bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose finding study of the intratumoral administration of the oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG).
Authors: Desjardins Annick , Sampson John H. , Vlahovic Gordana , Peters Katherine B. , Randazzo Dina , Threatt Stevie , Herndon James Emmett , Bullock Chevelle A , Miller Elizabeth S , Boulton Susan , Lally-Goss Denise , McSherry Frances , Lipp Eric S , Friedman Allan H. , Friedman Henry S. , Bigner Darell D. , Gromeier Matthias 
Published: September 2018

e13533 Background: The live attenuated oral poliovirus vaccine was modified to contain a heterologous internal ribosomal entry site stemming from human rhinovirus type 2, creating PVSRIPO. PVSRIPO recognizes CD155, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We report results of the dose finding trial evaluating PVSRIPO delivered intratumorally by convection-enhanced delivery (CED). Methods: Eligible patients were adults with recurrent supratentorial WHO grade IV MG; solitary tumor 1-5.5cm in diameter; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS≥70%; and positive anti-polio titer. The original two-step continual reassessment method dose escalation was amended to decrease to dose level(DL) -1 and DL -2 after observing prolonged steroid use in patients treated on higher DLs. Results: As of 2/01/2017, 52 pts were treated on study (1 each at DL1 and DL3, 7 at DL2, 2 at DL4, 4 at DL5, 24 at DL -1 and 13 at DL -2). Only one DLT was observed, a grade 4 intracranial hemorrhage at the time of catheter removal on DL5. Grade 3 or higher adverse events possibly, probably or definitely related to PVSRIPO include: lymphopenia (grade 3, n = 1), steroid myopathy (grade 3, n = 1), cerebral edema (grade 4, n = 1), headache (grade 3, n = 1), dystonia (grade 3, n = 1), pyramidal tract syndrome (grade 3, n = 6), seizure (grade 3, n = 1; grade 4, n = 1), delusions (grade 3, n = 1), hypertension (grade 3, n = 1), and thromboembolic events (grade 3, n = 2). At a median follow-up of 20.1 months, 20.8% of pts remain alive at 36-month post PVSRIPO infusion, compared to 4% of an historical control. Four pts remain alive more than 22 months post treatment without having received any additional intervention following PVSRIPO at 57.5+, 56.4+, 27.9+ and 23.2+ months. Conclusions: Infusion of PVSRIPO via CED is safe and encouraging efficacy results are observed. The dose finding study is now completed and we are initiating clinical trials evaluating combination of PVSRIPO with other therapies. Clinical trial information: NCT01491893.
3D Mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells promote resistance to current standard-of-care therapy.
Authors: Bota Daniela Annenelie , Yan Huaming , Romero-López Monica , Benitez Lesli , Di Kaijun , Frieboes Hermann , Hughes Christopher C.W. , Lowengrub John S 
Published: September 2018

e13535 Background: Glioblastoma (GBM), the most aggressive brain tumor in human patients, is highly heterogeneous and intensively vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and by promoting resistance to therapy. Recently, crosstalk between GSCs and vascular endothelial cells that line capillaries has been shown to considerably promote GSC self-renewal and tumor progression. GSCs have been shown to also transdifferentiate into bona-fide vascular endothelial cells (GEC). GECs inherit mutations present in GSCs and are resistant to traditional anti-angiogenic therapies. Methods: We develop a multispecies mathematical model to investigate the 3D spatiotemporal dynamics of vascularized GBM progression and response to cancer therapies. Results: The model predicts GSCs drive invasive fingering and that GECs spontaneously form a network within the hypoxic core, consistent with published experimental findings. We demonstrate that standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with anti-angiogenic therapies reduce GBM tumor sizes but increase invasiveness. Anti-GEC treatments block the GEC support of GSCs and reduce tumor sizes but can lead to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduce tumor invasiveness and sizes, but are ultimately limited in reducing tumor sizes because GECs can maintain GSCs. Anti-GEC therapies are required to remove the tumor completely. Conclusions: Our results suggest that a combinatorial regimen targeting the vasculature, GSCs and GECs, using drugs already approved by the FDA, can reduce both tumor sizes and invasiveness and could lead to tumor eradication without recurrence when the treatment is stopped.
The association and prognostic significance of programmed death-ligand 1 (PD-L1) and isocitrate dehydrogenase (IDH-1) mutation in glioblastome multiforme(GBM) patients.
Authors: Sener Dede Didem , Tatlı Doğan Hayriye , Asan Fatma Betul , Gumuskaya Berrak , Ayik Sule , Sendur Mehmet Ali Nahit , Ulas Arife , Bilgin Burak , Hizal Mutlu , Akinci Bulent , Silay Kamile , Yalcin Bulent 
Published: September 2018

