bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a New BCMAxCD3 Duobody® Antibody for Multiple Myeloma
Authors: Pillarisetti Kodandaram , Baldwin Eric , Babich Alexander , Majewski Nate , Barone Linda , Li Yingzhe , Zhang Xiaochun , Chin Diana , Luistro Leopoldo , Mendonça Mark , Nanjunda Rupesh , Rudnick Stephen , Bellew Kevin , Elsayed Yusri , Attar Ricardo M. , Gaudet François 
Published: October 2019

Abstract
B-cell maturation antigen (BCMA) is a tumor necrosis factor (TNF) family surface protein predominantly expressed on terminally differentiated B-cells. BCMA signals through P38/NF-κB pathway upon binding to its ligands; a proliferation inducing ligand (APRIL) and B-cell activator of the TNF family (BAFF) and promote anti-apoptotic gene expression. BCMA expression is elevated in plasma blasts, plasma cells from spleen and bone marrow and correlates with disease progression in multiple myeloma (MM). BCMA expression in premalignant MM settings such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) also gives an opportunity for early cancer interception. To target cancer cells expressing BCMA, we developed a BCMAxCD3 bispecific antibody using the Genmab DuoBody® technology (Ab-957) to recruit T cells to BCMA-expressing MM cells so that T cells could be activated and induced to kill BCMA+ cancer cells. This antibody can induce cytotoxicity of BCMA+ MM cell lines in vitro (H929 cells: EC50=0.15nM, MM1.R cells: EC50=0.06nM, RPMI8226 cells: EC50=0.45nM) with a concomitant T cell activation (H929 cells: EC50=0.21nM, MM1.R cells: EC50=0.1nM, RPMI8226 cells: EC50=0.28nM). In contrast, this antibody was unable to kill BCMA- cancer cell line (MV4-11), demonstrating the specificity of the cytotoxicity. Ab-957 also inhibited tumor development or growth in two BCMA+ MM murine xenograft models inoculated with human T cells. Furthermore, this antibody could deplete BCMA+ cells in bone marrow samples from MM patient's in an ex-vivo assay with an average EC50 value of 2.5 nM. Lastly, Ab-957 is well-tolerated in cynomolgus monkey and is being developed for Phase I clinical trial in patients with multiple myeloma.

Disclosures
Pillarisetti: Janssen: Employment. Baldwin:Janssen: Employment. Babich:Janssen: Employment. Majewski:Janssen: Employment. Barone:Janssen: Employment. Li:Janssen: Employment. Zhang:Janssen: Employment. Chin:Janssen: Employment. Luistro:Janssen: Employment. Mendonça:Janssen: Employment. Nanjunda:Janssen: Employment. Rudnick:Janssen Pharmaceuticals R&D: Employment. Bellew:Janssen: Employment. Elsayed:Janssen: Employment, Other: stock options. Attar:Janssen: Employment. Gaudet:Janssen Pharmaceuticals R&D: Employment, Other: Stock options, Patents & Royalties: pending, not yet issued.
Transplant Associated Thrombotic Microangiopathy in Individuals with Fanconi Anemia
Authors: Myers Kasiani C. , Jodele Sonata , Nelson Adam S. , Goodridge Erica , Mehta Parinda A , Mueller Robin , Dandoy Christopher E. , Lane Adam , El-Bietar Javier A. , Davies Stella M 
Published: October 2019

