bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTIM-06. EVALUATING THE ASSOCIATION BETWEEN PERIPHERAL BLOOD IMMUNOLOGIC RESPONSE AND THERAPEUTIC RESPONSE TO IMMUNE CHECKPOINT INHIBITION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA AND GLIOSARCOMA
Authors: Watowich Matthew , Yaghi Nasser , Briceno Nicole , Ahn Susie , Wall Kathleen , Evans Karen , Polskin Lily , Komlodi-Pasztor Edina , Sahebjam Solmaz , Watanabe Masashi , Gilbert Mark 
Published: November 2022

Abstract
Immune checkpoint inhibition (ICI) has failed to demonstrate significant efficacy in glioblastoma. With the underlying hypothesis that generation of an immune response in peripheral is necessary for a brain tumor response, we are enrolling patients with newly diagnosed glioblastoma on an ICI immunotherapy clinical trial with longitudinal monitoring of immune function. The purpose of this work is to improve patient selectivity for response to ICI treatment by identifying peripheral immunologic response via immunophenotyping and functional analyses. Currently, 10 of a planned 48 patients have been treated with combination nivolumab and ipilimumab (NCI-21-C-0015). We analyzed blood samples of the first two patients, from pretreatment through cycle 5 of combination ICI to confirm methods used in this clinical trial. Longitudinal evaluation of immunologic response using comprehensive flow cytometric analysis and an in vitro T cell stimulation paradigm with nivolumab and ipilimumab supplementation, serving as an ex vivo predictor of immune response, are reported. Immunophenotyping via flow cytometry successfully documented patients’ peripheral immune cell phenotypes, and ELISpot and in vitro stimulation assays successfully measured patients’ immune cell functional capacitance. Both patients analyzed have shown increased proportions of effector/memory phenotypes within peripheral T cells, and a decrease in peripheral lymphocyte/monocyte ratio during treatment, potentially indicating lymphocyte sequestration in bone marrow or recruitment to the tumor microenvironment. ELISpot analysis documented interferon-γ production capability of T cell is maintained during treatment. Moreover, preliminary analysis of patients’ T cell proliferative capacity in PBMC utilizing in vitro anti-CD3 stimulation indicated T cells become increased in proliferative capability during treatment. These findings support the feasibility of longitudinal assessments, demonstrating that immunologic responsiveness and functionality can be detected with these blood monitoring strategies. Additional patients’ samples will be tested to allow confirmation of trends in immunologic response, and correlations with patient outcomes will be reported at time of presentation.
CTIM-08. A PILOT STUDY OF ABEMACICLIB WITH BEVACIZUMAB IN RECURRENT GLIOBLASTOMA PATIENTS WITH LOSS OF CDKN2A/B OR GAIN OR AMPLIFICATION OF CDK4/6
Authors: Murillo Jennifer , Pan Edward , Youssef Michael , Raslan Omar , Maher Elizabeth , Bachoo Robert 
Published: November 2022

Abstract

The recurrence rate for glioblastomas is essentially 100% and median overall survival (OS) for recurrent glioblastoma patients is usually poor, approximately 6-8 months from first recurrence. There is an unmet need in recurrent glioblastomas for novel therapeutic options with favorable safety profiles and potentially longer OS.

PURPOSE
The goal was to assess the impact of treating recurrent Glioblastoma patients whose tumors harbor loss of CDKN2A and/or CDKN2B, and/or copy gains or amplifications of CDK4 and/or CDK6 with dual therapy Abemaciclib with Bevacizumab.

METHODS
This was a single institution, pilot study (N = 10) of recurrent glioblastoma patients given the combination of Abemaciclib with Bevacizumab. Study patients received the combination of Abemaciclib at 150 mg po bid daily along with intravenous Bevacizumab at 10 mg/kg once every 2 weeks within a 28-day cycle. Staging brain MRIs with contrast were obtained every 8 weeks. Trial patients were removed from the study for significant treatment toxicities, clinical or MRI progression, patient choice, or death.

