bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II, Open-Label, Dose-Escalating Study of MDX-060 Administered Weekly for 4 Weeks in Subjects with Refractory/Relapsed CD30 Positive Lymphoma.
Authors: Ansell Stephen M. , Byrd John C. , Horwitz Steven M. , Borchmann Peter , Engert Andreas , Strair Roger , Khan Khuda D. , Fischkoff Steven A. , Yellin Michael 
Published: April 2020

Abstract
Background: MDX-060 is a fully human anti-CD30 IgG1k monoclonal antibody that induces Fc-receptor mediated killing of CD30 expressing cell lines and inhibits the growth of CD30-expressing tumor cells in a murine xenograft model. We previously reported data from the first 31 patients in a Phase I/II open-label, dose escalation study of MDX-060 in patients with relapsed or refractory CD30+ lymphomas. The purpose of the study is to determine the safety and tolerability profile of the drug, and to preliminarily evaluate efficacy. We now update the findings of this study, including reporting the results of a new higher dose cohort.
Methods: In the Phase I portion of the study, MDX-060 was administered intravenously at dose levels of 0.1, 1, 5, or 10 mg/kg weekly for 4 weeks to cohorts of 3–6 patients. In the Phase II portion of the study additional patients were administered MDX-060 intravenously at 10 (n=10) or 15 (n=17) mg/kg weekly for 4 weeks. Responses were assessed at month 2.
Results: To date, MDX-060 has been administered to 48 patients; 40 with Hodgkin’s disease (HD), 6 with anaplastic large cell lymphoma (ALCL) and 2 with other CD30 positive lymphomas. MDX-060 has been well tolerated, and a maximum tolerated dose has not been identified. There were 2 drug-related serious adverse events, 1 patient in the 1 mg/kg dosing cohort had Grade 3 elevated liver transaminase, and 1 patient in the 15 mg/kg cohort had Grade 3 pneumonia/Grade 4 ARDS. Objective clinical responses have been observed in 5 patients. Two patients had complete responses; 1 patient with ALCL in the 1 mg/kg cohort lasting 100 days, and 1 patient with HD in the 15 mg/kg cohort lasting 117 days. Retreatment of the ALCL patient with MDX-060 resulted in a second complete response. Three patients had partial responses; 1 patient with HD in the 5 mg/kg cohort lasting 92 days, and 1 patient with HD in the 15 mg/kg cohort, which is continuing at 176 days. In addition, 1 patient with ALCL in the 15 mg/kg cohort had a partial response. Stable disease was observed in 17 patients following MDX-060 administration with a median duration of 132 days (range:15–387 days). Baseline soluble CD30 levels in the plasma were evaluated, but did not appear to correlate with clinical outcome.
Conclusions: Preliminary evidence indicates MDX-060 to be well tolerated in heavily pre-treated patients with CD30+ lymphomas, with minimal toxicity, and with clinical activity observed at 1 mg/kg, 5 mg/kg and 15 mg/kg. Additional patients are being accrued at 1 mg/kg and 5 mg/kg to more accurately assess efficacy at these dose levels.
CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms.
Authors: Chemnitz Jens M. , Riley James L. , Frauwirth Kenneth A. , Braunstein Inbal , Kobayashi Sumire V. , Linsley Peter S. , Thompson Craig B. , Parry Richard V. 
Published: April 2020

Abstract
CTLA-4 and PD-1 are receptors that negatively regulate T cell activation. Ligation of both CTLA-4 and PD-1 blocked CD3/CD28 mediated upregulation of glucose metabolism and Akt activity, but each accomplished this regulation using separate mechanisms. CTLA-4 mediated inhibition of Akt phosphorylation is sensitive to okadaic acid, providing direct evidence that PP2A plays a prominent role in mediating CTLA-4 suppression of T cell activation. In contrast, PD-1 signaling inhibits Akt phosphorylation by preventing CD28 mediated activation of phosphatidylinositol 3-kinase (PI3K). The ability of PD-1 to suppress PI3K/Atk activation was dependent upon the ITSM located in its cytoplasmic tail. Lastly, PD-1 ligation is more effective in suppressing CD3/28 induced changes in the T cell transcriptional profile, suggesting that differential regulation of PI3K activation by PD-1 and CTLA-4 ligation results in distinct cellular phenotypes. Together, these data suggest that CTLA-4 and PD-1 inhibit T cell activation through distinct and potentially synergistic mechanisms.
Accelerated FDA Approval of Drugs Used To Treat Hematologic Malignancies: Are Policy Changes Needed?.
Authors: Lyons Elizabeth A. , McKoy June M. , Belknap Steven , Carson Kenneth R. , Bennett Charles L. 
Published: April 2020

