tbuckley/cabot-search huggingface dataset:
RARE-01. IN VIVO IMMUNOMODULATING EFFECT OF LXR-623 AND ITS SYNERGISM WITH CHECKPOINT BLOCKADE AGAINST CHORDOMAS IN A HUMANIZED MOUSE MODEL
Authors: Wataru Ishida, Riccardo Serra, Noah Gorelick, Yuanxuan Xia, Joshua Casaos, Christine Shrock, Alexander Perdomo-Pantoja, Betty Tyler, Sheng-fu Lo
Journal: Neuro-Oncology (2018)

We previously developed a humanized mouse model of chordomas, which allowed us to investigate the interaction between human chordomas and human immune cells. This platform is particularly useful for studying immunotherapy against rare cancers such as chordomas, where murine equivalents are currently unavailable. We aim to utilize this model to study synergism between PD-1 blockade and LXR-623, a synthetic agonist of liverX receptors, a class of anti-neoplastic agents disrupting cancer cholesterol-metabolism. Our preliminary data suggest that LXR-623 downregulates PD-L1 on chordoma cell lines and reduces immunosuppressive myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. To achieve immune system reconstitution/humanization, 20 NSG-SGM3 mice were engrafted with human fetal thymus and CD34+ stem cells, whose HLA-types were partially-matched with those of the U-CH1 chordoma cell lines. They were divided into the following groups (n=5 for each group): control group (isotype antibodies (Abs) + vehicle), LXR-623 monotherapy group (isotype Abs + LXR-623 100mg/kg, i.p., daily for 4 weeks), anti-PD-1 Abs monotherapy group (anti-human-PD-1-Abs (Clone: J116), 10 mg/kg, i.p., 3 times/week for 4 weeks), and combination group (anti-human-PD-1 Abs + LXR-623). Anti-tumor activities will be monitored via tumor size measurement, flow cytometric analyses of peripheral blood and spleen as well as chordomas, using various Abs including anti-mouse-CD45, anti-human-CD3, anti-human-CD4, anti-human-CD8, anti-human-CD11b, anti-human-CD14, anti-human-CD15, anti-human-CD19, anti-human-CD25, anti-human-CD45, anti-human-CD45RA, anti-human-CD45RO, anti-human-PD-1, and anti-human-FoxP3, multiplex cytokine analyses including IFN-gamma and TGF-beta, and multiplex-immunohistochemistry. We expect to observe the synergistic inhibitory effect of LXR-623 and anti-PD1-Abs against chordomas through PD-L1 downregulation and reduction in immunosuppressive MDSC levels mediated by LXR-623. We plan to sacrifice the last animal group on August 24th. Due to the lengthy nature of the experiment (humanization and treatment take 13–14 weeks), the data are not fully available at the time of submission but will be available by the late-breaking deadline.
STAT3: a link between CaMKII–βIV-spectrin and maladaptive remodeling?
Authors: Mohit Hulsurkar, Ann P. Quick, Xander H.T. Wehrens
Journal: Journal of Clinical Investigation (2018)

βIV-Spectrin, along with ankyrin and Ca2+/calmodulin-dependent kinase II (CaMKII), has been shown to form local signaling domains at the intercalated disc, while playing a key role in the regulation of Na+ and K+ channels in cardiomyocytes. In this issue of the JCI, Unudurthi et al. show that under chronic pressure overload conditions, CaMKII activation leads to βIV-spectrin degradation, resulting in the release of sequestered STAT3 from the intercalated discs. This in turn leads to dysregulation of STAT3-mediated gene transcription, maladaptive remodeling, fibrosis, and decreased cardiac function. Overall, this study presents interesting findings regarding the role of CaMKII and βIV-spectrin under physiological as well as pathological conditions.
Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial
Authors: Harriet M. Kluger, Veronica Chiang, Amit Mahajan, Christopher R. Zito, Mario Sznol, Thuy Tran, Sarah A. Weiss, Justine V. Cohen, James Yu, Upendra Hegde, Elizabeth Perrotti, Gail Anderson, Amanda Ralabate, Yuval Kluger, Wei Wei, Sarah B. Goldberg, Lucia B. Jilaveanu
Journal: Journal of Clinical Oncology (2018)

