bluuebunny/crossref_metadata_2025_split huggingface dataset:
CAR-T Cells Targeting gp350 Recognize Immortalized Cells Latently Infected with EBV
Authors: Danisch Simon , Slabik Constanze , Zeidler Reinhard , Ganser Arnold , Stripecke Renata 
Published: October 2019

Abstract

Objectives: Epstein-Barr virus (EBV) is associated with lymphoproliferative disease in immunocompromised hosts and with human B-cell lymphomas and carcinomas. Adoptive transfer of virus-specific T cells is not practical when memory T cells from HLA-matched donors are not available. Hence, we designed T cells expressing EBV-specific chimeric antigen receptors (CARs) to bypass the need of matched memory T cells. The surface-bound glycoprotein 350 (gp350) was used as target, because it is abundantly expressed during lytic EBV replication and it can also be detected in EBV-immortalized cells.
Methods: gp350-CARs were constructed by fusion of single-chain variable fragments of two high affinity gp530-specific human mABs (7A1 and 6G4) to CAR-backbones containing the CD28/CD3ζ domains. Transduction of human T cells from PBMC and cord blood with γ-retroviral vectors showed higher expression levels of 7A1-gp350-CAR than 6G4-gp350-CAR.
Results: We used 293T cells expressing gp350 and B95-8 immortalized cells from a tamarin monkey (6-10% gp350+) and human B cells immortalized with the EBV laboratory strain M81 (30% gp350+) in order to compare the potency of gp350-CAR T cells in vitro. Both 7A1-gp350-CAR and 6G4-gp350-CAR were activated and proliferated in the presence of gp350+ cells, inducing cytotoxicity of the target cells. Pilot experiments in a preclinical humanized mouse model consisting of Nod.Rag mice transplanted with human cord-blood (CB) stem cells and infected with an EBV/fLUC strain, we could confirm persistence of CB-matched 7A1-gp350-CAR T cells in spleen, bone marrow and lung for up to 6 weeks. In some animals, this was correlated with lower EBV dissemination measured by optical imaging and PCR.
Conclusions: We showed that EBV-specific CARs can reprogram naïve or memory T cells from PBMC or CB to react against EBV infected cells in an HLA-independent manner. This approach can be translated in the future for the generation of anti-EBV-CAR T cells for patients in Need.

Disclosures
Ganser: Novartis: Membership on an entity's Board of Directors or advisory committees.
Prediction of Response to Fostamatinib Based on the Presence of Plasma Platelet Autoantibodies in Adult Patients with Immune Thrombocytopenia (ITP) — Exploratory Analyses from Phase 3 Studies
Authors: Markovtsov Vadim V. , Yi Sothy , Young Chi , Duliege Anne-Marie , Masuda Esteban 
Published: October 2019

Abstract
Background: Initial results of an analysis of anti-platelet autoantibodies in patients with ITP from two phase 3 studies showed that patients were more likely to respond to treatment with the SYK inhibitor fostamatinib if they were positive for anti-platelet autoantibodies. Stable platelet responses to fostamatinib were reported in 36% of 28 patients who tested positive for anti-platelet autoantibodies and in 9% of 32 patients who tested negative (p<0.02). This analysis has been expanded to include 85 patients and to evaluate various platelet antigens.
Methods: Plasma samples from 85 patients in the phase 3 studies were collected with informed consent at 2 weeks after the first dose of fostamatinib. Samples were analyzed for anti-platelet autoantibodies via Luminex beads-based PakLx assayand FACS-based indirect platelet immunofluorescence test (iPIFT) using platelets from healthy volunteers.
Results: Of 85 patient samples, 38 (45%) were positive for one or more anti-platelet autoantibodies and 19 (22%) were from patients with a stable platelet response to fostamatinib. Of 38 patients positive for autoantibodies, 13 (34%) had stable platelet responses. Of 47 patients negative for autoantibodies, 6 (13%) had stable platelet responses.
Conclusions: The presence of anti-platelet autoantibodies appeared to be associated with a stable platelet response to fostamatinib. This exploratory analysis provides support for the hypothesis that fostamatinib prevents platelet loss through inhibition of autoantibody-directed platelet destruction in ITP. Further studies are ongoing.