Abstract
Objective: Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic stem cell transplantation (HSCT) due to vascular endothelial injury. TA-TMA most commonly affects the kidneys resulting in proteinuria, hypertension and often progresses to multi-organ failure in severe cases. We previously identified in our institutional prospective study of TA-TMA a higher incidence of TA-TMA in Fanconi anemia (FA) individuals. We hypothesized that exposure to cyclosporine (CSA), which has been implicated in TA-TMA, may have led to this increase. The goal of our current study was to examine the TA-TMA incidence in FA individuals undergoing HSCT with CSA exposure at our institution and its impact on transplant related morbidity and organ function.
Methods: We performed a retrospective chart review in all patients with FA undergoing first unrelated donor T-depleted HSCT (2010-2016) using a busulfan, fludarabine, cyclophosphamide and ATG preparative regimen to identify the incidence of transplant-associated TMA and clinical outcomes. Subjects were stratified by cyclosporine use.
Results: Forty-two patients underwent unrelated donor t-depleted HSCT using busulfan, fludarabine, cyclophosphamide and ATG during the study period. Additional GVHD prophylaxis with cyclosporine (CSA) was used in the first 29 subjects while subsequent subjects received no additional prophylaxis (n= 13). Incidence of TA-TMA in the CSA and Non-CSA groups was 66% (n=19/29) and 54% (n=7/13) respectively (p=0.51) and was increased from the overall institutional TA-TMA incidence of 34% (p=0.0011). Risk factors for severe TA-TMA were increased in the CSA-group with nephrotic range proteinuria in 53% compared with 14% of the non-CSA group in tested patients and increased complement activation by sC5b-9 levels 100% vs 20%. Median duration of active TA-TMA was longer in the CSA-group at 85 days compared with 41 in the non-CSA group. Complications of TA-TMA including hypertension, kidney injury, dialysis, pericardial effusion and pulmonary hypertension were all increased in the CSA group compared to the non-CSA group.
Conclusion: Incidence of TA-TMA after HSCT is increased in FA compared to other HSCT recipients. Individuals receiving cyclosporine for GVHD prophylaxis had more severe TA-TMA than those who did not receive it, affecting transplant related morbidity and long-term renal function. Increased incidence of TA-TMA in individuals with FA may point to novel mechanisms of vascular endothelial injury. Better understanding of these mechanisms may allow for improved transplant risk stratification or new therapeutic approaches in solid tumor therapy.

Disclosures
Davies: Novartis: Honoraria.
the IKZF1-IRF4 Axis Regulates Macrophage Polarization and Macrophage-Mediated Anti-Tumor Immunity
Authors: Bruns Heiko , Mougiakakos Dimitrios , Bach Christian , Böttcher Martin , Bittenbring Joerg Thomas , Büttner Maike , Gelse Kolja , Rehli Michael , Wimmer Julia , Beier Fabian , Gezer Deniz , Krönke Jan , Balzer Heidi , Moi Stephanie , Spriewald Bernd , Mackensen Andreas , Busch Leonhard 
Published: October 2019

Abstract
In addition to antimicrobial activity, macrophages regulate tissue development, remodeling, and repair. In terms of neoplastic growth, tumor-associated macrophages (TAMs) are even considered pro-tumorigenic based on their angiogenic and T-cell suppressive properties. In multiple myeloma (MM) macrophages represent an abundant component of the stromal cell compartment and are believed to support proliferation, survival, and drug resistance of MM cells. Those pro-tumorigenic functions are partly instructed by T-helper (TH)-2 cytokines such as interleukin-4 (IL-4) and IL-10, which skew TAM differentiation towards an alternatively activated, or so-called M2-like, phenotype. In contrast, M1 macrophages generally considered as potent effectors in response to microbial products or interferon-γ (IFN-γ), are characterized by superior antigen-presentation, abundant production of pro-inflammatory cytokines such as interleukin-12 (IL-12), and consequently, promote a polarized type I immune response against infections as well as malignant cells. Transcriptional regulation is a key determinant for macrophage polarization. The Ikaros (IKZF1) transcription factor is critical for lymphoid development and is found in all hematopoietic progenitors as well as in T-, B-, NK-cells and macrophages. Interestingly, IKZF1 is overexpressed in MM and selectively degraded by lenalidomide, which is approved in MM therapy. The potential role of IKZF1 in modulating macrophage polarization has not been elucidated yet.
Here, we show that IKZF1expression is found highly elevated in M2-like macrophages and in MM TAMs. IKZF1 deletion in human macrophages by small interfering RNA (siRNA) or by lenalidomide yields an upregulation of M1-specific cytokines (IL-12 and IL-1b), chemokines (CXCL10 and CCL5), and costimulatory molecules (CD86 and CD40) and leads to a potent TH1-TH17 response. In fact, lenalidomide-pretreated macrophages display strong tumoricidal effects when co-cultured with MM cell lines as opposed to their untreated counterparts promoting MM proliferation and viability. Utilizing immunoprecipitation-sequencing (ChIP-Seq) we reveal that IKZF1 governs IRF4 and IRF5 expression in human macrophages. Recent studies demonstrate that IRF4 controls M2 macrophage polarization, while IRF5 regulates the M1 phenotype respectively. We could show that a lenalidomid-mediated M1-phenotype induction is efficiently abrogated by IRF4 overexpression or IRF5 silencing.
Overall, these findings unravel a novel role for IKZF1 in orchestrating macrophage polarization via the IRF4/IRF5 pathway.

