bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSIG-21. BAF60C/SMARCD3 REGULATES TUMOR CELL DISSEMINATION IN MEDULLOBLASTOMA
Authors: Hu Baoli , Poore Brad , Sharma Vaibhav , Guan Yongchang , Agnihotri Sameer , Pollack Ian , Hu Baoli 
Published: December 2020

Abstract
Medulloblastoma, the most common malignant brain tumor in children, is a diverse and heterogeneous disease. Molecular characterization of MB revealed four major subgroups, WNT, SHH, Group 3, and Group 4. Although surgical resection, radiotherapy, and chemotherapy are effective at eliminating some forms, patients with the aggressive tumors cannot be cured with conventional therapies, particularly in Group 3. Group 3 is the most aggressive subtype of this disease, accounting for about 25%-30% of cases, and characterized by frequent metastasis at diagnosis and the worst prognosis among all the subgroups. Metastatic dissemination is a major treatment challenge and strongly associated with poor prognosis in patients with medulloblastoma. However, the molecular mechanisms of tumor cell early dissemination and late metastasis remain largely unknown. Here, we found that Group 3 has elevated expression of BAF60C/SMARCD3, a subcomponent of SWI/SNF complex, which significantly mobilizes nucleosomes and remodels chromatin. Clinically, elevated SMARCD3 mRNA resulted in a poorer prognosis in medulloblastoma patients, which was further validated in 63 patient tumors by immunohistochemical staining for SMARCD3. Interestingly, tumors that had metastasized often had elevated expression of SMARCD3, in all subgroups of medulloblastomas and Group 3 only. An orthotopic mouse model further supported that SMARCD3 is highly expressed in metastatic tumors compared to primary tumors. Importantly, CRISPR-Cas9-mediated SMARCD3 deletion decreased cell migration and invasion in multiple medulloblastoma cell lines. Mechanistically, SMARCD3 deletion led to decreased H3K27me3, suggesting that SMARCD3 may cooperate with PRC2 in regulation of gene expression. Strikingly, SMARCD3 deletion downregulated Reelin signaling pathway, an essential role in neuronal positioning during neurodevelopment, which indicates that tumors with highly expressed SMARCD3 hijack a developmental signaling to promote their dissemination and aggressiveness. Together, our results suggest that inhibition of SMARCD3 controlling downstream signaling may effectively prevent tumor dissemination and improve clinical outcomes in children with medulloblastoma.
CTIM-03. PHASE II STUDY OF REGORAFENIB IN BEVACIZUMAB REFRACTORY RECURRENT GLIOBLASTOMA
Authors: Rauf Yasmeen , Schilero Cathy , Peereboom David , Ahluwalia Manmeet 
Published: December 2020

Abstract

BACKGROUND
Most patients with glioblastoma (GBM) receive bevacizumab as part of their treatment. There is no good therapeutic option after bevacizumab failure. Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic activity as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging (MRI). Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment.

METHODS
Patients with progression of GBM after treatment with Bevacizumab will be eligible for the study. Oral administration of Regorafenib at 160 mg once daily will be administered for 3 weeks on /1 week off. Weekly dose escalation of regorafenib from 80 mg to 160 mg/day will be employed as per the Redos strategy. Patients start the treatment 80 mg/day in week 1, with weekly dose escalation to 120 mg in week 2, then 160 mg week in 3 if no significant drug-related toxicities are observed. They will be continued on treatment with Regorafenib 160 md /day till tumor progression or toxicity. They will get MRI brain every 4 weeks during the study.

RESULTS
Primary endpoint is median Overall survival. Secondary endpoints include progression free survival at 6 months and the median time to progression and objective response rate using the modified RANO criteria. The overall safety and tolerability of regorafenib by CTCAE version 5.0. will also be reported.

CONCLUSION
This is an ongoing clinical trial.
CTIM-13. CLINICAL EFFICACY OF MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, IN RECURRENT GBM DELIVERED BY CONVECTION ENHANCED DELIVERY (CED)
Authors: Sampson John , Achrol Achal , Aghi Manish , Bankiewiecz Krystof , Bexon Martin , Brem Steven , Brenner Andrew , Chandhasin Chandtip , Chowdhary Sajeel , Coello Melissa , Ellingson Benjamin , Floyd John , Han Seunggu , Kesari Santosh , Merchant Fahar , Merchant Nina , Randazzo Dina , Vogelbaum Michael , Vrionis Frank , Zabek Miroslaw , Butowski Nicholas 
Published: December 2020

Abstract

BACKGROUND
MDNA55 is an IL4R-targeted toxin in development for GBM, a universally fatal disease. IL4R is over-expressed in GBM, the tumor microenvironment, and high expression is associated with poor outcomes in GBM.