RESULTS
A total of 10 patients were enrolled in the study. There were 3 patients initially enrolled that were evaluated for safety followed by the additional 7 patients meeting clinical accrual from Jan. 2020-Sept. 2021. A total of 9 patients received at least one cycle (M = 6, F = 3). Preliminary findings revealed a median PFS of 14 weeks (range 5 weeks–25 weeks) and median OS of 20 weeks (range 5-70 weeks).

CONCLUSION
The combination of Abemaciclib with Bevacizumab compared to monotherapy Bevacizumab, surprisingly, had poorer outcomes. In a 2014 Bevacizumab study in recurrent glioblastomas, the median PFS was 13 weeks and OS 34.8 weeks compared to our combination therapy study of 14 weeks and 20 weeks, respectively. It is postulated that the use of Bevacizumab with Abemaciclib caused a drug-drug interaction that led to poor outcomes in our pilot study.
CTIM-13. LOCAL ADOPTIVE CELLULAR IMMUNOTHERAPY WITH CYTOKINE-INDUCED KILLER (CIK) CELLS FOR HIGH GRADE GLIOMAS: A PILOT STUDY WITH LONG-TERM FOLLOW-UP AND POTENTIAL FACTORS FOR SURVIVAL BENEFITS
Authors: Duan Hao , Chen Yukun , He Zhenqiang , Sai Ke , Mou Yonggao 
Published: November 2022

Abstract

BACKGROUND
Immunotherapy is emerging as a promising approach for the treatment of high grade gliomas (HGGs). We reported the long-term follow-up of 6 HGG patients treated by local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor cavity following operation. Meanwhile, Gene expression profiles and immune microenvironments of tumors were further compared between the long-term and short -term survivors.

METHODS
Clinicopathological characteristics and outcomes of patients were reviewed and updated. Gene expression profiles, expressions of cytokines and infiltrations of immune cells in tumors were investigated by RNA sequencing, an electrochemiluminescence assay and immunohistochemistry staining, respectively

RESULTS
Fever and symptoms of encephaledema occurred in 5 patients after local administration of CIK cells, and could be efficiently relieved by mannitol and dexamethasone. Four patients died from progressive disease during follow-up, and their overall survival ranged from 6 to 26 months. Remarkably, 2 patients have survived more than 200 months without evidence of recurrence. Comparing with the tumors of the short-term survivors, 353 genes which were highly associated with tumor microenvironment immune were differentially expressed (false discovery rate (FDR) &lt; 0.05 and log2 fold change (FC) ≥ 1) in the tumor of the long-term survivor. Higher expressions of cytokines, especially IL-8 and IL-10, were observed in the tumor of the long-term survivor, while the infiltrations of M2 polarized macrophages were significantly higher in the tumors of short-term survivors.

CONCLUSION
Long-term survival of HGG patients could achieve after local administration of CIK cells into tumor cavity postoperatively. High expressions of cytokines and low infiltrations of M2 polarized macrophages in the tumors potentially benefited the CIK cell therapy.
CTIM-15. RESULTS OF A PHASE IB TRIAL OF RECOMBINANT POLIO:RHINOVIRUS IMMUNOTHERAPY FOR RECURRENT PEDIATRIC HIGH GRADE GLIOMA
Authors: Thompson Eric , Landi Daniel , Brown Michael , Friedman Henry S , McLendon Roger , Bolognesi Dani , Schroeder Kristin , Becher Oren , Friedman Allan , Walter Ashley , Threatt Stevie , Jaggers Denise , Desjardins Annick , Gromeier Matthias , Bigner Darell , Ashley David 
Published: November 2022

Abstract

BACKGROUND
Outcomes of recurrent pediatric high grade glioma (pHHG) are poor with a median overall survival (OS) of &lt; 6 months. Viral immunotherapy such as the polio:rhinovirus chimera, PVSRIPO, is a novel treatment approach for recurrent pHHG. PVSRIPO is genetically engineered to prevent neurovirulence. In adults with recurrent glioblastoma treated with PVSRIPO, 21% survived &gt; 36 months. The poliovirus receptor, CD155, is ubiquitously expressed in malignant pediatric brain tumors including pHHG.