Disclosures
No relevant conflicts of interest to declare.
Improved Values for Acquired Von Willebrand Syndrome and Better Clinical Outcome in Patients with Heartmate III Compared to Heartmate II
Authors: Geisen Ulrich , Brehm Kerstin , Trummer Georg , Beyersdorf Friedhelm , Berchtold-Herz Michael , Heilmann Claudia , Schelling Johannes , Schlagenhauf Axel , Zieger Barbara 
Published: October 2019

Abstract
Objectives: Impaired binding of Von Willebrand factor (VWF) to platelets and to collagen due to an acquired Von Willebrand syndrome (AVWS) has been observed in patients with left ventricular assist device (LVAD) support. AVWS seems to enhance bleeding symptoms in LVAD patients. The onset of AVWS occurs a few hours after LVAD implantation and affects platelet counts and function as well. The new HeartMate III (HM III) is a left ventricular assist device featuring several design-improvements that show promise to ameliorate the severity of AVWS in comparison to its predecessor, the Heartmate II (HM II). In this study, our aim was to analyze AVWS-parameters and platelet function in patients with HM II compared to patients with HM III support.
Methods: Data sets of 31 patients under HM II support and 20 patients under HM III support were analyzed pre-surgery as well as 1, 3, 7, and 30 days post-surgery. Collagen binding capacity (VWF:CB), VWF antigen (VWF:Ag) as well as VWF:CB/VWF:Ag-ratios were determined. Presence of high molecular weight multimers of VWF was investigated. Platelet counts were monitored and platelet function was tested using light transmission aggregometry.
Results: The VWF:CB/VWF:Ag ratios were significantly higher in patients with HM III than HM II at day 1, 3, and 7 after implantation. More HM III patients had intact high molecular weight multimers of VWF compared to HM II during the whole study-period (HMII: 9%; HMIII: 25%). Platelet counts and functions were comparable in both study groups. The mean duration in the Intensive Care Unit was shorter in the HM III-group than in the HM II-group (HM II: 43±52 days; HM III: 28±23 days).
Conclusion: Severity of AVWS was milder in patients with HM III compared to HM II, especially during the days after surgery, when usually most hemorrhagic events occur. Loss of high molecular weight multimers 30 days after VAD-implantation was observed in a lower percentage of HMIII-patients compared to HMII-patients suggesting a long-lasting beneficial effect. Taken together, these data show that design-improvements in the new HM III compared to the HM II result in an amelioration of AVWS that could result in lower bleeding diathesis.

