tbuckley/cabot-search huggingface dataset:
IMMU-43. ZIKA VIRUS TO TREAT GLIOMA: TURNING COLD TUMORS HOT
Authors: Luciano Mazzoccoli, Sharmila Nair, Arijita Jash, Jennifer Govero, Tong Hu, Sujan Shresta, Pei-Yong Shi, Jeremy Rich, Michael Diamond, Milan Chheda
Journal: Neuro-Oncology (2020)

Abstract GBM is a hallmark example of an immunotherapy-resistant tumor. Previously, we discovered that Zika virus (ZIKV) has a natural honing capacity to specifically kill GBM stem cells (GSCs). Using two syngeneic glioma models, GL261 and CT2A, we found that in vivo intratumoral ZIKV treatment reduces tumor size and extends median survival far beyond that expected for its anti-GSC effects; additionally, approximately 50% of mice were long-term survivors. We now report that ZIKV treatment is associated with an increase in tumor-specific CD8+ T cells and activated myeloid cells expressing MHC-II and NOS2. Treatment with CD8-depleting antibody abrogates the survival advantage conferred by ZIKV, demonstrating that CD8+ T cells are required for ZIKV efficacy. Remarkably, ZIKV treatment also confers protection against tumor re-challenge 1.5 years after the original treatment, and this too is dependent on CD8+ T cells. Lastly, in a bilateral tumor implantation model, intratumoral ZIKV treatment of one tumor increases overall survival, suggesting ZIKV is efficacious because it generates a global anti-tumor response. Building on the observation that ZIKV treatment increases CD8+ T cells in the tumor bed, we combined ZIKV with α-PD1 immunotherapy. We found survival was dramatically increased compared to either treatment alone. Finally, to improve safety of potential ZIKV treatment for patients, we generated an immune-sensitized virus. This strain remains efficacious as a single agent and in combination with immunotherapy in vivo. Overall, our results suggest ZIKV treatment addresses two key problems in our current treatment of GBM: it specifically targets highly resistant GSC and initiates a potent anti-tumor immune response against the remaining tumor. Our work reveals the mechanistic basis of ZIKV efficacy and demonstrates the potential for ZIKV as a therapy for GBM.
CSIG-21. BAF60C/SMARCD3 REGULATES TUMOR CELL DISSEMINATION IN MEDULLOBLASTOMA
Authors: Baoli Hu, Brad Poore, Vaibhav Sharma, Yongchang Guan, Sameer Agnihotri, Ian Pollack, Baoli Hu
Journal: Neuro-Oncology (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-13. CLINICAL EFFICACY OF MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, IN RECURRENT GBM DELIVERED BY CONVECTION ENHANCED DELIVERY (CED)
Authors: John Sampson, Achal Achrol, Manish Aghi, Krystof Bankiewiecz, Martin Bexon, Steven Brem, Andrew Brenner, Chandtip Chandhasin, Sajeel Chowdhary, Melissa Coello, Benjamin Ellingson, John Floyd, Seunggu Han, Santosh Kesari, Fahar Merchant, Nina Merchant, Dina Randazzo, Michael Vogelbaum, Frank Vrionis, Miroslaw Zabek, Nicholas Butowski
Journal: Neuro-Oncology (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 &amp;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 &amp;gt; 100% is promising for this devastating disease.
Assessment of German Public Attitudes Toward Health Communications With Varying Degrees of Scientific Uncertainty Regarding COVID-19
Authors: Odette Wegwarth, Gert G. Wagner, Claudia Spies, Ralph Hertwig
Journal: JAMA Network Open (2020)

In this survey of German residents, a majority of respondents indicated a preference for open communication of scientific uncertainty in the context of the COVID-19 pandemic.For those who are currently skeptical of governmental containment measures, communication expressing uncertainty appeared to be particularly effective in motivating them to comply with the measures.The generalizability of these results may be limited by our sample, which consisted of only German residents.These results are unexpected to the extent that research in other nonmedical and medical domains suggests that the communication of uncertainty prompts avoidance and increased levels of discomfort. 2,6We speculate that our respondents-and perhaps people worldwide-may be more open to the communication of uncertainty in the context of COVID-19 because the individual and collective experience of the pandemic is one of rapidly changing knowledge and absence of certainty.It may even be that admitting and communicating scientific uncertainty to the public fosters trust.