METHODS
The primary objective of this Phase 1b clinical trial was to evaluate the safety and feasibility of PVSRIPO for recurrent pHGG. PVSRIPO was given at a single dose, 5x107 50% tissue-culture infectious dose (TCID50) administered by convection enhanced delivery (CED) to children with biopsy-confirmed recurrent pHHG between ≥ 1 and ≤ 5.5 in diameter. 3 mL of PVSRIPO was delivered at 0.5 mL/hr via a single catheter.

RESULTS
Eight patients were treated with PVSRIPO including 5 males and 3 females with a median age of 16.5 (range 9-19). Six patients had recurrent glioblastoma, 2 had recurrent anaplastic astrocytoma. The median number of previous recurrences prior to enrollment was 3.5 (range 1-5). Four patients received bevacizumab on-study for treatment-related peritumoral inflammation/edema. Six of 8 patients experienced 26 treatment related adverse events (AEs) possibly, probably, or definitely related to protocol treatment. There were no Grade 4 or 5 AEs. There were 3 Grade 3 AEs: 2 headaches and 1 seizure. There were no AEs related to biopsy or CED catheter insertion/removal. Median OS was 4.13 months (range 1.23-NA). One patient is currently alive at &gt; 21 months. Monocyte and T cell inflammatory phenotypes and total CD4+ T cells were increased in peripheral blood after treatment.

CONCLUSIONS
CED of PVSPRIO is both safe and feasible for the treatment of recurrent pHHG. Histologic correlative results will also be presented.
CTIM-16. PHASE 1 TRIAL OF RUXOLITINIB, TEMOZOLOMIDE, AND RADIATION IN HIGH-GRADE GLIOMAS
Authors: Ahluwalia Manmeet , Khosla Atulya , Rauf Yasmeen , Murphy Erin , Chao Samuel , Suh John , Stevens Glen , Peereboom David 
Published: November 2022

Abstract

BACKGROUND
Ruxolitinib is a small molecule inhibitor of JAK1 (Janus kinase 1) and JAK2 and JAK3. Dysregulation of the JAK/STAT pathway is associated with increased proliferation and survival of malignant cells. Preclinical evidence supporting inhibition of the JAK-STAT pathway arrogated glioma growth led to the design of this trial.

METHODS
Newly diagnosed patients with unmethylated MGMT HGG (arm 1) received ruxolitinib and 60 Gy radiation for 6 weeks over 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 was 10 mg twice daily, level 2 (15 mg twice daily), level 3 (20 mg twice daily), and level -1 was 5 mg twice daily. Patients with methylated MGMT HGG (arm 2) received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method and compared using the log-rank test.

RESULTS
60 HGG were treated in the study and there was no dose-limiting toxicity. Survival data was calculated for 37 GBM patients. The OS for arm 1 was 18.17 months (10.15, NA) and was not reached for arm 2. The 1-year OS was 0.77 for all GBM patients, was 0.62 for arm 1 (unmethylated MGMT) and 0.93 for arm 2 (unmethylated MGMT).

CONCLUSIONS
A dose of 20 mg twice daily of ruxolitinib is safe with radiation and temozolomide. Preliminary survival data appears promising compared to the historical benchmarks for both the methylated MGMT and unmethylated MGMT groups. Genomic markers of response will be presented. A randomized phase 2 trial is planned.
CTIM-22. THE COMBINATION OF LOMUSTINE AND THE IMMUNOCYTOKINE L19TNF IS A PROMISING TREATMENT FOR RECURRENT GLIOBLASTOMA
Authors: Look Thomas , Puca Emanuele , Stucchi Riccardo , De Luca Roberto , Roth Patrick , Neri Dario , Weller Michael , Hemmerle Teresa , Weiss Tobias 
Published: November 2022