Disclosures
Geisen: Roche: Research Funding. Berchtold-Herz:Novartis: Consultancy; Thoratec: Consultancy. Zieger:CSL Behring: Research Funding; Baxalta: Research Funding; Bayer: Research Funding; German Research Foundation, Bonn, Germany [ZI 486/7-1]: Research Funding.
Glutaminase Inhibitor CB-839 Enhances Proteasome Inhibitor Sensitivity in Multiple Myeloma Cells
Authors: Thompson Ravyn M. , Reyes Leticia , Smith Brittany , Dolloff Nathan G. 
Published: October 2019

Abstract
Multiple myeloma (MM) remains largely incurable due to the emergence of therapeutic resistance. We therefore set out in this study to identify druggable molecular mechanisms that convey resistance to proteasome inhibitors (PIs; e.g., bortezomib/VELCADE, carfilzomib/KYPROLIS), which are cornerstone agents in the treatment of MM. In comparing isogenic pairs of PI sensitive and resistant cells, we observed stark differences in cellular bioenergetics between the divergent phenotypes. While glycolysis rates between cell lines were similar, PI resistant cells exhibited increased mitochondrial respiration characterized by higher basal oxygen consumption rates (OCR) and overall respiratory capacity. Additionally, PI resistant cells were found to have lower activation of the AMP kinase (AMPK) energy stress pathway and increased levels of NAD(P)H, which serve as electron carriers in the mitochondrial process of oxidative phosphorylation. We determined that glutamine was the principle source of fuel driving mitochondrial respiration as removal of glutamine completely inhibited OCR as well as cell proliferation, whereas glucose and pyruvate were dispensable. Given the propensity for mitochondrial respiration in PI resistant cells and the dependence on glutamine for this process, we hypothesized that targeting glutamine utilization by PI resistant cells would restore their sensitivity to the cytotoxic effects of PIs. To test this possibility, we inhibited glutamine metabolism using the small molecule GLS1 inhibitor CB-839. CB-839 repressed basal OCR and total respiratory capacity and reduced cell viability to varying degrees in a panel of PI sensitive and resistant MM cell lines. Most notably, we found that CB-839 synergistically enhanced the cytotoxic activity of multiple PIs, including bortezomib, carfilzomib, ixazomib, and oprozomib, in a genetically diverse panel of 15 PI sensitive and resistant MM cell lines. The effects of CB-839 were the most apparent in combination with carfilzomib (Crflz), where it enhanced Crflz-induced death by >4-fold. CB-839 enhanced Crflz-induced apoptosis as measured by the activation of caspase 3, 7, 8 and the cleavage of the caspase-3 substrate PARP. Mechanistically, the combination of CB-839 and Crflz induces a strong and synergistic ER stress response, characterized by the induction of ATF4 and CHOP. Our findings suggest that the acquisition of PI resistance may involve adaptations in cellular bioenergetics that may be exploited therapeutically by targeting glutamine metabolism. Furthermore, our results support the combination of clinical stage compound CB-839 with PIs, particularly Crflz, for the treatment of refractory MM.

Disclosures
No relevant conflicts of interest to declare.
The Impact of Antithymocyte Globulin (ATG) Dose in Allogeneic Hematopoietic Stem Cell Transplantation with HLA Mismatched Donors
Authors: Choi Yunsuk , Lee Ho Sup , Lee Je-Hwan , Moon Joon Ho , Shin Ho-Jin , Lee Won Sik 
Published: October 2019