Disclosures
Markovtsov: Rigel: Employment, Equity Ownership. Yi:Rigel: Employment, Equity Ownership. Young:Rigel: Employment, Equity Ownership. Duliege:Rigel: Employment, Equity Ownership. Masuda:Rigel Pharmaceuticals: Employment, Equity Ownership.
Targeted Next Generation Sequencing for Myeloid Neoplasm in Pakistani Patients
Authors: Shahid Saba , Ahmed Shariq , Siddiqui Saima , Sohail Misha , Shamsi Tahir S. 
Published: October 2019

Abstract
Introduction:
Myeloid malignancies are heterogenous diseases caused by excessive accumulation of apparently myeloid clone of cells. Genomic studies on myeloid malignancies in recent years have identified new genetic alterations with biological and clinical significance. In addition to cytogenetics and morphological examination these genetic mutation play an important role in diagnosis, prognosis and treatment of the patient. We assessed the frequency and clinicopathologic significance of 54 genes in myeloid neoplasm patients by using targeted next-generation sequencing.
Methods:
About 50 samples were collected from OPD at National Institute of Blood Diseases (NIBD), that consisting of 17 MDS, 18 AML and other myeloid neoplasms. They comprises of 33 males and 17 females with median age of 33 years (range: 5-69 years). The myeloid sequencing panel of 54 genes (complete coding exons of 15 genes and exonic hotspots of 39 genes) was sequenced. The panel total coverage was 141 kb in genomic sequence. TruSight myeloid sequencing (Illumina, CA) libraries were prepared and runs were performed on a MiSeq (Illumina) genome sequencer. The generated data were analyzed by on-instrument software or TruSeq Amplicon® and BaseSpace Apps®.
Results:
Overall 3092 variants were identified, after excluding intronic and synonymous variants, 380 missense variants were found in 50 patients. Around 38 mutations in 22 genes were identified in 23 out of 50 samples (46 %). The recurrent mutations found in RUNX1, ASXL1, GATA2 and CEPBA genes in our cohort.
Conclusion:
Most of the myeloid neoplasms are not easily manageable with limited treatment options. Therefore, targeted gene panel by next generation sequencing was an appropriate method for precise identification of mutations in myeloid neoplasms at our institution. Based on the obtained findings we will be able to design patient management plan with respect to individualize genetic mutations in the clinical setting.

Disclosures
No relevant conflicts of interest to declare.
MiR155 Sensitized B-Lymphoma Cells to PD-L1 Blockade Via PD-1/PD-L1-Mediated Lymphoma Cell Interaction with CD8+T Cells
Authors: Zheng Zhong 
Published: October 2019

Abstract
Diffuse large B-cell lymphoma (DLBCL) represents the most common neoplastic disorder of B-lymphocytes. Besides genetic aberration of lymphoma cells themselves, dysfunction in immune cells can lead to lymphoma cell resistance to immunochemotherapy. Immune checkpoint inhibitors have emerged as successful treatment strategies for DLBCL. However, the underlying mechanisms that lymphoma cells escape from anti-tumor immune responses need to be further investigated.
MiR155 was assessed by quantitative RT-PCR in a large cohort of patients with newly diagnosed DLBCL. Serum miR155 was significantly elevated, correlated with tumor miR155, and indicated poor prognosis. In peripheral blood, miR155 overexpression was associated with decreased CD8+T cells, reduced IFN-γ level and inhibition of T-cell receptor signaling. RNA sequencing was performed on blood samples of 82 DLBCL patients, which indicated that 73 genes closely related with lymphoma were differentially expressed between high miR155 group and low miR155 group. Above genes were plotted by heatmap. Dysregulation of multiple signaling pathway enriched by KEGG pathway analysis. Gene set enrichment analysis (GSEA) analysis manifested that miR155 is closely related with T cell receptor signaling pathway, cell cycle pathway and cytokine-cytokine receptor interaction pathway.
In co-culture systems of B-lymphoma cells with immune cells, miR155 modulated Fas-mediated apoptosis of CD8+T cells, which was targeted by PD-1 and PD-L1 antibodies. As mechanism of action, miR155 enhanced lymphoma cell PD-L1 expression, recruited CD8+T cells via PD-1/PD-L1 interaction, and inhibited AKT/ERK phosphorylation of CD8+T cells. Moreover, EBV-positive patients showed higher serum miR155 than EBV-negative patients. In vivo in a murine xenograft model established with subcutaneous injection of A20 cells, PD-L1 blockade particularly retarded the growth of miR155-overexpressing tumors, consistent with AKT/ERK phosphorylation and CD8+T cell persistence.
Taken together, as a serum oncogenic biomarker of DLBCL, miR155 indicated the sensitivity of B-lymphoma cells to PD-L1 antibody via PD-1/PD-L1-mediated interaction with CD8+T cells. Persistence of CD8+T cells could be an alternative target of action of PD-L1 antibody in treating B-lymphoid malignancies.