Abstract
Glioblastoma is the most aggressive primary brain tumor and adults and poorly immunogenic. Treatment options for recurrent glioblastoma after standard of care chemoradiation are limited Several immunotherapeutic strategies including peptide vaccination and immune checkpoint inhibition have so far failed to improve survival and except from potentially regorafenib, no other agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. Here, we investigate a new treatment combination based on the alkylating chemotherapy lomustine and the tumor-stroma targeting antibody-cytokine fusion protein L19TNF in preclinical glioma models and patients with recurrent glioblastoma. The combination treatment with lomustine and L19TNF demonstrated strong synergistic anti-tumor activity in several immunocompetent orthotopic glioma models curing the majority of tumor-bearing mice, whereas other mono- or combination therapies for example with anti-PD1 had only limited anti-glioma activity. Investigations of the mechanism of action revealed that lomustine plus L19TNF led to intratumoral necrosis, DNA damage and triggered a strong local anti-tumor immune response with increased MHC-I expression, presentation of neoepitopes and increased abundance of tumor-infiltrating lymphoid cells. In the first patients treated within a phase I/II clinical trial (NCT04573192), the treatment was well tolerated, and durable objective tumor responses and disease stabilizations could be observed also in patients with an unmethylated MGMT promoter.
CTIM-28. MULTILAMELLAR MRNA LIPID PARTICLES INDUCE IMMUNOLOGIC REPROGRAMMING IN CANINE AND HUMAN GLIOBLASTOMA PATIENTS
Authors: Mendez-Gomez Hector , DeVries Anna , Stover Brian , Zhang Dingpeng , Grippin Adam , Von Roemeling Christina , Weidert Frances , Karachi Aida , Qdaisat Sadeem , Thomas Nagheme , McGuiness James , Castillo Paul , Huang Jianping , Ligon John , Silver Natalie , Kellish Patrick , Doty Andria , Carrera-Justiz Sheila , Prados Michael , Mueller Sabine , Rahman Maryam , Ghiaseddin Ashley , Mitchell Duane , Sayour Elias 
Published: November 2022

Abstract

BACKGROUND
Although mRNA vaccines have been deployed with great success against COVID-19, unlocking this technology against glioblastoma will necessitate new lipid-nanoparticle formulations that overcome cancer tolerance and immunosuppression.

OBJECTIVE/METHODS
We sought to develop a novel mRNA vaccine system to make tolerogenic tumor antigens appear more dangerous through use of unmodified nucleosides (pathogen associated molecular patterns, PAMPs) and highly cationic lipid shells that elicit a systemic damage response against cancer antigens.

RESULTS
We developed a novel vaccine formulation that increases payload packaging of tumor amplified mRNA into multilamellar (onion-shaped) particles for systemic (intravenous) administration. We demonstrate significant immunogenicity and efficacy of multilamellar RNA-NPs in syngeneic murine models for high-grade glioma (KR158b-pp65), and diffuse midline glioma (H3K27M DMG). Remarkably, RNA-NPs significantly improve median survival outcomes of DMG bearing mice beginning therapy at endpoint (Day 35 after midline intracranial implantation). Unlike prototypical mRNA vaccines that activate endosomal toll-like receptors (i.e. TLR7), multilamellar RNA-NPs elicit immunologic response predominantly through intracellular pathogen recognition receptors (RIG-I); long-term survival benefits from RNA-NPs were completely abrogated in RIG-I knockout mice. In canines (pet dogs) with spontaneous gliomas, RNA-NPs elicit massive recruitment/activation of peripheral blood mononuclear cells (PBMCs) which correlate with their trafficking into lymphoreticular organs (in follow-up murine studies). In canines receiving neoadjuvant RNA-NPs, prior to glioma biopsy, we see significant reprogramming of the glioma microenvironment with increased gene signatures for antigen processing/presentation, interferon signaling and cytotoxicity. Upon translation into human clinical trials for glioblastoma patients (NCT04573140), RNA-NPs elicit rapid (within hours) release of cytokines (e.g. IL-1, IL-6, IL-12 TNF-α, interferons) and chemokines (e.g. MIP1α, MCP-1, IP-10), which correlate with mobilization of PBMCs and activation of dendritic cells/CD8 lymphocytes.