METHOD
MDNA55-05 is an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in rGBM patients at 1st or 2nd recurrence with an aggressive form of GBM (de novo GBM, IDH wild-type, not-resectable at recurrence, ~ 50% expressing high levels of IL4R). Primary endpoint is mOS, secondary endpoint includes impact of IL4R status on mOS. A Synthetic Control Arm (SCA) served as an external comparator constructed from patient registries at neurosurgery centers under IRB-approved protocols. Propensity score weighting corrected for imbalances in baseline characteristics between the two groups.

RESULTS
MDNA55 showed an acceptable safety profile at doses up to 240μg. In all evaluable subjects (n=44) mOS was 11.6 and OS-12 was 46%. A sub-population (n=32) consisting of all IL4RHigh subjects + only IL4RLow subjects treated with high dose (median 180µg) showed most benefit: mOS is 15 months, OS-12 is 55%. Tumor control, assessed by mRANO criteria, was seen in 81% (26/32) of this sub-population, including those that had pseudo-progression (15/26). In these subjects, tumor control was associated with longer mPFS (4.7 months) and mOS (15.0 months) than those with progressive disease (mPFS 1.0 month, mOS 7.7 months). Comparison against the SCA demonstrated &gt; 100% increase in mOS: 15.7 months vs 7.2 months (HR 0.52, 95% CI 0.30, 0.91).

CONCLUSIONS
MDNA55 demonstrates improved survival and tumor control in this study design and has potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. There are no approved therapies for rGBM that can extend survival by 50%; the potential for MDNA55 to extend survival by &gt; 100% is promising for this devastating disease.
CTIM-15. PRELIMINARY RESULTS OF A PHASE II STUDY OF NIVOLUMAB WITH HYPOFRACTIONATED RE-RADIATION AND BEVACIZUMAB FOR RECURRENT MGMT METHYLATED GLIOBLASTOMA
Authors: Grommes Christian , Mehta Minesh , Miller Alexandra , Daras Mariza , Piotrowski Anna , Boire Adrienne , Butler Brittany , Stone Jacqueline , Pentsova Elena , Kotecha Rupesh , Morrison Tara , Odia Yazmin , Mellinghoff Ingo , Beal Kathryn 
Published: December 2020

Abstract
Standard of standard of care for glioblastoma (GBM) remains unsatisfactory with universal disease recurrence and a median survival of &lt; 2 years. Immune checkpoint inhibitors (ICI) have shown limited single-agent activity in GBM thus far. GBMs with methylated MGMT promoter and no baseline corticosteroid dependence may be most likely to derive benefit from ICI. The combination of ICIs with radiation has shown promising activity in other human cancers. Combining nivolumab and re-RT/bevacizumab in GBM may augment ICI activity through immunogenic effects of radiation, may reduce the risk of radiation necrosis by addition of bevacizumab at the time of radiation, and may reduce the need for corticosteroids. In this multicenter phase II study, nivolumab is combined with re-irradiation and optional concurrent bevacizumab followed by nivolumab in patients with first recurrence of IDH-wildtype and MGMT methylated glioblastoma. Primary objective is to improve 1-year overall survival (OS) from 33 (based on EORTC 26101) to 50%. Nine-three patients are required to show a significant finding with an α of 0.05 and 81% power. Thirteen of 93 patient (14%) have been enrolled with a median age of 59 (range 42–71) with a median KPS of 90 (range 70–90). Treatment has been tolerated well without any grade ≥ 4 toxicities and only one grade 3 (amylase elevation). The most common adverse events were pruritus and hypothyroidism in 3/13 (23%). The median progression-free survival (PFS) is 7 months with a 6months PFS of 55.6%. The 12months OS is 66.7%. Patients with recurrent MGMT methylated, IDH-wildtype glioblastoma tolerate trial treatment with acceptable toxicities. Clinical efficacy in the first patients enrolled shows a promising effect. Enrollment is ongoing.
CTIM-16. INTERSTITIAL PHOTODYNAMIC THERAPY WITH 5-ALA FOR MALIGNANT GLIOMA RECURRENCES
Authors: Lietke Stefanie , Schmutzer Michael , Schwartz Christoph , Weller Jonathan , Aumiller Maximilian , Heckl Christian , Forbrig Robert , Niyazi Maximilian , Stepp Herbert , Sroka Ronald , Tonn Joerg-Christian , Rühm Adrian , Thon Niklas 
Published: December 2020