Disclosures
No relevant conflicts of interest to declare.
Comparable Outcomes of Myeloablative Conditioning Regimen without ATG in CBT for Pediatric Patients with Hematological Malignancies with a Weight of More Than 30 Kilograms Vs. Less Than 30 Kilograms
Authors: Luo Chenhui , Sun Zimin , Xia Lijun 
Published: October 2019

Abstract
Purpose
Cord blood transplantation (CBT) is an effective option for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and myelodysplastic syndrome (MDS), but children with heavier weight (weighing more than 30kg) always have inferior outcomes than children with lighter weight. This article aims to identify the outcomes of myeloablative conditioning regimen (MAC) without antithymocyte globulin (ATG) in CBT for pediatric patients with different weight.
Methods
We conducted a retrospective analysis including 142 pediatric patients weighing less than 30kg and 130 pediatric patients weighing more than 30kg from May 2008 to September 2017 in our center. All the children were given a combination of cyclosporine (CsA) and mycophenolate mofetil (MMF) without ATG for graft-vs.-host disease (GVHD) prophylaxis. Most of the lighter children and two third of the heavier children were given busulfan(Bu) based MAC while another one third of the heavier children were given total body irradiation (TBI) based MAC.
Results
Children with different weight had no difference in gender, disease status, disease risk, and blood type. However, heavier children were older and had more loci of human leukocyte antigen(HLA) mismatch (P=0.000 and P=0.016). More children weighing more than 30kg suffered ALL than children weighing less than 30kg (P<0.05). The cumulative neutrophil engraftment rate by 42 days and the platelet engraftment rate by 120 days were almost the same in heavier children group and lighter children group (97.7% vs. 94.4% and 86.2% vs. 86.6%, p=0.284 and p=0.313, respectively). Non-relapse mortality (NRM) and relapse rate were also similar in these two groups (16.3% vs. 12.3% and 22.0% vs. 21.9%, p=0.345 and p=0.923, respectively). While the incidence of chronic GVHD (cGVHD) was higher in heavier children group (17.9% vs. 9.4%, P<0.05), but not grade II to IV acute GVHD (aGVHD) nor grade III to IV aGVHD. Three years of overall survival (OS), disease-free survival (DFS) and GVHD-free/relapse-free survival (GRFS) showed no significant difference in these two groups.
Conclusions
This study is the first to demonstrate the similar curative effect of myeloablative conditioning regimen without antithymocyte globulin in CBT for pediatric patients with different weight. A large-scale prospective study is needed.

Disclosures
No relevant conflicts of interest to declare.
Hepatitis E Virus Infection after Haploidentical Hematopoietic Stem Cell Transplantation:Incidence and Clinical Course
Authors: Tang Fei-Fei , Mo Xiao-Dong , Wang Yu , Yan Chen-Hua , Chen Yu-Hong , Chen Huan , Han Wei , Chang Ying-Jun , Zhang Hai-Ying , Xie Yan-Di , Ma Hui , Wei Lai , Xu Lan-Ping , Huang Xiao-Jun , Zhang Xiaohui 
Published: October 2019