TMOD-34. PATIENT-DERIVED XENOGRAFT AND CELL LINE MODELS FACILITATE NOVEL TREATMENT DISCOVERY IN CENTRAL NERVOUS SYSTEM LYMPHOMAS
Authors: David Meredith, Kin Hoe Chow, Pei-Lun Kao, Yu Zeng, Rileen Sinha, Aniket Shetty, Michael Tolstorukov, Tony Tran, Smitha Yerrum, Ugonma Chukwueke, Wenya Linda Bi, Omar Arnaout, Timothy Smith, Keith Ligon, Lakshmi Nayak
Journal: Neuro-Oncology (2020)

Abstract Lymphomas of the central nervous system (CNSL) are rare tumors with few treatment options; however, recent genomic studies have uncovered several druggable targets. To facilitate novel treatment discovery, we sought to establish patient-derived xenograft (PDX) models and cell lines from patients with newly diagnosed or recurrent CNSL. PDX models were attempted from fresh tumor samples from 18 consented patients for whom rich clinical annotation was available. Orthotopic intracranial injections were performed via stereotactic injection. Cell line generation was attempted from both primary tumors (PDCL) and PDX samples (PDXCL). Characterization included histopathology, targeted exome sequencing, low-pass whole-genome sequencing for copy number evaluation, and expression profiling of matched patient tumors and PDXs. Drug response testing was performed using CellTiterGlo. From 18 samples attempted, 8 PDX models were successfully generated: 2 primary CNS diffuse large B-cell lymphoma (DLBCL), 5 secondary CNS DLBCL, and 1 secondary cutaneous T-cell lymphoma (CTCL). Mean time to moribund was 66 days. All 8 PDXs grew successfully as orthotopic models, and 4 also grew in subrenal capsule. Additionally, 6 PDCL and 2 PDXCL were established (&amp;gt; P3). Models faithfully represented primaries, showing nearly identical histopathology, immunoprofiles, and genomic signatures. To support expanded and rapid preclinical use of these models in drug testing we documented that PDX could be explanted to create short-term cell preparations or long-term cell lines with a 100% and 40% success rate, respectively. Proof of principle testing showed that explanted DLBCL PDX cells and cell lines showed sensitivity to copanlisib and venetoclax, which were not efficacious in the CTCL PDX. These findings showcase a diverse collection of CNSL models demonstrating high fidelity to primary tumors at the genomic and phenotypic levels, emphasizing their utility for preclinical studies and as patient avatars to rapidly determine sensitivities to existing and novel regimens prior to initiation of therapy.
STEM-28. NANOPARTICLES ENCAPSULATING A CONNEXIN43 MIMETIC PEPTIDE LIMIT GLIOMA STEM CELL SURVIVAL AND GLIOBLASTOMA PROGRESSION
Authors: John Will, Emily Thompson, Megan Harrigan, James Smyth, Zhi Sheng, Robert Gourdie, Harry Sontheimer, Johan Foster, Samy Lamouille
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor in the US. The current treatment regimen for GBM still retains an alarmingly poor prognosis, with median survival of only 14.6 months. Failure to generate more effective treatment strategies is due to the infiltrative nature of GBM tumor cells, which hinders complete surgical resection, and cellular heterogeneity within GBM tumors, with a sub-population of glioma stem cells (GSCs) resistant to irradiation treatment and chemotherapeutic agents including temozolomide. As a result, all treated GBM patients will experience tumor recurrence, highlighting the need for novel approaches in targeting such refractory tumor cell populations to successfully treat GBM tumors and prevent recurrence. Using super resolution localization microscopy, we have identified that increased interaction of connexin43 (Cx43) with microtubules in GSCs confers tumorigenic behavior to these cells. We employed a Cx43 mimetic peptide named JM2 (juxtamembrane 2) that encompasses the microtubule binding sequence of the Cx43 carboxy-terminus. This peptide drug efficiently and specifically disrupts the interaction of Cx43 with microtubules and limits GSC survival, proliferation, and migration, without affecting normal human astrocytes. Next, we implemented the therapeutic strategy of JM2 encapsulation within biodegradable polymeric nanoparticles (NPs) to reduce administration frequency and patient discomfort, and increase peptide stability and activity. We confirmed sustained release of JM2 from these poly(lactic-co-glycolic) acid biodegradable NPs, and JM2 bioactivity through disruption of Cx43 interaction with microtubules. Administration of JM2-NPs inhibits GSC-derived neurosphere formation in vitro and patient GBM-derived organoid growth ex vivo. Finally, using an orthotopic xenograft brain tumor mouse model, we demonstrate in vivo that JM2-NPs significantly decrease the number of GSCs within brain tumors, and inhibit the formation of highly invasive GBM tumors. Our findings on generation of JM2-NPs to target GSC survival lays the foundation for future clinical trials in newly diagnosed GBM patients.
