Gullu Gorgun

Oregon Health and Science University, Knight Cancer Institute · Medicine, Division of Hematology and Medical Oncology

Significance Proteasome inhibitors show remarkable anti-multiple myeloma (MM) activity in preclinical and clinical studies. However, resistance develops in the majority of patients, and novel treatments are urgently needed. Histone deacetylase 6 (HDAC6) has been shown to mediate aggresomal protein degradation and could be a potential target for com...

Histone methylations are tightly regulated by a balance between methyltransferases and demethylases that mediate the addition and removal of these modifications. Importantly, dysregulation of histone methylation is implicated in pathogenesis of cancers, including multiple myeloma (MM). For example, the t(4;14) (p16;q32) is present in 15 - 20% of MM...

Heat shock protein (HSP)90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90α/β inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RA...

TAS-116 is a novel, oral, selective HSP90α/β inhibitor. Chemical structure of TAS-116. (EPS)

The RAF inhibitor dabrafenib induces paradoxical activation of ERK signaling in RAS-mutated MM cells. NCI-H929 and RPMI-8226 cells were treated with the indicated concentrations of dabrafenib for 24 h. Whole-cell lysates were subjected to western blotting using p-B-Raf, B-Raf, p-C-Raf, C-Raf, p-MEK1/2, MEK1/2, p-ERK, ERK, and β-actin Abs. (EPS)

RAS knockdown induces cell cycle modulation and enhances cytotoxicity induced by bortezomib and doxorubicin in RAS-mutated MM cells. NCI-H929 and KMS11 cells were transiently transfected with non-targeting or NRAS siRNA and then treated with or without bortezomib (0–10 nM) or doxorubicin (0–400 nM) for 48 h. In each case, cell viability was assesse...

TAS-116 triggered a decrease in mitochondria transmembrane potential. MM.1S cells were treated with or without 2 μM TAS-116 for 4, 8, or 24 h, with addition of MitoCapture reagent (MitoCapture Apoptosis Detection kit, Calbiochem) for the last 20 minutes, followed by flow cytometric analysis. (EPS)

TAS-116 enhances mitochondrial apoptosis induced by RAS-RAF-MEK-ERK pathway inhibitors. (A) NCI-H929 and RPMI-8226 cells were treated with the indicated concentrations of TAS-116 either alone or in combination with tipifarnib, dabrafenib, or AZD6244 for 24 h. Whole-cell lysates were subjected to western blotting using Bim and α-tubulin Abs. (B) NCI...

TAS-116 combination indices (CI) with tipifarnib, dabrafenib, or AZD6244 in NCI-H929 cells. The tables correspond to the Fa and CI values in Fig 4A. CI was calculated using CompuSyn software. (EPS)

TAS-116 combination indices (CI) with tipifarnib, dabrafenib, or AZD6244 in MM.1S cells. The tables correspond to the Fa and CI values in Fig 4D. CI was calculated using CompuSyn software. (EPS)

TAS-116 combination indices (CI) with tipifarnib, dabrafenib, or AZD6244 in INA6 cells. The tables correspond to the Fa and CI values in Fig 4B. CI was calculated using CompuSyn software. (EPS)

TAS-116 combination indices (CI) with tipifarnib, dabrafenib, or AZD6244 in RPMI-8226 cells. The tables correspond to the Fa and CI values in Fig 4C. CI was calculated using CompuSyn software. (EPS)

PD1/PD-L1 signaling promotes tumor growth while inhibiting effector cell-mediated anti-tumor immune responses. Here we assessed the impact of single and dual blockade of PD1/PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma (MM) cell growth in the BM milieu. Surface expression of PD1...

Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide (Len) and pomalidomide trigger anti-tumor activities in multiple myeloma (MM) by targetting cereblon and thereby impacting IZF1/3, c-Myc and IRF4. Histone deacetylase inhibitors (HDACi) also downregulate c-Myc. We therefore determined whether IMiDs with HDACi trigger significant MM cell growt...

Histone deacetylase (HDAC) inhibitors have been extensively investigated as therapeutic agents in cancer. However, the biologic role of class IIa HDACs (HDAC4, 5, 7 and 9) in cancer cells, including multiple myeloma (MM), remains unclear. Recent studies show HDAC4 interacts with activating transcription factor 4 (ATF4) and inhibits activation of en...

Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow (BM). Despite the significant advances in treatment, MM is still a fatal malignancy. This is mainly due to the supportive role of the BM microenvironment in differentiation, migration, proliferation, survival, and drug resistance of the malignant...

Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that interacts with various client proteins in eukaryotic cells:(1) Akt (PI3K/Akt pathway), interleukin-6 R (JAK/STAT pathway), Bcr-Abl (RAS/ERK pathway), Cyclin-dependent kinase 4, 6, 9 (cell cycling) and I kappa B kinases (NF-kappa B pathway).(2) The expression of HSP90 is up...

Introduction: Multiple myeloma patients who are refractory to lenalidomide and bortezomib have a dismal prognosis. Pomalidomide is a new immunomodulatory agent approved for the treatment of relapsed and refractory multiple myeloma (RRMM) that is unique in that it demonstrates promising activity but appears to be associated with lower toxicity than...

Despite promising preclinical results with mTOR kinase inhibitors in multiple myeloma (MM), resistance to these drugs may arise via feedback activation loops. This concern is especially true for IGF-1 receptor (IGF-1R), because IGF-1R signaling is downregulated by multiple AKT and mTOR feedback mechanisms. We have tested this hypothesis in MM using...

The PI3K/Akt pathway plays a crucial role in the pathogenesis of multiple myeloma (MM) in the bone marrow (BM) milieu. However, efficacy of selective and potent Akt inhibition has not yet been fully elucidated. In this study, we therefore examined the biologic impact of selective and potent Akt inhibition by a novel allosteric inhibitor TAS-117. TA...

Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.

Histone deacetylases (HDACs) represent novel molecular targets for the treatment of various types of cancers, including multiple myeloma (MM). Many HDAC inhibitors have already shown remarkable anti-tumor activities in the preclinical setting; however, their clinical utility is limited due to unfavorable toxicities associated with their broad range...

Small molecule multi-targeted CDK inhibitors (CDKIs) are of particular interest due to their potent antitumor activity independent of p53 gene alterations. P53 deletion is associated with a very poor prognosis in multiple myeloma (MM). In this regard, we tested the anti-MM activity of RGB-286638, an indenopyrazole-derived CDKI with Ki-nanomolar act...

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous, immature myeloid cell population with the ability to suppress immune responses. MDSCs have been characterized in infections, inflammatory diseases, and solid tumors; however, their presence and role in the tumor-promoting, immune-suppressive microenvironment in hematologic malignancies r...

Lenalidomide is an amino-substituted derivative of thalidomide with direct antiproliferative and cytotoxic effects on the myeloma tumor cell, as well as antiangiogenic activity and immunomodulatory effects. Together with the introduction of bortezomib and thalidomide, lenalidomide has significantly improved the survival of patients with relapsed an...

Niels WCJ van de Donk,1,2 Güllü Görgün,1 Richard WJ Groen,1,3 Jana Jakubikova,1 Constantine S Mitsiades,1 Teru Hideshima,1 Jacob Laubach,1 Inger S Nijhof,2 Reinier A Raymakers,2 Henk M Lokhorst,2 Paul G Richardson,1 Kenneth C Anderson11Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 2Department...

NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma in the context of the bone marrow microenvironment. Both canonical and noncanonical pathways contribute to total NF-κB activity. Recent studies have shown a critical role for the noncanonical pathway: selective inhibitors of the canonical pathway present a limited a...

Multiple myeloma (MM) cells are characterized by high protein synthesis resulting in chronic endoplasmic reticulum (ER) stress, which is adaptively managed by the unfolded protein response. Inositol-requiring enzyme 1α (IRE1α) is activated to splice X-box binding protein 1 (XBP1) mRNA, thereby increasing XBP1s protein, which in turn regulates genes...

1838 Introduction Graft-versus-myeloma (GvM) effect following allogeneic stem cell transplantation (allo-SCT) is well established and often accompanied by graft-versus-host disease (GVHD). Unfortunately, most patients still relapse following allo-SCT, underscoring the need for new transplant strategies. Interestingly, studies evaluating the protea...

2916 Inhibition of the PI3K/mTOR pathway is a promising therapeutic strategy in targeting multiple myeloma (MM) cells in the bone marrow (BM) microenvironment, which abnormally activates PI3K/mTOR signaling cascade mediating proliferation, anti-apoptosis and drug resistance. Exploring the targeting of PI3K/mTOR pathway has led to the development of...

133 Multiple myeloma (MM) cells are characterized by high protein synthesis resulting in chronic endoplasmic reticulum (ER) stress, which is adaptively managed by the unfolded protein response (UPR). Therefore blockade of UPR could provide a novel therapeutic option in MM. Upon UPR, inositol-requiring enzyme 1α (IRE1α) is activated by auto-phosphor...