e13536 Background: We aimed to assessed thePD-L1, PD-1 expression, TILs and IDH-1 mutation associations and their prognostic importance in GBM. Methods: Newly diagnosed and all were operated GBM patients who folllowed between February 2006 to February 2017 were included retrospectively in the study. We assessed the PD-L1, PD-1 expression, CD4(+) ve CD8(+)TILs, IDH-1 mutation in initial tumor specimens. Immunohistochemistry was performed using Ventana® antibody (clon-SP263, ROCHE) for PD-L1 and PD-1, real time PCR used for IDH-1 mutation analysis. Intensity was graded as low, moderate, dense for PD-1, CD4, CD8 TILs. PD-L1 evaluated in percents. The cutoff value assumed as ≥5% for PD-L1 positivity. We used Kaplan Meier, Cox regression tests and SPSS 23. Results: Fourty eight patients included in the study. The mean age was 54± 14,4 and 34 (70%) patients were male. Thirty (70 %) patients were received chemoradiotherapy with temozolamide and 20 (41%) of them also received chemotherapy.We identified two different staining pattern of PD-L1 expression as diffuse fibrillary [13(27%)] and membranous staining [14(29%)]. IDH-1 mutation was found in 30 (62%) patients. We found that TILs were more intensely located in the perivascular area than intratumoral area and in that TILs, PD-1 intensity were dense. We also found a correlation between the percentages of PD-L1 positivity and the density of TILs in the intratumoral and perivascular areas (p < 0,002, r = 0,46). The intensity of both TILs in perivascular areas were significantly lower in PD-L1 (-) tumors than in PD-L1 (+) tumors (p < 0,001). We didn’t find any association between IDH-1 and PD-L1 or TILs. According to survival and multivariate analysis; age, sex, PD-L1 positivity and IDH-1 mutation status did not appear to have a significant effect on survival. (log rank 0,08; 0,30; 0,89; 0,14 respectively) The presence of dense intratumoral CD8(+) and PD-1 (+)TILs were found as positive; advanced age and membranous PD-L1 staining was found as negative independent prognostic factors. Conclusions: Different staining pattern of PD-L1 in tumor tissue and PD-1 positivity in TILs may be a prognostic importance in GBM
Comparison of tissue DNA to circulating tumor DNA in patients with brain metastases.
Authors: Lanman Tyler A. , Kesari Santosh , Patel Sandip Pravin , Bazhenova Lyudmila , Parker Barbara A. , Daniels Gregory A. , Fanta Paul T. , Plaxe Steven C. , Schwaederle Maria Clemence , Kurzrock Razelle , Piccioni David Eric 
Published: September 2018