Abstract
Background: In 1992, the FDA extended the accelerated approval program from HIV and AIDs, to include drugs for other diseases that are serious or life-threatening, appear to provide benefit over available therapy, or for which no other therapy is available. Approval is based on a surrogate endpoint, and pharmaceutical companies are required to confirm safety and efficacy by conducting clinical trials with clinically relevant outcomes. Since 1995, eight drugs used to treat hematologic malignancies have received accelerated approval.
Methods: Information available to the public under the Freedom of Information Act was surveyed for new drug applications and supplements for new uses approved by the Division of Oncology Products from January 1, 1995 to August 31, 2003. The package insert and corresponding published literature for the approval of each drug were reviewed for indication, time from drug submission to approval, surrogate endpoint, number of patients in trial, percent response and status of full approval.
Results: Of the eight drugs which received accelerated FDA approval, approval was granted within 6 months for three (these also received priority review), 1 was approved within 6–12 months; and 4 were approved after 1 year of FDA review. Approvals were based on the surrogate clinical outcome of response rate. Pivotal studies were often small, with &lt; 100 patients (n=3) and 100–250 patients (n=4). The overall response rate was &lt; 33% for four drugs. Only one of the approvals has been converted to full approval (imatinib). Post-marketing studies have identified three potentially fatal adverse drug reactions related to two drugs (gemtuzumab associated veno-occlusive diesease, gemtuzumab associated severe infusion reactions and imatinib associated upper GI bleeds).
Conclusion: To date, accelerated FDA approval for eight hematologic oncology drugs has been granted based on pivotal trials with small sample sizes and low response rates (with the exception of imatinib). Conversion to full approval has rarely occurred (N=1) and post-marketing identification of severe adverse drug reactions, in what were initially off-label settings, has occurred for two of the drugs. Modification of the accelerated approval process for hematologic oncology drugs should be considered.
FDA approval information for accelerated approval drugs used to treat hematologic malignancies.
Drug Name Indication Time to Approval (Months) N in Trial Overall Response Rate (%) Alemtuzumab CLL 16.5 93 33 Bortezomib Myeloma 3.7 188 14 Cytarabine liposomal Lymphomatous meningitis 5.5 17 41 Denileukin diftitox T-cell lymphoma 14 206 16 Gemtuzumab CD33 positive AML 7 142 26 Ibritumomab tiuxetan Low-grade NHL 15.6 157 62 Imatinib mesylate CML 3 1027 66 Tositumomab NHL 48 40 63
Membrane Type 1-Matrix Metalloproteinase Is Directly Involved in G-CSF Induced Human Hematopoietic Stem and Progenitor Cell Mobilization.
Authors: Avigdor Abraham , Schwartz Shimon , Goichberg Polina , Petit Isabelle , Hardan Izhar , Resnick Igor , Slavin Shimon , Nagler Arnon , Lapidot Tsvee 
Published: April 2020