2902 NF-kB plays a crucial role in the pathogenesis of multiple myeloma (MM). In MM cells, NF-kB pathway is constitutively activated and regulates transcription of genes whose protein products mediate proliferation, survival and drug resistance. In the context of the bone marrow (BM) microenvironment, NF-kB modulates the expression of cytokines (ie...

128 The interaction of myeloma (MM) cells with bone marrow accessory cells and/or the extracellular matrix induces genomic, epigenomic and functional changes which promote tumor development, progression, cell adhesion mediated-drug resistance (CAM-DR), and immune suppression. To develop the most efficient anti-MM treatment strategy and prevent tumo...

Advances in tumor biology have demonstrated a point of critical importance: tumor are established as an intersection of malignant clone cells and surrounding stromal cells. The stroma is composed of nonhematopoietic cells, including connective tissue cells, blood vessels, nerves, fat and smooth muscle cells, in the extracellular matrix niche. Recen...

Aurora kinases, whose expression is linked to genetic instability and cellular proliferation, are being investigated as novel therapeutic targets in multiple myeloma (MM). In this study, we investigated the preclinical activity of a small-molecule multitargeted kinase inhibitor, AT9283, with potent activity against Aurora kinase A, Aurora kinase B,...

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Aurora Kinases are a family of mitotic regulators. Aurora Kinase A (AURKA) plays a crucial role in centrosome separation and spindle assembly and is required for mitosis and bipolar mitotic spindle formation. Aurora Kinase B (AURKB), a member of the chromosomal passenger...

2994 Despite recent advances with new drugs such as bortezomib, thalidomide and lenalidomide, multiple myeloma (MM) remains an incurable disease. Used as single agents, these compounds have shown marked antitumor activity, but the number of patients with relapsed and refractory disease remains high. Combination of these agents with other classes of...

2996 Histone deacetylase 6 (HDAC6), a cytoplasmic enzyme, is a member of Class IIb HDAC family and catalyses the deacetylation of histones. Acetylation of histones induces chromatin relaxation leading gene transcription; conversely, deacetylation of histones induces chromatin condensation and silencing of gene transcription. HDAC6 regulates importa...

4074 Aberrant protein folding results in the accumulation of misfolded/unfolded proteins in the endoplasmic reticulum (ER), which in turn triggers ER stress followed by unfolded protein response (UPR), an adaptive response against ER stress. Since multiple myeloma (MM) cells have high protein synthesis, they are sensitive to ER stress and require s...

791 Targeting PI3K/Akt/mTOR signaling is among one of the promising therapeutic strategies in multiple myeloma (MM), since it facilitates MM cell survival and development of drug resistance in the context of the bone marrow microenvironment. Specifically, regulation of PI3K activity, which mediates MM cell growth and drug resistance, by mTOR comple...

(Chemical Equation Presented) Aurora serine/threonine-protein kinases localize in the centrosome and play a crucial role in cell division by regulating chromatid segregation in mitotic cells; moreover, defective chromatid segregation causes genetic instability, leading to tumorigenesis. Aurora kinases were first identified in Xenopus Eg2, yeast Ipl...

The bone marrow (BM) microenvironment consists of extracellular-matrix and the cellular compartment including immune cells. Multiple myeloma (MM) cell and BM accessory cell interaction promotes MM survival via both cell-cell contact and cytokines. Immunomodulatory agents (IMiDs) target not only MM cells, but also MM cell-immune cell interactions an...

In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110delta signaling in multiple myeloma (MM). Knockdown of p110delta by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110delta specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines an...

Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a n...

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway mediates multiple myeloma (MM) cell proliferation, survival, and development of drug resistance, underscoring the role of mTOR inhibitors, such as rapamycin, with potential anti-MM activity. However, recent data show a positive feedback loop from mTOR/S6K1 to Akt,...

Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of...

Constitutive B-cell lymphoma 6 (Bcl-6) expression was undetectable in multiple myeloma (MM) cell lines, except U266 cells. However, it was up-regulated by coculture with bone marrow (BM) stromal cell-culture supernatant (SCCS). Bcl-6 expression in patient MM cells in the BM was positive. Anti-interleukin-6 (IL-6)-neutralizing antibody significantly...

950 The bone marrow (BM) microenvironment consists of extracellular matrix and the cellular compartment including bone marrow stromal cells (BMSCs) and immune cells. Interaction between multiple myeloma (MM) cells and BM cells induces growth, survival, migration, and drug resistance in MM, via both cell-cell contact and cytokines. Even though MM ce...