Abstract
Introduction: Hepatitis E virus (HEV) is increasingly found to cause hepatitis in allogeneic hematopoietic stem cell transplantation (HSCT) patients. However, little is known about HEV infection in patients treated with haploidentical HSCT (haplo-HSCT). Here, we retrospectively evaluate the incidence and clinical course of HEV infection in haplo-HSCT patients.
Methods: From January 2014 to July 2017, 177 patients with unexplained elevated transaminases after receiving haplo-HSCT at Peking University Institute of Haematology were screened for HEV infection using HEV serology. HEV RNA were performed when HEV-IgG and/or IgM antibodies were positive.
Results: Acute HEV infection was identified in seven of these patients (3.9%), none of whom had developed a chronic HEV infection. The median time from haplo-HSCT to HEV infection was 17.5 (range, 6-55) months. Median peak alanine transaminase during HEV infection was 716 (range, 164-1763) U/L. In 7 cases, HEV infection was confirmed by the presentation of anti-HEV IgM + anti-HEV IgG (rising) (n=5) or HEV-RNA + anti-HEV IgM + anti-HEV IgG (n=2). None patients died of HEV infection directly. Two patients with HEV infection died showing signs of ongoing hepatitis and the median duration of HEV infection was 2.7 months. Five patients cleared HEV and the median duration of HEV infection was 1.5 (range, 1.0-5.7) months.
Conclusions: In conclusion, HEV infection is a rare but serious complication after haplo-HSCT. We recommend screening of HEV infection in haplo-HSCT.

Disclosures
No relevant conflicts of interest to declare.
Possible Factors on Efficacy and Safety of CAR-T Therapy in Relapsed or Refractory Aggressive B-Cell Lymphoma
Authors: Huang Haiwen , Jiang Yibin , Jin Zhengming , Li Caixia , Wu Depei 
Published: October 2019

Abstract
Background:
Recent advances have improved the treatment of B-cell malignancies, but patients who have disease resistant to primary or salvage treatment or who relapse after transplantation have an extremely poor prognosis. Studies of chimeric antigen receptor T-cell (CAR-T) therapy have shown high response rates and long response duration in refractory B-cell lymphomas after the failure of conventional therapy, which suggest that this therapy may be potentially curative. To explore the possible factors on efficacy and safety of CAR T-Cell therapy in relapsed or refractory aggressive B-cell lymphomas, we conducted the clinical trial of CAR-T Cell Treating Relapsed/Refractory B-cell lymphomas (NCT03196830).
Methods:
From March 2017 to April 2018, 25 patients were enrolled into our clinical trial. According to the surface expression of tumor cells by either flow cytometry or immunohistochemistry, different targets of CAR T-cells were infused, ionly anti-CD19 (n=11), sequential infusion of anti-CD22 and anti-CD19 (n=8), and sequential infusion of anti-CD20 and anti-CD19 (n=6). Patients received conditioning treatment (low-dose cyclophosphamide, 300 mg/m² per day, and fludarabine, 30 mg/m² per day) on days -5, -4, and -3 before the administration of autologous CAR T-cells. The primary endpoint was the proportion of patients with an objective response. Secondary endpoints included safety and biomarker assessments.
Results:
Among the 25 patients who were enrolled, response was successfully evaluated
for 24. The objective response rate was 75%, and the complete response rate was 33%. With a median follow-up of 3.2 months, 54% of the patients continued to have a response, with 25% continuing to have a complete response. Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 24% and 16% of the patients, respectively. One of the patients died during treatment. Serum biochemical index analysis confirmed the associations of peak serum interleukin-2, -6, -10, INF-γ, ferritin, C-reactive protein (CRP) concentrations and the level of lactate dehydrogenase (LDH) before therapy with the grade 3 or higher CRS, as well as peak serum interleukin-6, -10, INF-γ, CRP, ferritin and the level of LDH before therapy with grade 3 or higher neurologic events.
Conclusion:
Our study demonstrates the efficacy and safety of CAR-T therapy relapsed or refractory aggressive B-cell lymphoma. The level of LDH before therapy was higher in patients who developed grade 3 or serious CRS, which suggest that we should improve safety by reducing tumor burden before CAR T-cells infusion. Due to the small number of enrolled cases, no significant improvement of efficacy was observed, this result needs to be further confirmed by expanding the number of study cases.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Omalizumab: Efficacy and Safety in Mast Cell Disorders
Authors: Lemal Richard , Fouquet Guillemette , Terriou Louis , Vaes Mélanie , Livideanu Cristina , Frenzel Laurent , Barete Stéphane , Canioni Danielle , Lhermitte Ludovic , Bay Jacques-Olivier , Rossignol Julien , Arock Michel , Lortholary Olivier , Hermine Olivier 
Published: October 2019