Abstract
Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) as a cytotoxic photosensitizer has been shown to be a feasible treatment option for malignant gliomas. We present outcome measures and a risk profile analysis of salvage iPDT in a large monocentric cohort with local tumor recurrence following standard therapy. This study included consecutive adult patients undergoing salvage iPDT for small, circumscribed, biopsy-proven malignant glioma recurrences not deemed eligible for safe complete resection of contrast enhancing tumor. A modified 3-D treatment-planning software was used to calculate the treatment-volume and the position of the stereotactic light diffusers within the lesion. Outcome measurements included estimated time-to-treatment-failure (TTF), post-recurrence survival (PRS) and the risk profile of iPDT. Prognostic factors were obtained from logistic regression models. The institutional review board approved the study. A total of 44 patients (median age: 49.4 years, range 33.4–87.0 years, 17 female) were included. Recurrent tumors included 37/44 glioblastomas WHO grade IV and 7/44 anaplastic astrocytomas WHO grade III. Thirty (68.2%) tumors were MGMT methylated. Median treatment volume was 3.3 ccm (range, 0.5–22.8 ccm). A median number of 4 (range: 3–8) laser fibers were used. Median illumination time was 60min (range: 60–167 min). Symptomatic edema (8/44) or intratumoral hemorrhagic imbibition (7/44) did not result in any permanent morbidity. Median TTF was 7.1 months and median PRS was 13.0 months. The 2- and 5-years PRS rates were 25.0% and 4.5%. Treatment response was heterogeneous and not significantly associated with patient characteristics, treatment-related factors or molecular markers. In conclusion, iPDT was associated with promising outcome measurements in local malignant glioma recurrences in highly selected patients. Transient neurologic deterioration did not lead to any permanent morbidity. The procedure deserves further prospective evaluation particularly to identify mechanisms of favorable treatment response and prognostic factors associated with long-term survival.
CTIM-18. DENDRITIC CELL VACCINATION IN CONJUNCTION WITH ADJUVANT TLR-3 AGONIST ADMINISTRATION ENHANCES PRO-INFLAMMATORY IMMUNE RESPONSES AND IS ASSOCIATED WITH EXTENDED SURVIVAL IN MALIGNANT GLIOMA PATIENTS
Authors: Chavez Carolina , Everson Richard , Orpilla Joey , Lee Alexander , Khattab Sara , Antonios Joseph , Salazar Andres , Cloughesy Timothy , Liau Linda , Sun Lu , Hugo Willy , Prins Robert 
Published: December 2020

Abstract
Despite recent advances with immunotherapy in other tumor types, malignant glioma patients have not shown a therapeutic benefit, potentially due to the insufficient activation of an immune response. We and others have documented immune responses and extended survival following dendritic cell (DC) vaccination in small clinical trials. In this Phase II clinical trial, we randomized malignant glioma patients to receive autologous tumor lysate pulsed DC vaccination with and without adjuvant toll-like receptor (TLR) agonists. Treatment with TLRs in cancer patients has been shown to activate the innate immune response by inducing the expression of pro-inflammatory factors and cytokines. Twenty-three patients with WHO grade III or IV glioma received three intradermal injections of autologous tumor lysate-pulsed DC on days 0, 14, and 28 in conjunction with either a placebo adjuvant, TLR-7 agonist (Resiquimod), or TLR-3 agonist (Poly ICLC). We observed a difference in survival for the DC-vaccinated patients who received adjuvant Poly ICLC treatment of 54 months over adjuvant placebo (20 months) and adjuvant Resiquimod (28 months) groups (P = 0.04). The patient cohorts were balanced for WHO grade, IDH mutation, and MGMT methylation status. Mass cytometry (CyTOF) analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased levels of the monocyte populations CD14+CD16- and CD14dimCD16+ after Poly ICLC treatment. In addition, gene expression analysis of the PBMC populations using single cell RNA sequencing demonstrated increased expression of pro-inflammatory genes after adjuvant Poly ICLC and Resiquimod treatment. Nonetheless, a greater fold change increase and a larger pro-inflammatory repertoire was observed in the Poly ICLC group. Overall, these findings demonstrate that adjuvant Poly ICLC increases the number of circulating monocytes and induces a large pro-inflammatory response, which may account for the survival differences observed over adjuvant Resiquimod and placebo.
CTIM-22. PHASE 1 TRIAL OF OSIMERTINIB WITH STEREOTACTIC RADIOSURGERY (SRS) IN PATIENTS WITH BRAIN METASTASES FROM EGFR POSITIVE NON-SMALL-CELL LUNG CANCER (NSCLC)
Authors: Rauf Yasmeen , Kotecha Rupesh , Fadul Camilo , Evanoff Wendi , Suh John , Chao Samuel , Murphy Erin , Yu Jennifer , Angelov Lilyana , Barnett Gene , Mohammadi Alireza , Ahluwalia Manmeet 
Published: December 2020