Anti-inflammatory therapy for COVID-19 infection: the case for colchicine
Authors: Aaron Z Reyes, Kelly A Hu, Jacob Teperman, Theresa L Wampler Muskardin, Jean-Claude Tardif, Binita Shah, Michael H Pillinger
Journal: Annals of the Rheumatic Diseases (2020)

The search for effective COVID-19 management strategies continues to evolve. Current understanding of SARS-CoV-2 mechanisms suggests a central role for exaggerated activation of the innate immune system as an important contributor to COVID-19 adverse outcomes. The actions of colchicine, one of the oldest anti-inflammatory therapeutics, target multiple mechanisms associated with COVID-19 excessive inflammation. While many COVID-19 trials have sought to manipulate SARS-CoV-2 or dampen the inflammatory response once patients are hospitalised, few examine therapeutics to prevent the need for hospitalisation. Colchicine is easily administered, generally well tolerated and inexpensive, and holds particular promise to reduce the risk of hospitalisation and mortality due to COVID-19 in the outpatient setting. Successful outpatient treatment of COVID-19 could greatly reduce morbidity, mortality and the demand for rare or expensive care resources (front-line healthcare workers, hospital beds, ventilators, biological therapies), to the benefit of both resource-replete and resource-poor regions.
NCOG-28. SURGERY FOR RECURRENT GBM IMPROVES SURVIVAL INDEPENDENT OF PROGNOSTIC FACTORS
Authors: Mathew Voisin, Gelareh Zadeh
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The survival benefit of surgery for recurrent GBM in the current literature is variable, and often attributed to improvements in surgical technique over time. Studies examining outcomes over prolonged periods are lacking. The primary objective of our study was to determine if surgery for recurrent GBM confers a survival benefit compared to patients not undergoing repeat surgery. The secondary objective of our study was to investigate the effect of known prognostic factors on survival for patients undergoing repeat surgery for GBM. METHODS We analyzed our brain tumour biobank database from 1992 to 2018 for all adult patients that underwent repeat surgery for primary recurrent GBM. This cohort was compared to publicly available data from The Cancer Genome Atlas (TCGA). Survival and prognostic factors were compared within and between groups using Kaplan-Meier survival curves and Cox proportional hazards models. RESULTS A total of 676 patients were included (surgery cohort = 91, non-surgery cohort = 585). The surgery group had a lower age at diagnosis (50.6 vs 58.2 years old, p = &amp;lt; 0.001) and higher Karnofsky Performance Status (KPS) (81.4 vs 77.5, p = 0.002) at diagnosis than the non-surgery group. Other known prognostic factors including IDH status and MGMT methylation status were balanced between groups. Overall median survival was higher in the surgery group than the non-surgery group (30.6 months vs 13.9 months, p = &amp;lt; 0.0001). Within the surgery group, prognostic factors including age, sex, KPS, IDH status, MGMT status, extent of resection by surgeon, tumour location, and time to recurrence were not associated with additional survival benefit. CONCLUSIONS Patients that undergo surgery for recurrent GBM are of younger age and lower KPS at time of initial diagnosis. In patients that undergo repeat surgery, known patient and tumour prognostic factors are not associated with additional survival benefit.