Abstract
Background: Antithymocyte globulin (ATG) is usually included in conditioning regimens in hematopoietic stem cell transplantation (HSCT) from HLA mismatched donors to reduce the incidence of graft versus host disease (GVHD) and rejection. In this study, we intended to assess the clinical impact of ATG dose in HSCT from HLA mismatched donors.
Patients and Methods: We retrospectively analyzed 268 consecutive patients with acute myeloid leukemia (n=159), acute lymphoblastic leukemia (n=49) or myelodysplastic syndrome (n=60) receiving busulfan based conditioning and HSCT with HLA mismatched sibling, unrelated, or haplo-identical family donors in five centers of Korea between 2005 and 2015.
Results: The median age was 44.5 (range, 15-75) years. Fourty-two patients were treated with myeloablative conditioning and 226 patients with reduced intensity conditioning regimen. ATG at a total dose of 0 (n=31), 2.5-7.5 mg/kg (n = 16), 9 mg/kg (n = 164) or 12mg/kg (n=57) was given to patients according to protocol. 140 patients received HSCT in complete remission and 73 patients in relapse or refractory status. The median follow up duration for surviving patients was 33.8 (range, 2.0-100.6) months. The 3-year overall survival (OS) and event free survival (EFS) rate for all patients was 44.7% and 39.2% There was no significant difference of OS according to ATG dose (P=0.153), but ATG dose of 2.5-7.5mg/kg was significantly associated with better EFS than 0, 9 mg/kg, or 12mg/kg of ATG groups (79.1% vs. 45.4%, 38.9%, and 31.7%, respectively, P=0.038) (Table 1). In addition, ATG dose significantly affected on relapse (P=0.046). The relapse incidence in patients receiving 2.5-7.5 mg/kg of ATG was lower compared to those given 0, 9, or 12 mg/kg of ATG (6.7% for 2.5-7.5mg/kg of ATG group vs. 29.5%, 34.0%, and 46.9% for 0, 9, and 12 m/kg of ATG groups, respectively). The incidences of acute GVHD grades II-IV were 32.6%, 25.0%, 29.4% and 24.6% in patients receiving 0. 2.5-7.5, 9, and 12 mg/kg of ATG, respectively. The incidence of extensive chronic GVHD tended to be lower according to the increase of ATG dose (36.8%, 34.5%, 27.4%, and 21.1% for 0. 2.5-7.5, 9, and 12 mg/kg of ATG dose, respectively).In multivariate analysis, ATG dose of 9 mg/kg (P=0.023) and 12 mg/kg (P=0.036) was associated with shorter EFS compared to 2.5-7.5 mg/kg of ATG.
Conclusion: 9mg/kg of ATG dose or more in HLA mismatched busulfan based HSCT with HLA mismatch donors increased the risk for relapse and reduced the EFS.

Disclosures
No relevant conflicts of interest to declare.
Efficacy of CD101, a Novel Echinocandin, in Mouse Models of Aspergillosis and Azole-Resistant Disseminated Candidiasis
Authors: Ong Voon , Bartizal Ken , Miesel Lynn 
Published: October 2019

Abstract
Background: CD101 is a novel echinocandin with long-acting pharmacokinetics and exceptional stability in development for prevention and treatment of serious fungal infections. The in vivo efficacy of CD101 was evaluated using neutropenic mouse models of azole-resistant candidiasis and aspergillosis.
Methods: An azole-resistant strain of Candida albicans (R357; resistant to fluconazole [Flu], voriconazole, and posaconazole but susceptible to amphotericin B [AmB] and echinocandins) isolated from human blood was used for the mouse candidiasis model. A test strain of Aspergillus fumigatus (ATCC 13073) was used for the mouse aspergillosis model. Mice were rendered neutropenic by cyclophosphamide and then infected by injections of C. albicans (105 CFU/mouse) or A. fumigatus (104 CFU/mouse) into the tail vein. Test articles were administered starting 2 hours after infection. In the mouse candidiasis model, groups of 5 mice each received one dose of AmB (3 mg/kg IV), Flu (20 mg/kg orally), or CD101 (3, 10 or 30 mg/kg by intraperitoneal administration [IP]). After 72 hours post-infection, mice were euthanized and C. albicans counts in kidney tissue (CFU/g) were measured. In the mouse aspergillosis model, groups of 10 mice each received one dose ofAmB (2 mg/kg IP) or CD101 (2 mg/kg IV and IP). Survival was monitored daily for 10 days. Differences between vehicle and test article groups were assessed for significance by one-way ANOVA followed byDunnett's test and Fisher's Exact test in the candidiasis and aspergillosis models, respectively.
Results: One dose of CD101 3 mg/kg produced a >99.9% (or > 3-log; P<0.001) reduction in C. albicans CFU compared with vehicle through at least 72hours post-dose following a single IP dose.AmB showed similar, albeit less robust, efficacy (>99% or >2-log reduction in CFU; P<0.05), whereas fluconazole was less efficacious (83.9% or <2-log reduction in CFU). In the aspergillosis model, CD101 administered 2 mg/kg IV or IP showed similar efficacy to that ofAmB 2 mg/kg IP, both with significantly longer survival than vehicle (P<0.05; Figure).
Conclusions: A single dose of CD101 3 mg/kg produced significant reduction in C. albicans burden compared with vehicle (P<0.001) in the neutropenic mouse model of azole-resistant candidiasis, demonstrating efficacy comparable, if not better, to that of AmB at the same dose. One dose of CD101 also demonstrated efficacy in the mouse model of aspergillosis. These data support the continued development of CD101 for treatment of serious infections caused by Candida, including azole-resistant strains, and Aspergillus spp.
Figure Percent Survival in a Neutropenic Mouse Model of Aspergillosis Figure. Percent Survival in a Neutropenic Mouse Model of Aspergillosis