Abstract

BACKGROUND
Osimertinib is an oral, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor activating mutation (EGFRm) and the resistance mutation (T790M) that is FDA approved for patients with EGFR mutant lung cancer. The synergism between Osimertinib and radiation likely enhances DNA damage, leading to increased cell apoptosis. For patients with EGFR positive NSCLC with brain metastases, we hypothesize that the combination of Osimertinib and SRS will lead to better long term control of brain metastases as well as the systemic disease.

METHODS
This is an open label, single arm, phase I multi-institution study. It will employ a 3 + 3 design. After enrollment onto the study, patients will be started on Osimertinib at the predetermined level daily for 0–7 days, after which all patients will undergo radiosurgery and then receive Osimertinib daily concurrently until disease progression, withdrawal or until unacceptable toxicity. SRS will be given in single fraction as determined by the treating radiation oncologist and neurosurgeon.

RESULTS
Primary endpoint include Safety, tolerability and maximum tolerated dose (MTD) of Osimertinib, when administered in combination with SRS in patients with EGFR positive NSCLC with brain metastases. Secondary endpoints include Six-month intra-cranial and extra-cranial progression-free survival (PFS-6), overall survival, overall response rate, both intracranial and extra cranial in patients with EGFR positive NSCLC brain metastases.

CONCLUSION
This is an ongoing clinical trial.
CTIM-29. CRUCIAL APPLICATION OF SINGLE CELL GENE EXPRESSION FOR MONITORING CHANGES IN GLIOBLASTOMA PATIENTS WITH SUSTAINED RADIOGRAPHIC RESPONSE TO CMV pp65-LAMP RNA-PULSED DENDRITIC CELL-BASED VACCINES
Authors: Yegorov Oleg , Yang Changlin , Dechkovskaia Anjelika , Rahman Maryam , Ghiaseddin Ashley , Mitchell Duane 
Published: December 2020

Abstract

BACKGROUND
The application of single cell sequencing as a novel immune monitoring platform can be used to identify the molecular mechanisms of immune response to dendritic cell- based vaccines, trace the cell types and states involved, and uncover novel biomarkers for immunotherapy. We applied single-cell RNA Seq analysis of longitudinal peripheral blood mononuclear cells (PBMCs) in patients with newly-diagnosed GBM enrolled on the ATTAC II clinical trial (FDA IND BB-16530; Clinicaltrials.gov # NCT02465268) who experienced a sustained radiographic response to autologous CMV pp65-LAMP RNA-pulsed DC vaccines plus GM-CSF and tetanus-diphtheria booster administered during adjuvant cycles of dose-intensified temozolomide.

METHODS
We constructed 5’ gene expression libraries and T cell receptor enriched libraries for 10x Genomics single-cell 5’ and VDJ sequencing, generated from PBMCs collected prior to and during patient immunization using dendritic cells loaded with messenger ribonucleic acid encoding the human cytomegalovirus (CMV) matrix protein pp65 conjugated with the lysosomal associated membrane protein (LAMP) sequence.

RESULTS
Overall, we sequenced a total of 189,808 single-cell transcriptomes from 5 patients. We leveraged these transcriptome-wide features to distinguish 15 peripheral immune cell subtypes in tested PBMCs. Analysis revealed dynamic changes in immune cell subsets over the course of first three vaccines, including increases in cytotoxic CD8 T cells, CD4 T cells, and NK cell subsets. Increased markers of T cell activation were observed during vaccination. Surprisingly, we observed a very high-level frequency of natural killer T (NKT) cells in the patient with a complete durable response compared to other patients. After three DC vaccines, the level of NKT cells in PBMC of this patient increased up to 10%.