Abstract
G-CSF induced hematopoietic stem/progenitor cell (HSC/HPC) mobilization is regulated by a complex interplay between extracellular matrix (ECM), cytokines/chemokines, adhesion molecules, and proteases, which affect stem cell retention and proliferation in the bone marrow microenvironment. Several studies suggest that membrane type 1-matrix metalloproteinase (MT1-MMP), expressed on the surface of various cell types, is a key enzyme for normal cell motility and tumor cell migration and invasion. We found that enriched human CD34+ cells express various surface MT1-MMP levels, depending on the cell source and G-CSF treatment. CD34+ cells obtained from BM of healthy donors treated with G-CSF were found to have the highest mean fluorescence intensity (&gt;900 arbitrary units), while level of expression was lower in CD34+ cells derived from G-CSF mobilized peripheral blood from healthy donors (159±40), human steady-state (SS) BM (80±19), and human cord blood (41±4). Following 48 hr incubation of human SS-BM CD34+ cells with G-CSF, the expression of MT1-MMP increased 2-fold compared to untreated cells, whereas treatment with other cytokines, such as SCF, SDF-1 and IL-6, had only a minimal impact.
Immunocytochemical analysis of human cord blood CD34+ enriched cells plated on fibronectin or hyaluronate-coated cover slips revealed that in response to SDF-1, MT1-MMP changes its localization in the polarized and spreading cells, suggesting a role in the process of HPCs directional migration. Indeed, incubation with neutralizing antihuman MT1-MMP Ab, targeting its catalytic site, significantly reduced human progenitor migration towards a gradient of SDF-1 in transwells. Interestingly, low concentrations of tissue inhibitor of the metalloproteinase-2 (TIMP-2) enhanced SDF-1 induced transwell migration, while higher concentrations hampered this process. More importantly, 5 daily injections of G-CSF to NOD/SCID mice previously engrafted with human cells, up-regulated MT1-MMP expression on CD45+ and CD34+ human cells in the BM and peripheral blood of the mobilized chimeric mice compared to untreated, control chimeras. Treatment of chimera mice with antihuman MT1-MMP Ab on days 3–5 of G-CSF induced mobilization, significantly reduced the number of CD45+ and CD34+ human cells in peripheral blood. In summary, based on our data we suggest that following G-CSF treatment, increased levels of MT1-MMP on the surface of human progenitors in the BM facilitates their mobilization most probably due to pericellular ECM degradation and/or activation of other regulatory molecules, pointing to the essential role of MT1-MMP in G-CSF induced mobilization.
NOD Hematopoietic Stem Cells Exhibit Autonomous Behavior and a Competitive Advantage in Allogeneic Recipients That Maps to the Idd9 Locus.
Authors: Chilton Paula M. , Rezzoug Francine , Ratajczak Janina , Ratajczak Mariusz , Huang Yiming , Tanner Michael K. , Fugier-Vivier Isabelle J. , Ildstad Suzanne T. 
Published: April 2020

Abstract
Multiple hematopoietic defects have been defined in NOD mice and in humans with type I diabetes, including defects in myeloid cells and antigen presenting cells that correlate with diabetes progression. Since the replacement of HSC in NOD mice can eliminate the progression of autoimmunity and control on-going autoimmune responses, we characterized the function of HSC from NOD mice. We found that purified HSC from NOD mice have an autonomous behavior when transplanted in allogeneic recipient strains as reflected by significantly enhanced engraftment in allogeneic recipients. NOD HSC were able to compete for engraftment with syngeneic HSC even when the NOD and syngeneic HSC were given at a 1:1 ratio. NOD BMC produced a higher number of splenic colonies compared to B10.BR BMC in the allogeneic day 12 CFU-S assay. We also demonstrated that NOD HSC had a high resistance to irradiation, as reflected by the cell survival 20 hours after irradiation and in the in vitro CFC assay. These data suggest that NOD HSC escape alloreactivity and compete with normal HSC. The enhanced engraftment ability in allogeneic recipients of NOD HSC was not due to an increase in frequency of primitive HSC, enumerated by day 35 cobblestone area forming cells (CAFC). This finding was further confirmed by the fact that there was no difference in the long-term repopulating cell phenotype (CD49e+/CD49ddim) between HSC obtained from NOD, B10.BR or C57BL/10 mice. Notably, NOD bone marrow cells exhibit significantly enhanced chemotaxis to SDF-1 in vitro and significantly increased HSC adhesion to primary stroma. This was associated with an increase in the expression of VCAM-1, ICAM-1 and ICAM-2 on NOD HSC. Using NOD mice congenic at selected Idd loci with C57BL/10, we determined that the enhanced engraftment potential of NOD HSC mapped to the Idd9 (insulin-dependent diabetes) locus and, as such, the TNF receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSC. In conclusion, NOD HSC exhibit increased autonomy in vivo and in vitro compared to non-diabetic strains, and engraft better in allogeneic recipients, possibly due to enhanced migration and adherence to the microenvironment. This finding may be of interest for a better understanding of disease pathogenesis and in developing cell-based strategies to cure diabetes.
Ex Vivo Production of Transfusable Red Blood Cells at Large Scale from Cord Blood CD34+ Cells Using a Coculture System with Human Telomerase Catalytic Subunit (hTERT)-Transfected Human Stromal Cells at Early Phase and with Acitivated Macrophage from Cord Blood CD34+ Cells at Late Phase.
Authors: Fujimi Akihito , Matsunaga Takuya , Kobune Masayoshi , Kawano Yutaka , Tanaka Ikuta , Takemoto Naofumi , Akiyama Takehide , Hamada Hirofumi , Niitsu Yoshiro 
Published: April 2020