Pembrolizumab is active in melanoma, but activity in patients with untreated brain metastasis is less established. We present long-term follow-up of pembrolizumab-treated patients with new or progressing brain metastases treated on a phase II clinical trial ( ClinicalTrials.gov identifier: NCT02085070).We enrolled 23 patients with melanoma with one or more asymptomatic, untreated 5- to 20-mm brain metastasis not requiring corticosteroids; 70% of patients had prior systemic therapy. Pembrolizumab was administered for up to 24 months. Brain metastasis response, the primary end point, was assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST). Pretreatment tumors were analyzed for T-cell infiltrate and programmed death ligand 1.Six patients (26%) had a brain metastasis response. Eight patients (35%) did not reach a protocol evaluation scan and were unevaluable for brain metastasis response as a result of progression or need for radiation. Brain metastasis and systemic responses were concordant, with all ongoing at 24 months. The median progression-free and overall survival times were 2 and 17 months, respectively. Eleven patients (48%) were alive at 24 months. This included three unevaluable patients. One of these three patients had hemorrhaged, and two had symptoms from perilesional edema requiring radiosurgery, but all three patients remained on commercial pembrolizumab more than 24 months later. None of the 24-month survivors received subsequent BRAF inhibitors. Neurologic adverse events occurred in 65% of patients; all adverse events but one were grade 1 or 2. Three patients had seizures, which were treated with anticonvulsants. Most responders had higher pretreatment tumor CD8 cell density and programmed death ligand 1 expression, whereas all nonresponders did not.Pembrolizumab is active in melanoma brain metastases with acceptable toxicity and durable responses. Multidisciplinary care is required to optimally manage patients with brain metastases, including consideration of radiation to large or symptomatic lesions, which were excluded in this trial. Two-year survival was similar to patients without brain metastasis treated with anti-programmed cell death 1 agents. Concordant brain and extracerebral responses support use of pembrolizumab to treat small, asymptomatic brain metastases.
Antibiotic resistant bacteria cause nearly one in five infections in wealthy countries, report warns
Authors: Susan Mayor
Journal: BMJ (2018)

Resistance to second and third line antibiotics is set to increase by 70% by 2030 if effective public health measures are not implemented, a report has warned.1

Nearly a fifth of infections occurring in Europe, North America, and Australia are due to antibiotic resistant bacteria, said the report from the Organisation for Economic Cooperation and Development (OECD).

Researchers analysed available data on antibiotic resistance, including figures from the European Centre for Disease Prevention and Control, to model future patterns of resistance and identify “best buy” public …
EXTH-30. IN SITU AUTOVACCINATION MEDIATED BY ONCOLYTIC ADENOVIRUS DELTA-24-RGDOX INDUCES EFFICACIOUS IMMUNITY AGAINST METASTATIC MELANOMA
Authors: Hong Jiang, Teresa Nguyen, Dong Ho Shi, Xuejun Fan, Joy Gumin, Chantale Bernatchez, Frederick Lang, Candelaria Gomez-Manzano, Juan Fueyo
Journal: Neuro-Oncology (2018)