CONCLUSIONS
These results emphasize the importance of subset specific profiling to achieve higher resolution in monitoring immune responses compared with bulk expression profiling in patients receiving immunotherapeutic treatment.
CTNI-02. TBCRC049: A PHASE II STUDY TO ASSESS THE SAFETY AND EFFICACY OF THE COMBINATION OF TUCATINIB, TRASTUZUMAB AND CAPECITABINE FOR THE TREATMENT OF LEPTOMENINGEAL METASTASIS IN HER2 POSITIVE BR1AST CANCER
Authors: Murthy Rashmi , O’Brien Barbara , Berry Donald , Navin Nicholas , Johnson Jason , Gule-Monroe Maria , Leone Jose , Specht Jennifer , Melisko Michelle , Morikawa Aki , Storniolo Anna , Brufsky Adam , Pohlmann Paula , Park Deric , Park Ben , Krop Ian , Lin Nancy , Rimawi Mothaffar , Wolff Antonio , Forero-Torres Andres , Stringer-Reasor Erica 
Published: December 2020

Abstract
Treatment options for patients with leptomeningeal metastasis (LM) from HER2-positive breast cancer (HER2+ BC) are limited and prognosis is poor. Tucatinib is an oral, potent, HER2 specific tyrosine kinase inhibitor with good tolerability and combinatory anti-tumor activity, including partial responses in heavily treated patients and those with brain metastases (BM). This is a phase 2 single-arm study to evaluate the efficacy of tucatinib, trastuzumab and capecitabine in HER2+ BC with newly-diagnosed LM. CNS disease will be evaluated at screening and every 6 weeks by neuroaxis MRI, CSF cytology, and neurological assessments per RANO-LMD (adapted) and RANO-BM criteria. Extra-CNS disease will be evaluated at screening and every 12 weeks by CT scan per RECIST criteria. All patients will be followed for survival. Symptom burden and quality of life assessments, as well as correlative blood and CSF samples, will be collected. Eligible patients include adults with HER2+ BC, KPS &gt; 50, and newly-diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Patients with treated or concurrent/new BM are allowed. Patients treated with capecitabine within the last 12 months are excluded. This study has a Gehan-like design with an interim futility analysis and overall intent to estimate OS. For the interim analysis, success is defined as CNS PFS for 12 weeks. Enrollment will end if fewer than two successes are observed in the first 15 patients. Secondary endpoints include safety, CNS PFS at 12 weeks, RR in CNS and extra-CNS, and symptom burden/quality of life. The regimen will be considered worthy of future study if the median OS is &gt; 4.4 months. Fourteen of 30 patients have accrued thus far. The study is active at multiple Translational Breast Cancer Research Consortium sites around the country.
CTNI-08. A PHASE 1–2 CLINICAL TRIAL OF EO1001, A NOVEL IRREVERSIBLE PAN-ErbB INHIBITOR WITH PROMISING BRAIN PENETRATION
Authors: Wheeler Helen , Bacha Jeffrey , Brown Dennis , Kanekal Sarath , Sankar Neil , Nisbet Ian , Skoff Kathy , Shen Wang , ZhenZhong Wang , Pedersen Harry 
Published: December 2020

Abstract
Mutations causing errant ErbB activation are implicated in many cancers, including tumors correlated with high incidence of CNS metastasis. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs, particularly in advanced disease. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. EO1001 is being advanced into first-in-man studies under the Australia Clinical Trials Notification (CTN) scheme (ANZCTR Reg.#ACTRN12320000589343p). METHODS: Adult patients with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver function are eligible. Toxicity is assessed by NCI CCTCAEv5 and tumor response is assessed by RECISTv1.1. CNS exposure is evaluated in in select patients with confirmed CNS disease involvement via CSF collection. An accelerated dose-escalation design is employed. One subject per dose cohort will be recruited until drug related toxicity (≥ G2) is observed, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). DOSE ESCALATION: Cycle 1: Patients will receive a single dose EO1001 on day 1 and single dose pharmacokinetics will be performed. Beginning on day 8, EO1001 will be administered once daily for 21 days; multi-dose pharmacokinetics will be performed. Cycles 2–6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. MTD EXPANSION: Oral EO1001 will be administered once daily at the MTD in continuous 28-day cycles for up to 6 cycles (24 weeks). An update on the progress of this trial will be presented.