Disclosures
Ong: Cidara Therapeutics, Inc.: Employment. Bartizal:Cidara Therapeutics, Inc.: Employment, Other: Stockholder. Miesel:Eurofins Panlabs: Employment; Cidara Therapeutics, Inc: Research Funding.
Invasive Mold Infections in Acute Leukemia Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Chien Sheng-Hsuan , Liu Yao-Chung , Fan Nai-Wen , Liu Chia-Jen , Chiou Tzeon-Jye , Gau Jyh-Pyng , Liu Jin-Hwang 
Published: October 2019

Abstract
Introduction:
Patients with acute leukemia exposed higher risk for developing invasive fungal infections and the invasive fungal infection is also an important cause of morbidity and mortality during allogeneic hematopoietic stem cell transplantation (allo-HSCT). In addition to candida species, the invasive mold infection (IMI) is most common in invasive fungal infections and the incidence rate is increasing in recent years. Although recent diagnostic approach and treatments for IMI are advanced, the prognosis remains poor. It is essential to understand the risk factors for developing IMI among acute leukemia patients undergoingallo-HSCT. Here, we conducted a retrospective study to demonstrate demographics, microbiology, and risk factors for the development of IMI among 245 adult acute leukemia patients undergoingallo-HSCT at our institution during a 10-year period.
Method
We reviewed 245 adult acute leukemia patients undergoingallo-HSCT from January 2003 to December 2014. Clinical characteristics including age, sex, underlying disease, type of allogeneic transplant, conditioning regimens, European Group for Blood and Bone marrow Transplantation (EBMT) risk score, and presence of acute graft-versus-host disease (aGVHD) or chronic GVHD (cGVHD) were collected and analyzed. Cox proportional hazard model was adopted to explore the independent risk factors for IMI development. The Kaplan-Meier method was performed to estimate the cumulative incidence and the curve was compared using the log-rank test
Results
Twenty out of 245 patients developed IMI during study period and the median time to onset after transplantation was 391 days (interquartile range, 220-552 days). The cumulative incidence of IMI in this cohort was 1.9 %, 5.1%, and 12.8% at 6 months, 12 months, and 24 months, respectively. Aspergillus species were the most common and presented in 55% of mold infections. The significant risk factors to predict mold infection after transplantation (Table 1) were smoking (hazard ratio [HR] 4.28, 95% confidence interval [CI] 1.40-13.12; P=0.011), EBMT risk score > 2 (HR 4.37, 95% CI 1.35-14.09; P=0.013), and extensivecGVHD(HR 3.10, 95% CI 1.20-8.00; P=0.019). The cumulative incidence of mold infection in smokers was significantly higher than non-smokers (log-rank P < 0.001) and the Kaplan-Meier curve was shown in Figure 1.
Conclusion
We identified three risk factors-smoking, EBMT risk score > 2 and extensivecGVHDto predict IMI among acute leukemia patients undergoingallo-HSCT. Smoking may damage respiratory tract epithelium as well as defense-microorganism mechanism and it would lead to IMI easily duringallo-HSCT. This cohort study suggests that early identification of high-risk patients and to provide better prevention strategies would reduce the incidence and severity of IMI in these patients.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.