We have reported that Delta-24-RGDOX, an oncolytic adenovirus expressing the immune co-stimulator OX40 ligand (OX40L), induces efficacious anti-glioma immunity in syngeneic intracranial glioma models of immune competent mice. Here we sought to determine if the local injection of the virus triggers a systemic immune response against metastatic melanomas. We found that Delta-24-RGDOX expressed OX40L and induced cell lysis in both human and mouse melanoma cells. To study the abscopal effect of Delta-24-RGDOX against metastatic melanomas, we established s.c./s.c. and s.c./i.c. melanoma models with B16-Red-FLuc cells in C57BL/6 mice. In the s.c./s.c. model, we found that three doses of intratumoral injection of the virus significantly inhibited the growth of the injected and the untreated distant tumors, resulting in prolonged survival of the mice (70% long-term survival; P = 0.001). The surviving mice were resistant to a rechallenging with the implantation of similar tumor cells, but not when lung cancer cells were implanted, strongly suggesting the development of specific tumor immune memory. Using flow cytometry analysis, we found that Delta-24-RGDOX treatment resulted in increased frequency of CD3+ T lymphocytes, CD3+CD4+ helper T cells, CD3+CD8+ cytotoxic T cells and effector T cells, and a decrease in the amount of T regulatory cells. In addition, we observed an increment of effector CD4+ and CD8+ T cells frequency with PD-1 expression on spleen and blood cells, indicating a systemic activation of anti-tumor circulatory cells. In the s.c./i.c. model, viral injection into the s.c. tumor induced anti-melanoma activity in the brain, resulting in growth inhibition of both tumors and prolonged survival of the animals. In agreement with these data, viral injection in the s.c. tumor increased the frequency of the T effector cells in the brain tumor. In summary, local treatment of melanoma with Delta-24-RGDOX results in suppression of distant tumors including brain melanoma.
Antifibrotic Therapy Disrupts Stromal Barriers and Modulates the Immune Landscape in Pancreatic Ductal Adenocarcinoma
Authors: Kianna Y. Elahi-Gedwillo, Marjorie Carlson, Jon Zettervall, Paolo P. Provenzano
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDA) remains one of the deadliest forms of cancer, in part, because it is largely refractory to current therapies. The failure of most standard therapies in PDA, as well as promising immune therapies, may be largely ascribed to highly unique and protective stromal microenvironments that present significant biophysical barriers to effective drug delivery, that are immunosuppressive, and that can limit the distribution and function of antitumor immune cells. Here, we utilized stromal reengineering to disrupt these barriers and move the stroma toward normalization using a potent antifibrotic agent, halofuginone. In an autochthonous genetically engineered mouse model of PDA, halofuginone disrupted physical barriers to effective drug distribution by decreasing fibroblast activation and reducing key extracellular matrix elements that drive stromal resistance. Concomitantly, halofuginone treatment altered the immune landscape in PDA, with greater immune infiltrate into regions of low hylauronan, which resulted in increased number and distribution of both classically activated inflammatory macrophages and cytotoxic T cells. In concert with a direct effect on carcinoma cells, this led to widespread intratumoral necrosis and reduced tumor volume. These data point to the multifunctional and critical role of the stroma in tumor protection and survival and demonstrate how compromising tumor integrity to move toward a more normal physiologic state through stroma-targeting therapy will likely be an instrumental component in treating PDA. Significance: This work demonstrates how focused stromal re-engineering approaches to move toward normalization of the stroma disrupt physical barriers to effective drug delivery and promote antitumor immunity. See related commentary by Huang and Brekken, p. 328
Use of Risk Assessment Tools to Guide Decision-Making in the Primary Prevention of Atherosclerotic Cardiovascular Disease: A Special Report From the American Heart Association and American College of Cardiology
Authors: Donald M. Lloyd-Jones, Lynne T. Braun, Chiadi E. Ndumele, Sidney C. Smith, Laurence S. Sperling, Salim S. Virani, Roger S. Blumenthal
Journal: Circulation (2019)

Risk assessment is a critical step in the current approach to primary prevention of atherosclerotic cardiovascular disease. Knowledge of the 10-year risk for atherosclerotic cardiovascular disease identifies patients in higher-risk groups who are likely to have greater net benefit and lower number needed to treat for both statins and antihypertensive therapy. Current US prevention guidelines for blood pressure and cholesterol management recommend use of the pooled cohort equations to start a process of shared decision-making between clinicians and patients in primary prevention. The pooled cohort equations have been widely validated and are broadly useful for the general US clinical population. But, they may systematically underestimate risk in patients from certain racial/ethnic groups, those with lower socioeconomic status or with chronic inflammatory diseases, and overestimate risk in patients with higher socioeconomic status or who have been closely engaged with preventive healthcare services. If uncertainty remains for patients at borderline or intermediate risk, or if the patient is undecided after a patient-clinician discussion with consideration of risk enhancing factors (eg, family history), additional testing with measurement of coronary artery calcium can be useful to reclassify risk estimates and improve selection of patients for use or avoidance of statin therapy. This special report summarizes the rationale and evidence base for quantitative risk assessment, reviews strengths and limitations of existing risk scores, discusses approaches for refining individual risk estimates for patients, and provides practical advice regarding implementation of risk assessment and decision-making strategies in clinical practice.
ATIM-16. PHASE 1 STUDY RESULTS OF M7824 (MSB0011359C), A BIFUNCTIONAL FUSION PROTEIN TARGETING TGF- AND PD-L1, AMONG PATIENTS WITH RECURRENT GLIOBLASTOMA (rGBM)
Authors: Mustafa Khasraw, Michael Weller, David Lorente Estelles, Kathryn Kolibaba, Chee Lee, Craig Gedye, Macarena De La Fuente, David Vicente, David Reardon, Laureen Ojalvo, Christoph Helwig, Carole Gourmelon, Morris Groves
Journal: Neuro-Oncology (2018)