e13546 Background: Brain metastases are often a late complication of cancer, not easily amenable to biopsy, and may contain additional molecular alterations not found in the original tumor. We sought to analyze the concordance between tissue DNA and cell-free circulating tumor DNA (ctDNA) in patients who developed brain metastases, and determine how the ctDNA profile changed with time. Methods: We retrospectively analyzed 31 patients with brain metastases who underwent next-generation sequencing (NGS) from both ctDNA and tumor tissue DNA. Breast, lung, ovarian, renal, melanoma, and colon primaries were included (42, 32, 13, 7, 3, and 3%, respectively). Tissue DNA was from primary tumor, systemic metastasis or brain (39, 39, and 7%, respectively). A median number of five alterations was found in each tissue group. Alterations in ctDNA were compared to tumor DNA and analyzed for relative frequencies, concordance, and novel alterations. Overall survival (OS) and time between DNA sample collections was analyzed. Results: All 31 patients had detectable mutations in tumor tissue. 25 patients (80.6%) had detectable ctDNA alterations and 14 patients (45.2%) had at least one identical ctDNA alteration that was concordant with tissue DNA. The most commonly altered genes (in both ctDNA and tissue DNA) were TP53 and EGFR. Breast cancer had both the highest proportion of patients with ≥ 1 ctDNA alterations (92.3%) and the highest proportion of patients who had ≥ 1 alterations in common with tissue DNA (61.5%). 23 of the 25 patients (92%) with detectable ctDNA alterations had additional alterations not found in tissue DNA, which increased with time from tumor DNA sampling. Median time between ctDNA extraction and tissue biopsy was 6.5 months for cases with common alterations, and 12.4 months for those without common alterations. There was trend to decreased OS with increasing ctDNA burden. Conclusions: We found that ctDNA is comparable with tissue DNA sequencing in patients with brain metastases. This concordance decreases with increasing time from tissue diagnosis, reflecting the changing nature of tumor genetics and highlighting the utility of ctDNA as a feasible way to monitor changes and identify additional potentially targetable alterations.
EGFR/CD16A tetravalent bispecific antibody AFM24 to engage NK-cells to kill EGFR expressing tumor cells and safety results in cynomolgus monkey studies.
Authors: Kerber Anne , Kluge Michael , Reusch Uwe , Ellwanger Kristina , Fucek Ivica , Weichel Michael , Haneke Torsten , Knackmuss Stefan , Rajkovic Erich , Treder Martin 
Published: September 2018

e14001 Background: The epidermal growth factor receptor is a target for the treatment of solid tumors, like CRC, HNSCC and NSCLC. Therapeutic success of EGFR-targeting agents depends on mutations defining resistance to these agents, thus an effective EGFR-targeting therapy overcoming resistance would offer an attractive new treatment option. Natural killer (NK-) cells play a central role in the innate immune system and can destroy cancer cells. NK-cell-engaging bispecific antibodies may offer a safe and effective therapy to target EGFR-expressing tumor cells irrespective of their mutational status. Methods: AFM24 was generated using proprietary human anti-EGFR and anti-CD16A variable domains and characterized for binding, stability, manufacturability, efficacy and safety in biophysical and functional assays in vitro and in vivo. Assays for binding to target/effector cells and cytotoxicity were performed in the presence of physiologically relevant IgG levels using EGFR+ tumor cell lines with and without RAS. The safety profile of AFM24 was investigated in vitro for off-target activity and in vivo in cynomolgus monkeys. Results: AFM24 showed excellent biophysical properties and picomolar EC50 values in cytotoxicity assays. It was more potent than cetuximab, or an antibody with cetuximab-derived anti-EGFR variable domain. Importantly, AFM24 was less prone to IgG interference and eliminated cell lines harboring negative predictive biomarkers in in vitro cytotoxicity assays, even in the presence of relevant serum IgG levels. AFM24 demonstrated in vivo efficacy in a humanized hu-NOG mouse model. Furthermore, AFM24 exhibited a favorable safety profile in cynomolgus monkeys. It was well tolerated up to 94 mg/kg in a single dose, maximum tolerated dose study (MTD) when administered as a 2 hour infusion. Conclusions: Our data suggest that AFM24 is a highly potent and potentially safer drug candidate suitable for the treatment of EGFR-expressing cancers with the potential to overcome resistance to other EGFR-targeting agents and to avoid toxic side effects seen with other anti-EGFR therapeutics.
Pritumumab binding to glioma cells induces ADCC and inhibits tumor growth.
Authors: Kesari Santosh , Babic Ivan , Mukthavaram Rajesh , Jiang Pengfei , Nomura Natsuko , Pingle Sandeep C. , Juarez Tiffany , Yang Junbao , Yenugonda Venkata , Nurmemmedov Elmar , Glassy Mark Charles 
Published: September 2018