CONCLUSION
First-in-human application of systemic multilamellar RNA-NP vaccines results in significant biologic effects and rapid immunologic reprogramming.
CTNI-01. EFFECT OF PRE-OPERATIVE STEREOTACTIC RADIOSURGERY ON BRAIN METASTASIS: ANALYSIS OF DNA AND RNA GENOMIC PROFILES FROM PHASE-II CLINICAL TRIAL NCT03398694
Authors: Shireman Jack , Huff Wei , Monaco Gina , Agrawal Namita , Watson Gordon , Dey Mahua 
Published: November 2022

Abstract

BACKGROUND
With improved systemic therapy that has limited impact on the intracranial compartment, the incidence of brain metastasis (BM) from solid cancers is rising. Treatment varies based on presentation, however, for patients with &lt; 4 symptomatic BMs current clinical practice involves surgical resection followed by stereotactic radiosurgery (SRS) to the resection cavity. Post-operative SRS is associated with increased risk of leptomeningeal disease (LMD) and local recurrence. We hypothesize that pre-operative SRS will decrease the incidence of LMD as well as local recurrence, and increase patient’s OS by delivering a lethal dose of radiation to tumor cells before they are disturbed by surgical resection. In a Phase II clinical trial (NCT03398694) we are treating patients with 1-4 symptomatic BMs with pre-operative SRS while collecting DNA and RNA sequencing data from core and peripheral edges of the resected tumor to examine the genomic effects of SRS on tumor.

METHODS
Post-SRS resected tumor specimens were divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50% isodose line. Previously resected untreated BMs were used as control.

RESULTS/CONCLUSIONS
Our initial data analyses show that pre-treatment with SRS results in significant genomic changes at DNA and RNA levels throughout the tumor when compared to non-radiated tumors. In matched center and peripheral samples DNA damage levels, measured by high impact mutation load, were similar indicating no evidence of radiation dose fall off effect on DNA damage. However, differing DNA damage locations and RNA expression profiles between center and matched samples are present, which may indicate unequal DNA repair processes between the center and periphery of tumors. Furthermore, global DNA mutation and RNA expression profiles differed significantly between the metastasis of different primary cancers signaling the importance of the primary cancer location in determining viable therapeutic targets.
CTNI-04. TRAM-01: A PHASE 2 STUDY OF TRAMETINIB FOR PEDIATRIC PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 AND PLEXIFORM NEUROFIBROMAS
Authors: Kiaei Dorsa Sadat , Larouche Valerie , Décarie Jean-Claude , Tabori Uri , Hawkins Cynthia , Lippe Sarah , Ellezam Benjamin , Ospina Luis H , Theoret Yves , Desjardins Leandra , Metras Marie-Elaine , Sultan Serge , Cantin Edith , Routhier Marie-Eve , Mailloux Chantal , Bertrand Marie-claude , Caru Maxime , McKeown Tara , Vairy Stephanie , Legault Geneviève , Bouffet Eric , Ramaswamy Vijay , Coltin Hallie , Lafay-Cousin Lucie , Hukin Juliette , Erker Craig , Jabado Nada , Dehaes Mathieu , Perreault Sébastien 
Published: November 2022

Abstract

BACKGROUND
Plexiform neurofibromas (PN) are observed in up to 50% of patients with neurofibromatosis type 1 (NF1). Trametinib has been used widely to treat PN but limited data has been reported on its efficacy within a clinical trial.

METHODS
This ongoing multicenter phase II trial includes patients with pediatric low-grade glioma and PN. Patients received daily oral trametinib (MEK inhibitor) for eighteen 28-day cycles. The volumes of PN were centrally quantified using a new semi-automatic 3D segmentation method.