TGF- signaling promotes tumor immunosuppression; TGF- inhibition in the tumor microenvironment may enhance the response to antiPD-L1 treatment. M7824 is an innovative, first-in-class, bifunctional fusion protein composed of a human antiPD-L1 IgG1 monoclonal antibody fused with two extracellular domains of TGF RII to function as a TGF- trap. We report safety and efficacy of M7824 in patients with rGBM. In this efficacy expansion cohort of the ongoing, phase 1 trial NCT02517398, patients with rGBM who progressed after chemoradiation received M7824 1200 mg q2w until disease progression, unacceptable toxicity, or trial withdrawal. The primary objective was disease control rate (DCR) per RANO; secondary objectives included safety/tolerability. Among 35 patients, median age was 57 years, 68.6% were male, and 91.4% were at first recurrence. At 15 months minimum follow-up, median treatment duration was 8.1 (range, 2.0–72.1) weeks; four patients remained on treatment at >1 year, and one additional patient decided to stop treatment per protocol at 12 months. Two patients had a partial response, and nine had stable disease (DCR, 31.4% [95% CI, 16.9–49.3]), of which two exhibited early progressive disease and subsequent durable stable disease ongoing for >12 months per investigators assessment. The most common treatment-related adverse events (TRAEs) were gingival bleeding (17.1%), asthenia (14.3%), pruritus, and rash (each 11.4%). Grade 3 TRAEs (6 patients, 17.1%) included diarrhea, eczema, increased liver/pancreatic enzymes, papular rash, papules, one grade 4 asymptomatic increased lipase, and one grade 5 intratumoral hemorrhage (investigator-assessed) coterminous with disease progression. M7824 demonstrated a manageable safety profile and encouraging efficacy in rGBM, including two durable partial responses and a DCR of 31.4%. Further investigation of M7824 in GBM is warranted; future development aims to define molecular characteristics of responders.
EPID-11. PROGRESSION OF IDH MUTANT GLIOMA AFTER FIRST RECURRENCE: DEVELOPMENT OF A FEASIBLE CLINICAL TRIAL ENDPOINT IN THE RECURRENT SETTING
Authors: Julie Miller, Franziska Loebel, Isabel Arrillaga-Romany, Daniel Mordes, Nina Lelic, Tracy Batchelor, A John Iafrate, Andrew Chi, Daniel Cahill
Journal: Neuro-Oncology (2018)

Isocitrate dehydrogenase (IDH) mutant tumors represent a distinct subtype among diffuse gliomas, with improved prognosis compared to grade-matched IDH wild-type tumors. As a basis for clinical trial design of IDH-targeting drugs, we sought to describe outcomes exclusively within the glioma subgroup defined by IDH1 mutation. We retrospectively analyzed 275 IDH mutant glioma patients (48.7% grade II and 51.3% grade III tumors; 65.5% astrocytic and 34.5% oligodendroglial tumors) treated at our institution. We calculated progression and survival statistics, including median time to second progression event following first episode of recurrence, using the method of Kaplan-Meier. Estimated survival proportions were correlated with molecular, histologic and clinical factors. During a median follow-up of 6.4 years, 44 deaths (7.6%) and 149 first progression events (54.1%) were observed, with estimated median PFS of 5.7 years (95% CI 4.7–6.4) and median OS of 18.7 years (95% CI 12.2 years - not reached). We validated the effect of grade, molecular diagnosis and treatment paradigms on PFS in our cohort and found results consistent with existing literature. Following the first episode of progressive disease, 79 second progression events occurred during a median follow-up period of 4.1 years. The estimated PFS following first progressive event (PFS-2nd) is 3.0 years (95% CI 2.1–4.1). This well-characterized cohort of IDH mutant glioma patients demonstrate progression and survival outcomes reflecting published literature and serves as a reasonable historical control population. Notably, the PFS interval accelerates during disease course, with interval between first to second recurrence (3.0 years) shorter than time from diagnosis to first recurrence (5.7 years). The novel survival statistic PFS-2nd offers an accurate and relevant surrogate outcome for the design of clinical trials investigating experimental drug efficacy at recurrence. These findings highlight that inappropriate comparison to historical baseline PFS may result in prematurely abandoning promising agents.
CMET-09. IMPACT OF STEROIDS ON THE EFFICACY OF IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH NON-SMALL CELL LUNG CANCER BRAIN METASTASES
Authors: Bicky Thapa, Adam Lauko, Hamid Borghei-Razavi, John Suh, Samuel Chao, Erin Murphy, Nathan Pennell, Vamsidhar Velcheti, Lilyana Angelov, Alireza Mohammadi, Michael Vogelbaum, Gene Barnett, Manmeet Ahluwalia
Journal: Neuro-Oncology (2018)