Abstract
New sources of red blood cells (RBC) would improve the transfusion capacity of blood centers. Several investigators have previously reported that erythroblasts could be obtained from hematopoietic stem cells including those of cord blood (CB) by in vitro culture. However, transfusion of erythroblasts may not be suitable for supplementation of acute blood loss because it should need some time lag until hemoglobin (RBC) boost in circulation due to the fact that transfused erythroblasts once lodged at bone marrow where they undergo maturation into RBCs which are bound to be released into circulation. We have developed a culture system for producing large quantity of enucleated RBCs (e-RBCs) as well as erythroblasts from CB in vitro: one unit e-RBCs (2 x 1012 RBCs) was obtained from one standard CB unit (corresponding to 2 x 106 CD34+ cells) using a coculture system with hTERT-transfected human stromal cells at early phase followed by with activated macrophage in liquid culture (American Society of Hematology 45th Annual Meeting, SanDiego, 2003). In the present study, we first analyzed the function of those manufactured e-RBCs in comparison of that of adult peripheral blood RBCs (PB-RBCs) or that of eryhthroblasts. The hemoglobin (Hb) content of the e-RBCs quantified by photometric determination was almost equivalent to that of adult PBRBC. A Hb A/Hb F ratio of e-RBC analyzed by high-performance liquid chromatography (HbA: HbF = 35: 65) was between those of CB RBCs (10: 90) and adult PB-RBC (99: 1). Oxygen dissociation curves of e-RBCs measured by Hemox-Analyzer was comparable to that of fresh adult PB-RBCs. The erythroblasts showed adhesive property to stromal cells in vitro but e-RBC did not. When we injected e-RBCs into NOD/SCID mice, they were detectable in circulation while erythroblasts were not. In conclusion, the e-RBCs produced by large-scale culturing system from CB CD34+ cells may be useful for acute blood loss.
New Technology for Red Blood Cell Preservation.
Authors: Tsvetkova Nelly M. , Torok Zsolt , Satpathy Gayana , Banerjee Mitali , Bali Rachna , Dwyre Denis M. , Kheirolomoom Azadeh , Little Erika , Crowe John H. , Tablin Fern 
Published: April 2020

Abstract
A method for freeze-drying red blood cells (RBCs) while maintaining a high degree of viability, has important implications in blood transfusion and clinical medicine. The disaccharide trehalose, found in animals capable of surviving dehydration can aid in this process. We are reporting a method for loading RBCs with trehalose followed by subsequent freeze-drying and rehydration. The loading of erythrocytes is based on the thermal properties of the RBC plasma membranes and provides efficient uptake of the sugar at 37°C in a time span of 7 hours. The data show that RBCs can be loaded with trehalose from the extracellular medium through a combination of osmotic imbalance and the phospholipid phase transition, producing an intracellular trehalose concentration of about 40 mM. Freeze-drying of trehalose loaded RBCs results in water contents in the range between 2 and 4 % and a level of survival of around 37 %, as measured by the extent of hemolysis. Surprisingly, freeze-dried and rehydrated RBCs showed high levels of ATP and 2,3-DPG and low methemoglobin. Biochemical analysis demonstrated that the activities of superoxide dismutase, catalase and acetylcholine esterase in freeze-dried RBCs are similar to those in fresh RBCs. These data provide an important step toward a stable erythrocyte product, which will be invaluable for transfusion and clinical applications. Supported by DARPA grant N66001-03-1-9827
Thromboelastographic (TEG) Characterization of Patients with Hematologic Malignancy and Chemotherapy Induced Thrombocytopenia (CIT).
Authors: Shah Jatin J. , Gomes Marcelo P.V. , Deitcher Steven R. 
Published: April 2020