RESULTS
As of May 15, 2022, 46 patients with PN were enrolled in the study and the recruitment was completed for this study arm. Thirty-four completed treatment and were available for analysis. For these patients, the median age was 10.5 years (range 0.7-19.8). The median volume of PN at baseline was 51cm3 (range 2.6 to 487.6). Among the 34 patients, 28 (82.4%) completed 18 cycles as planned. Two patients discontinued due to adverse reaction, three patients refused to continue treatment and one patient discontinued treatment based on physician decision. Median duration of treatment was 16.8 months (range 2.8 to 16.8). Median duration of follow-up was 30.4 months (range 8.2 to 42). A total of 38 PN were available for volumetric analysis. Using RECIST evaluation, the overall response rate was 13.1%. Volumetric assessment demonstrated an overall response rate of 64.7% (22/34 patients), and 65.8% (25/38 PN) of PN showed a decrease of more than 20% in volume. Median volume change was -30% (range -93.5 to 14.3). Thirty-one patients (91.1%) had durable response without progression (lasting ≥ 1 year). After discontinuation of treatment, one patient underwent surgery and three patients resumed MEK inhibitor.

CONCLUSION
We report outcome and volumetric quantification of PN treated with trametinib within a large clinical trial. Based on the current results, trametinib is effective and offers durable response.
CTNI-06. IMPROVING INSOMNIA IN PATIENTS WITH PRIMARY BRAIN TUMORS USING COGNITIVE BEHAVIORAL THERAPY: RESULTS FROM AN NRG NCORP PILOT TRIAL
Authors: Loughan Ashlee , Lanoye Autumn , Willis Kelcie , Fox Amber , Zukas Alicia , Ravyts Scott 
Published: November 2022

Abstract

BACKGROUND
Sleep disturbance is among the most common symptoms endorsed by patients with primary brain tumor (PwPBT), with many reporting clinically-elevated insomnia and poor management of sleep-related symptoms by their medical team. Though Cognitive Behavioral Therapy for Insomnia (CBT-I) remains the front-line treatment for sleep disturbance, CBT-I has yet to be evaluated in PwPBT.

METHODS
PwPBT were recruited locally by direct referral and fliers, and nationally by social media support group postings. Forty PwPBT and insomnia enrolled in a six-week group-based telehealth CBT-I phase IIa single-arm proof-of-concept trial: 50.0% female, 68.2% non-Hispanic white, 55.0% high-grade, 42.5% oligodendroglioma, Mage = 52.4 (SD = 12.0, range 31-77). Participants completed data collection at baseline and post-intervention. Self-report measures assessed insomnia (ISI), fatigue (BFI), mood (PHQ-9, GAD-7) and quality-of-life (QLQ-30). Cognitive assessment included measures of attention (WAIS-IV Digits, TMT), verbal fluency (COWAT) and memory (HVLT). Intervention effects for self-report outcomes were analyzed using paired t-tests; effects for cognitive outcomes were analyzed using repeated-measures ANCOVA controlling for age.

RESULTS
Among those with complete data (n=34), significant improvements were identified for insomnia (t(33) = 8.6, p &lt; .001, Cohen’s d = 1.5) and fatigue (t(30) = 4.7, p &lt; .001, Cohen’s d = 0.8) symptoms. Depression (t(33) = 5.2, p &lt; .001, Cohen’s d = 0.9) and anxiety symptoms (t(33) = 4.2, p &lt; .001, Cohen’s d = 0.7) also improved. Quality-of-life improved with respect to role (t(33) = 2.8, p = .01, Cohen’s d = 0.5), emotional (t(33) = 2.8, p = .01, Cohen’s d = 0.5), cognitive (t(33) = 3.9, p &lt; .001, Cohen’s d = 0.7), and social functioning (t(33) = 3.5, p = .001, Cohen’s d = 0.6)—but not physical functioning (t(33) = 0.5, p = .60, Cohen’s d = 0.1). No clinically or statistically significant cognitive changes were found.

CONCLUSION
This trial is the first to preliminarily assess efficacy of CBT-I, a non-pharmacological treatment for insomnia, in PwPBT. Results suggest promising benefit of CBT-I in insomnia severity, fatigue, mood, and most quality-of-life indices for individuals challenged by PBT and insomnia. These findings support further study in a scientifically rigorous phase IIb randomized feasibility trial.