e14004 Background: Pritumumab is a natural human IgG1 kappa antibody originally isolated from a regional draining lymph node of a patient with cervical carcinoma. This antibody binds ectodomain vimentin on the surface of tumor cells and has demonstrated some benefit to glioblastoma patients in limited clinical trials. We wanted to determine if pritumumab inhibits glioma growth in vivo and if binding to glioma cells induces cell-mediated immunity. Methods: Pritumumab was used in flow cytometry experiments with several glioma cell lines and patient-derived neurosphere lines. Antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assay was used with glioma target cells. Xenograft studies were performed in mice with and without intact B- and NK- cells. Results: We performed flow cytometry using pritumumab antibody and demonstrate binding of pritumumab to the surface of glioma cells and patient-derived glioma initiating cells. We observed significant induction of ADCC by pritumumab binding to glioma cells. Xenograft studies demonstrated pritumumab was effective in preventing tumor growth in nude mice but not in SCID mice. Intact cell-mediated immunity was necessary for pritumumab’s anti-tumor effect. Analysis of a blood brain barrier model showed significant binding of pritumumab in brain tumor areas and minimal distribution in normal brain tissues suggesting the antibody can cross the blood brain barrier. Conclusions: Our data demonstratepritumumab binds glioma cells in vitro and can induce ADCC. In addition, pritumumab can limit the growth of xenograft glioma tumors in vivo only in the presence of intact cell-mediated immunity. Together these data suggest pritumumab is suitable for development as an anti-tumor therapeutic.
A randomized, double-blind, single dose comparison of pharmacokinetics and safety of FKB238 with bevacizumab.
Authors: Kaito Hidekuni , van den Berg Frans , Niewiarowski Andrew , Boyce Malcolm 
Published: September 2018

e14007 Background: Bevacizumab is a recombinant humanized monoclonal antibody that binds selectively to vascular endothelial growth factor-A (VEGF-A). Bevacizumab was first approved for treatment of metastatic colon cancer under the brand name Avastin; it has since been approved for treating various other cancers. FKB238 is being developed as a biosimilar to Avastin. In this first-in-human study, safety, pharmacokinetics (PK) and immunogenicity of FKB238 were compared to those of branded Avastin from US and EU market. Methods: Ninety nine healthy male subjects were randomly assigned to receive a single 5 mg/kg intravenous infusion of either EU Avastin, US Avastin or FKB238 in a 1:1:1 ratio. Safety, PK and immunogenicity (anti-drug antibodies - ADA) were assessed up to 99 days after the infusion. Each PK parameter (AUC0-inf and AUC0–t as primary; Cmax and t1/2 as secondary) was analysed to assess similarity between FKB238 and EU Avastin, FKB238 and US Avastin, and EU Avastin and US Avastin. PK similarity is established if for each of the 2 primary PK parameters, the 90% confidence interval (CI) of the ratio of geometric means for the said 3-way comparison falls within 0.80-1.25. Results: A total of 99 subjects were randomized and 96 completed the study. The 90% CI for the ratio of geometric LS means of all 3 comparisons (FKB238/EU Avastin, FKB238/US Avastin and US Avastin/EU Avastin) for all 4 PK parameters were entirely within the pre-defined equivalence margin (0.80-1.25). Overall, 81% of subjects experienced an adverse event (AE) after treatment (FKB238: 97.0%; EU Avastin: 76.5%; US Avastin: 71.9%). Most AEs were mild or moderate in intensity (Grade 1 or 2 by CTCAE ver. 4); the most common were headache (16.2%), epistaxis (8.1%) and fatigue (5.1%). There were no serious AEs. All subjects had a negative ADA against study drug at their last visit. Conclusions: The study demonstrated PK similarity of FKB238, EU Avastin and US Avastin in healthy male subjects. FKB238 was well tolerated, with no serious AEs. All three study compounds showed comparable safety profile with no significant AEs or evidence of a propensity to form ADAs. This results support further development of FKB238 as a proposed biosimilar to Avastin. Clinical trial information: 163882.
SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/neu expression.
Authors: Menderes Gulden , Bonazzoli Elena , Bellone Stefania , Black Jonathan , Altwerger Gary , Pettinella Francesca , Masserdotti Alice , Zammataro Luca , Buza Natalia , Hui Pei , Wong Serena , Litkouhi Babak , Ratner Elena , Silasi Dan-Arin , Azodi Masoud , Schwartz Peter E. , Santin Alessandro 
Published: September 2018