Abstract
Background. Patients with mast cell diseases may suffer from various distressing symptoms, which can be insufficiently controlled with available therapies, severely affecting quality of life. There is thus a need for new and safe treatment options for these patients.
Objectives. We aimed to evaluate safety and efficacy of omalizumab administration in patients with a systemic mast cell disorder.
Methods. We included 56 patients with a systemic mast cell disorder who received omalizumab treatment between January 2015 and December 2017, after a pluridisciplinary review at the French National Reference Center for Mastocytosis (CEREMAST).
Results. A complete response was achieved for 1 patient (1.8%), a major response for 30 patients (53.6%) and a partial response for 12 patients (21.4%), resulting in an overall response rate of 76.8% (43/56 patients). The response was persistent at least 3 months in 33 patients (58.9%). Median time to first response was 2 months and median time to best response was 6 months. Omalizumab was dramatically effective on all superficial and general vasomotor symptoms and on most gastrointestinal or urinary symptoms, and partially effective on most neuropsychiatric symptoms (Figure 1). Safety profile was acceptable, except for one severe adverse event (cervical edema and dyspnea after the first injection of omalizumab). Side effects were reported in 16 patients (28.6%), mainly of low to mild intensity, yet causing interruption of treatment in 6 patients (10.7%).
Conclusion. Omalizumab is an effective treatment option in systemic mast cell disorders, and displays a favorable safety profile. Prospective studies remain necessary to confirm these encouraging results.

Disclosures
No relevant conflicts of interest to declare.
Retrospective Observational Study from the Experience in Our Center of the Employment of Daratumumab in Multiple Myeloma
Authors: Morente Constantin Estefanía , Romero Garcia Pablo , Garcia-Ruiz Maria Almudena , Rios Rafael , Clavero Sanchez Esther , Jurado Manuel 
Published: October 2019

Abstract
INTRODUCTION
Daratumumab is an anti-CD38 monoclonal antibody which is a recent success in the treatment of multiple myeloma (MM). It binds to the CD38 protein, which is highly expressed in MM tumor cells.
It is indicated in monotherapy in patients with relapsed MM, being refractory to treatment and having previously received a proteasome inhibitor and an immunomodulatory agent, with progression of the disease since the last treatment.
It can also be used, as stated recently in its data sheet, in combination with Lenalidomide and Dexamethasone or Bortezomib and Dexamethasone for the treatment of patients with MM who have received at least one previous treatment. It is being tested in combination with other drugs, which shows its enormous potential.
OBJECTIVES
We expose the experience with this drug in our center in recent years.
MATERIALS AND METHODS
We have evaluated patients treated with Daratumumab, recording: demographic data, previous number of lines of treatment, use in monotherapy or combination, date of initiation of treatment, response to it, date of suspension (if it occurred) and its cause, as well as total duration of the treatment (figure 1 and 2).
RESULTS
We studied 12 patients, 6 men and 6 women, treated with Daratumumab between 2016 and 2018. The average age is 63.75 years (range between 57 and 72).
On average, it was used in the 4th line of treatment, ranging between 2 cases in which it was the 2nd and 1 in which it was the 7th. In all patients, it was used in monotherapy.
Currently, 3 out of the 12 patients are still being treated with Daratumumab and they are in remission (objectified by PET-CT in 1 patient with only 4 months of treatment). 2 other patients are in partial remission (with 23 and 4 completed months of treatment, respectively). It was necessary to suspend the drug in 8 patients, in 7 cases due to progression of the disease. The remaining patient suffered, in the 1st administration, an adverse reaction of type III that was refractory to the symptomatic treatment and to the decrease of the infusion rate, which forced to withdraw the drug.
In 4 cases, the drug was discontinued and the result was "stable disease", so it remained until progression was evidenced. The average maintenance of the drug until progression was 4 months, ranging between 2 and 6 months. In the remaining 3 patients the disease progressed, so the drug was discontinued.
CONCLUSIONS
The MM treatment has to be individualized and adapted to the risks. The data obtained from our patients indicate that Daratumumab is a potentially valuable drug among the therapeutic arsenal against this pathology. However, we believe that the results would be much better if the treatment is started in earlier lines.

Disclosures
Rios: Amgen, Celgene, Janssen, and Takeda: Consultancy.