EXTH-30. EXPANDING THE UTILITY OF PRE-CLINICAL CONTRAST ENHANCED CT (CE-CT) FOR TUMOR DETECTION IN ORTHOTOPIC GBM MODELS USING RADIOMICS
Authors: Kate Connor, Emer Conroy, Kieron White, Liam Shiels, William Gallagher, Simon Keek, Abdalla Ibrahim, James Clerkin, David O’Brien, Philippe Lambin, Henry Woodruff, Annette Byrne
Journal: Neuro-Oncology (2020)

Abstract Despite magnetic resonance imaging (MRI) being the gold-standard imaging modality in the glioblastoma (GBM) setting, the availability of rodent MRI scanners is relatively limited. CT is a clinically relevant alternative which is more widely available in the pre-clinic. To study the utility of contrast-enhanced (CE)-CT in GBM xenograft modelling, we optimized CT protocols on two instruments (IVIS-SPECTRUM-CT;TRIUMPH-PET/CT) with/without delivery of contrast. As radiomics analysis may facilitate earlier detection of tumors by CT alone, allowing for deeper analyses of tumor characteristics, we established a radiomic pipeline for extraction and selection of tumor specific CT-derived radiomic features (inc. first order statistics/texture features). U87R-Luc2 GBM cells were implanted orthotopically into NOD/SCID mice (n=25) and tumor growth monitored via weekly BLI. Concurrently mice underwent four rounds of CE-CT (IV iomeprol/iopamidol; 50kV-scan). N=45 CE-CT images were semi-automatically delineated and radiomic features were extracted (Pyradiomics 2.2.0) at each imaging timepoint. Differences between normal and tumor tissue were analyzed using recursive selection. Using either CT instrument/contrast, tumors &amp;gt; 0.4cm3 were not detectable until week-9 post-implantation. Radiomic analysis identified three features (waveletHHH_firstorder_Median, original_glcm_Correlation and waveletLHL_firstorder_Median) at week-3 and -6 which may be early indicators of tumor presence. These features are now being assessed in CE-CT scans collected pre- and post-temozolomide treatment in a syngeneic model of mesenchymal GBM. Nevertheless, BLI is significantly more sensitive than CE-CT (either visually or using radiomic-enhanced CT feature extraction) with luciferase-positive tumors detectable at week-1. In conclusion, U87R-Luc2 tumors &amp;gt; 0.4cm3 are only detectable by Week-8 using CE-CT and either CT instrument studied. Nevertheless, radiomic analysis has defined features which may allow for earlier tumor detection at Week-3, thus expanding the utility of CT in the preclinical setting. Overall, this work supports the discovery of putative prognostic pre-clinical CT-derived radiomic signatures which may ultimately be assessed as early disease markers in patient datasets.
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: Carolina Chavez, Richard Everson, Joey Orpilla, Alexander Lee, Sara Khattab, Joseph Antonios, Andres Salazar, Timothy Cloughesy, Linda Liau, Lu Sun, Willy Hugo, Robert Prins
Journal: Neuro-Oncology (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.
NIMG-58. THE EFFECT OF CELL CONFLUENCE ON THE DISTRIBUTION OF TUMOR TREATING FIELDS
Authors: Tal Marciano, Shay Levi, Zeev Bomzon
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Tumor Treating Fields (TTFields) are known to exert anti-mitotic effects on cells. Numerical simulations investigating the electric field distribution within isolated cells have been reported. These studies have shown that during metaphase a uniform electric field forms within the rounded cells. This field is thought to disrupt spindle formation through alignment of the tubulin dimers with the field. Simulations also show that during cytokinesis, a non-uniform electric field forms at the furrow, leading to strong dielectrophoretic forces that further disrupt cell division. Cells in the tumor are densely packed. We used numerical simulations to investigate how the clustering of cells influences TTFields distribution. METHODS COMSOL was used to numerically simulate delivery of TTFields to clusters of round cells placed in a hexagonal arrangement. The influence of the distance between the cells on field distribution was investigated. The effect of pores in the cell membrane on field distribution was also investigated. RESULTS Placing round cells in clusters resulted in regions of highly non-uniform fields within the cells. Strong gradients in the electric field were also observed around pores placed in the membrane. Non-uniformity and gradients in the field could result in strong dielectrophoretic forces capable of disrupting key cellular structures such as the cytoskeleton and mitotic spindle, as well as cell membrane integrity. CONCLUSIONS The placement of cells in close proximity to one another creates gradients in the electric field, which could be associated with very strong dielectrophoretic forces that enhance the effects of TTFields on cells. Strong dielectrophoretic forces were also observed around the membrane pores. Previous studies have reported that TTFields increases membrane permeability [Chang et al Cell Death Discovery. 2018]. The strong dielectrophoretic forces in the membrane may provide a physical mechanism by which TTFields enhance membrane permeability.