e14009 Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. HER2 overexpression/amplification in EOC show considerable variation ranging from 8% to 66%. SYD985 (Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands) is a novel HER2-targeting antibody-drug conjugate (ADC) composed of the monoclonal antibody (mAb) trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin). The objective of this study was to compare the anti-tumor activity of SYD985 to trastuzumab emtansine (T-DM1) in EOC. Methods: The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. Results: SYD985 and T-DM1 induced similar ADCC in the presence of effector cells [i.e., peripheral blood lymphocytes (PBL)] against EOC cell lines with high, moderate and low HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1. Specifically, in HER2/neu 1+ cell lines the mean IC50’s were 0.072 µg/mL and 3.035 µg/mL for SYD985 vs T-DM1 (p < 0.0001), in HER2/neu 2+ cell lines 0.054 µg/mL and 1.168 µg/mL, (p < 0.0001) and in HER2/neu 3+ cell lines 0.024 µg/mL and 0.088 µg/mL, respectively, (p < 0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ EOC cells admixed with HER2/neu 3+ cells. In vivo studies confirmed that SYD985 is more active than T-DM1 in EOC and effective against HER2/neu 3+ xenografts. Additional (HER2/neu 2+ & 1+) EOC xenograft studies are ongoing. Conclusions: SYD985 is a novel ADC with remarkable in vitro activity against EOC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it may be active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in EOC patients harboring chemo-resistant disease are needed.
A clinical study to evaluate the efficacy and safety of docetaxel with ribavirin in patients with progressive castration resistant prostate cancer who have previously received docetaxel alone.
Authors: Kosaka Takeo , Maeda Takahiro , Shinojima Toshiaki , Nagata Hirohiko , Mizuno Ryuichi , Oya Mototsugu 
Published: September 2018

e14010 Background: We have previously reported a novel cell reprogramming approach, named drug efficacy reprogramming, as a new model for identifying candidate antitumor drugs targeting cancer stemness related gene network and identified ribavirin as a candidate drug for overcoming docertaxel resistant castration resistant prostate cancer.This non-randamized and open-labelled pilot clinical study explored the safety and efficacy of ribavirin, anti-virus drug, in combination with docetaxel in patients with progressive CRPC. Methods: In this clinical study, patients received intravenous docetaxel 60-70 mg/mm2 on day 1 of 3-6 weeks cycles plus Ribavirin 600 mg twice daily. The primary endopoint was safety, PSA response and objective response rate. Secondary end ponts included health-related quality of life overall survival.Patients with progressive CRPC based on PSA and/or radiographic criteria, PS 0-1, normal renal and hepatic function were eligible. Results:Five patients were enrolled in this study. Medium age was 73. Median serum PSA concentration was 53.1 ng/ml (range: 5.1-370.5).The median cycle and total dose of docetaxel received before the study was 31 cycles and 3625 mg, respectively. 80% of patients who had disease progression during docetaxel treatment. The median time from last docetaxel dose to disease progression before the participation was 1.5 months.Safety: Medium number of treatment cycles were 7 (range: 3-8) cycles. Grade 3/4 adverse events requiring dose modification were not observed. Grade 3 anemia and neutropenia were seen in two patients. Common adverse events were less than Grade 2. Efiicacy: 3 (60%) had some degree of PSA decline and 2 (40%) had a decline of ≧30 %. Median follow-up was 10.0 month. Median progression free survival was 6 month. Conclusions: This combination was well tolerated with promising response rate, justifying further investigation in docetaxel resistant CRPC. Clinical trial information: UMIN000012521.