Non-small cell lung cancer brain metastases (NSCLCBM) have dismal outcome. Immune checkpoint inhibitor (ICI) has promising activity in lung cancer; however, limited data exists on impact of steroids on efficacy of ICI in NSCLCBM. METHOD: We reviewed 120 NSCLCBM patients treated with ICI (2012–2017) at our center. Fifty-nine patients who received at-least 2 cycles of ICI after diagnosis of NSCLCBM with at least one follow-up MRI were included for analysis, others were excluded as they have received ICI before BM or did not have follow-up MRI. All patients had prior chemotherapy and received ICI (nivolumab/pembrolizumab) in second or third line. Overall survival (OS) was calculated from date of ICI therapy to date of death or last follow-up. Progression free survival (PFS) was calculated from date of ICI to date of progression. OS was estimated by Kaplan-Meier method and analyzed by Cox proportional hazards model. Median age was 61 years (39–77 years), median KPS of 90, 59% were females, 49 were adenocarcinoma (4 EGFR mutations, 2 ALK rearrangement). Forty-one patients had supratentorial lesions, 7 had infratentorial and 11 had both. Fifty-four patients underwent stereotactic-radiosurgery, 4 had whole brain radiation-therapy and 30 patients received steroids (28 at baseline before start of ICI and 2 patients within 2 cycles of ICI). Twenty-two patients received dexamethasone (2–8 mg/day), 8 received prednisone (5–20 mg/day). Median OS was 18.9 months and PFS was 9.9 months. Steroid use was associated with decreased PFS, 5.0 months vs 13.8 months (p value = 0.02). No significant difference was seen in OS with steroid treatment. On multivariable analysis, age at diagnosis significantly predicted OS (p = .034). Greater number of baseline intracranial lesions (p < .01) and concurrent steroids (p < .0005) correlated with decreased PFS. Steroid use in NSCLCBM is associated with decreased PFS with ICI.
RDNA-09. RADIATION DRIVES THE EVOLUTION OF ORTHOTOPIC XENOGRAFTS INITIATED FROM GLIOBLASTOMA STEM-LIKE CELLS
Authors: Joseph McAbee, Barbara Rath, Xiaolin Wu, Kevin Camphausen, Philip Tofilon
Journal: Neuro-Oncology (2018)

The clonal diversity and evolutionary dynamics inherent to GBMs is considered a major obstacle to effective treatment development. While studies have focused on temozolomide, a role for radiotherapy as a driver of GBM evolution has not been investigated. This study seeks to better understand the impact of radiotherapy, an important component of most treatment regimens, on GBM evolution. We intracranially implanted NSC11 and NSC20, CD133+ glioma stem-like cell lines, into nude mice. Bioluminescence imaging on day 21 post-implant confirmed the presence of tumor prior to randomization into control and radiotherapy groups (3x5Gy). Brain tumor xenografts were collected out to morbidity to assess morphological and histological changes following irradiation and to extract DNA for viral integration site analysis (VISA). Survival analysis demonstrates a significant survival advantage for mice undergoing radiotherapy (+31 days, NSC11; +36 days, NSC20). Gross examination at morbidity revealed brains bearing irradiated tumors contained tumor tissue that is more distinct, softer and more adherent, and more likely to efface olfactory bulb(s) than control tumor brains. H&E and SOX2 staining support these findings of a more infiltrative growth pattern in control tumors compared to irradiated tumors. VISA for NSC11 and NSC20 allowed for the examination of relative clonal diversity. Unsupervised hierarchical cluster analysis demonstrated a reduction in clonal diversity when transitioning from in vitro culture to in vivo conditions. Further reduction in clonal diversity is apparent when comparing control and irradiated tumors. To investigate whether the brain environment was necessary for the radiation-induced reduction in clonal diversity, NSC11 cells were irradiated in vitro and collected for VISA. Clonal diversity remained relatively consistent regardless of treatment. Our results demonstrate that radiation, in the context of the brain microenvironment, drives GBM evolution resulting in tumor morphology/histology modifications and tumor cell subpopulation selection. This process may have implications for treatment of recurrent GBM.