was well tolerated with early positive signal of immunological effect. Enrollment continues, now at dose level-2; CD200AR-L at 5micrograms/kg/dose.
CTIM-24. RANDOMIZED TRIAL OF NEOADJUVANT VACCINATION WITH TUMOR-CELL LYSATE INDUCES T CELL RESPONSE IN LOW-GRADE GLIOMAS
Authors: Taylor Jennie , Ogino Hirokazu , Nejo Takahide , Gibson David , Watchmaker Payal , Okada Kaori , Saijo Atsuro , Tedesco Meghan , Shai Anny , Wong Cynthia , Rabbitt Jane , Olin Michael , Moertel Christopher , Nishioka Yasuhiko , Salazar Andres , Molinaro Annette , Phillips Joanna , Butowski Nicholas , Clarke Jennifer , Oberheim-Bush Nancy Ann , Hervey-Jumper Shawn , Theodosopoulos Philip , Chang Susan , Berger Mitchel , Okada Hideho 
Published: November 2021

Abstract

BACKGROUND
The prognosis of WHO grade II low-grade gliomas (LGG) is varied with potential for long survival.Given their relatively intact immune system and slow growth rate, vaccines are an attractive treatment strategy for LGG in an attempt to defer more toxic treatments. The goals of this pilot study were to evaluate safety and immunological effects of vaccination with GBM6-AD, an allogeneic glioblastoma stem cell line lysate, with poly-ICLC in LGG.

METHODS
Eligible patients were ≥ 18 years old, ≥ 70 KPS, with recurrent LGG or imaging consistent with LGG, and amenable to resection. Patients were randomized to vaccine prior to surgery (Arm 1) or not (Arm 2) and all received adjuvant vaccine. Co-primary outcomes were safety and immune response in the tumor, with exploratory outcomes of survival and immunologic effects in peripheral blood.

RESULTS
A total of 17 eligible patients were evaluable – nine into Arm 1 and eight into Arm 2. Median age was 33 years, with median time from initial diagnosis of 4.7 years (0 – 20). Two patients (11.8%) previously received radiotherapy and seven (41.2%) prior systemic therapy. No dose limiting toxicities or grade 3 AEs were observed. Neoadjuvant vaccination induced up regulation of type-1 cytokines and chemokines in peripheral blood, and CD8+ T cell clones that reacted to the vaccine were also detected in the tumor. Median follow-up time from first post-operative vaccine was 20.8 months with median PFS of 11.0 months and time to change in therapy of 23.7 months. Of the six patients to receive additional treatment, three had second surgery only one confirming malignant progression to anaplastic oligodendroglioma.

CONCLUSION
Treatment was well-tolerated with no regimen-limiting toxicity. GBM6-AD plus poly-ICLC induced effector CD8+ T cell response in peripheral blood and enables some vaccine-reactive CD8+ T cells to migrate into the TME. Further investigation is warranted.