Abstract
The decision to provide prophylactic platelet transfusions to patients with hematologic malignancy and chemotherapy induced thrombocytopenia (CIT) is often based solely on the platelet count being below a somewhat arbitrary threshold. The ability to rapidly assess the overall (net) coagulation status (thrombotic and hemorrhagic tendencies) of these patients may help limit transfusion to those with a measurable bleeding tendency and reduce overall platelet product consumption. We performed pre- and post-platelet transfusion whole blood thromboelastography (TEG) in 20 pts with leukemia (16) or lymphoma (4) and CIT. Citrated venous blood was obtained prior to and 1 hour after single transfusions of 5 units of random donor platelets. Normal ranges were derived from TEG evaluation of 18 normal controls. Correlation between absolute and % changes in maximum TEG amplitude (MA, mm) and time to initial clot formation (R, min) and absolute and % changes in platelet count was assessed. Pts were defined as normal if MA = 45.7 to 64.9 and R = 8.3 to 19.9; hypocoagulable if MA&lt;45.7 and/or R&gt;19.9; hypercoagulable if MA&gt;64.9 and/or R&lt;8.3; and “mixed” for all other result patterns. Pre-transfusion TEG revealed 17/20 (85%) patients to be hypocoagulable, 1/20 (5%) to be hypercoagulable, and 2/20 (10%) to have a mixed pattern. All hypocoagulable patients had a baseline MA&lt;45.7 and 12/17 had an R&gt;19.9. Pre-transfusion platelet count correlated with baseline MA (r =.47, p=.038). No statistically significant correlation between absolute and % change in platelet count and absolute change in MA, % change in MA, absolute change in R, and % change in R existed. Post transfusion, 17/20(85%) patients had normal MA. Post transfusion, 7/17(41%) hypocoagulable patients had normal TEG, 7/17(41%) remained hypocoagulable, and 3/17(18%) became hypercoagulable. Both “mixed” patients became hypercoagulable; the hypercoagulable patient became normal. 3/5 patients with poor transfusion response (platelet count increase &lt; 10,000/mL) went from hypocoagulable to normal while the remaining 2/5 had MA but not R normalization. Based on our TEG data, 15% of hematologic malignancy patients with CIT did not have a baseline hypocoagulable pattern and may not have needed platelet transfusion. In the 85% who were hypocoagulable at baseline, 41% remained hypocoagulable despite platelet transfusion and may have benefited from additional hemostatic therapy. The patients that normalized did so with variable and at times minimal increases in platelet count. The 18% of baseline hypocoagulable patients that became hypercoagulable post-transfusion may have become transiently prone to thrombosis. Our data supports further evaluation of surrogate markers of overall hemostatic potential, like TEG, as a means of guiding and optimizing platelet transfusion practices.
EB10, an Anti-FLT3 Monoclonal Antibody, Selectively Targets ALL Cell Lines and Primary ALL Blasts without Interfering with Normal Hematopoiesis.
Authors: Piloto Obdulio , Brown Patrick , Li Li , Nguyen Bao , Kim Kyu-Tae , Huso David , Li Yiwen , Li Hongli , Wang Mei-Nai , Witte Larry , Hicklin Daniel J. , Small Donald 
Published: April 2020

Abstract
The class III receptor tyrosine kinase, FLT3, is expressed by &gt;90% of B-lineage acute lymphoblastic leukemias (ALL) blasts. In addition, it is expressed at extremely high levels in ALL patients with MLL-rearrangements or hyperdiploidy and sometimes mutated in these same patients. In this report, we investigated the effects of EB10, an anti-human FLT3 monoclonal antibody capable of preventing binding of FLT3 ligand (FL), on ALL cell lines and primary cells. In vitro studies, examining the ability of EB10 to inhibit FLT3 activation and downstream signaling in ALL cell lines and primary blasts, yielded variable results. In some cell lines FLT3 phosphorylation was inhibited and with it, downstream activation of pathways involving MAPK, AKT, and STAT5 phosphorylation. However, several cell lines actually exhibited FLT3 activation upon antibody treatment, possibly because of antibody-mediated receptor dimerization, and subsequent activation of downstream pathways. Nevertheless, through antibody-mediated cellular cytotoxicity (ADCC) such an antibody could still prove efficacious against leukemia cells in vivo. In fact, EB10 treatment significantly prolongs survival and/or reduces engraftment of ALL cell lines and primary ALL blasts in NOD/SCID mice. This effect might be even more pronounced in a host that was less immune compromised than are NOD/SCID mice. The leukemic cells surviving EB10 treatment in the mice were characterized by FACS analysis and found to express low levels or no FLT3. In contrast to the reduction in engraftment of human ALL primary blasts, EB10 treatment of NOD/SCID mice did not reduce engraftment of human hematopoietic CD34+ cells. Taken together, these data demonstrate that EB10 is selectively cytotoxic to ALL blasts while having little effect on normal hematopoiesis. Such an antibody, either naked or conjugated to radioactive isotopes or cytotoxic agents, may prove useful in the therapy of infant ALL as well as childhood and adult ALL patients whose blasts typically express FLT3.