295 BCL6 (B- cell lymphoma 6) is a proto-oncogene encoding a transcriptional repressor and regulates germinal center B cell differentiation. It is deregulated by chromosomal translocations or aberrant somatic hypermutation in a subset of diffuse large B cell lymphomas (Polo, JM. et al. PNAS, 2007). Importantly, small peptide inhibitor of BCL6 media...

2849 Poster Board II-825 Histone deacetylase inhibitors (HDACi) are emerging as a potential therapy for Multiple Myeloma (MM). Their antineoplastic activity depends not only on nucleosomal histone acetylation, but also on direct modulation of non-histone proteins, including p53 or HSP90. Previous studies suggest that histone deacetylases inhibitors...

3830 Poster Board III-766 Multiple myeloma (MM) is an incurable bone marrow derived plasma cell malignancy. Despite significant improvements in treating patients suffering from this disease, MM remains uniformly fatal due to intrinsic or acquired drug resistance. Thus, additional modalities for treating MM are required. Targeting cell cycle progres...

4915 Multiple studies have highlighted the critical role of mutation and loss of p53 function in multiple myeloma (MM) when acquiring a more aggressive phenotype and refractoriness to treatment. Therefore, agents capable of overcoming p53 mutational status are important in the context of MM therapeutics. We have previously reported the in vitro and...

3833 Poster Board III-769 Aurora kinases, a family of mitotic regulators, whose expression has been recently linked to genetic instability and cellular proliferation in several cancers including multiple myeloma (MM), are being studied as novel mitotic therapeutic targets. Aurora A plays a crucial role in centrosome separation and spindle assembly...

Multiple myeloma (MM) is a cancer of plasma cells with complex molecular characteristics that evolves from monoclonal gammopathy of undetermined significance, a highly prevalent premalignant condition. MM is the second most frequent hematologic cancer in the United States, and it remains incurable, thereby highlighting the need for new therapeutic...

Earlier studies have shown that ascorbic acid (vitamin C) inhibits bortezomib-induced cytotoxicity against cancer cells in vitro. However, the clinical significance of vitamin C on bortezomib treatment is unclear. In this study, we examined whether daily oral intake of vitamin C inhibits antimultiple myeloma (MM) activities of bortezomib. Vitamin C...

Preclinical animal models have largely ignored the immune-suppressive mechanisms that are important in human cancers. The identification and use of such models should allow better predictions of successful human responses to immunotherapy. As a model for changes induced in nonmalignant cells by cancer, we examined T-cell function in the chronic lym...

Multiple studies have shown the importance of PI3K/Akt/mTOR pathway in the pathogenesis of multiple myeloma (MM). Specifically, it mediates cell proliferation and development of drug resistance. Identifying mTOR as a key kinase acting downstream of Akt led to the prediction that rapamycin, a universal inhibitor of mTORC1-dependent S6K1 phosphorylat...

Vitamin C (ascorbic acid, AA) has antioxydative effects and is widely taken as a food supplement. Previous studies have shown that AA inhibits bortezomib-induced cytotoxicity in human cancer cell lines in vitro thought a direct interaction of both agents. Since bortezomib is a standard treatment option in multiple myeloma (MM), we have determined w...

The phosphatidylinositide 3-kinase (PI3K)/Akt pathway mediates cell proliferation, cell cycle regulation, apoptosis, and autophagy. Of the 8 distinct mammalian isoforms of PI3K, it is the class I PI3Ks (p110α, p110β, p110δ, and p110γ) that are responsible for Akt activation. Recently, p110δ expression has been shown in colon and bladder carcinoma,...

Multiple myeloma (MM) is an incurable bone marrow derived plasma cell malignancy. Despite significant improvements in treating patients suffering from this disease, MM remains uniformly fatal owing to intrinsic or acquired drug resistance. Thus, additional modalities for treating MM are required. In this study, we examined the anti-tumor activity o...

The bone marrow (BM) environment consists of extracellular matrix molecules and the cellular compartment including immune cells. Interaction between multiple myeloma (MM) cells, BM cells, and BM-derived soluble factors (BMSF), particularly cytokines, induces growth, survival, migration and drug resistance in MM cells. Even though MM cell interactio...

CD138 is expressed on differentiated plasma cells and is involved in the development and/or proliferation of multiple myeloma (MM), for which it is a primary diagnostic marker. In this study, we report that immunoconjugates comprised of the murine/human chimeric CD138-specific monoclonal antibody nBT062 conjugated with highly cytotoxic maytansinoid...

To identify genes or Tumor-Associated Antigens (TAA) potentially involved in the transition from Monoclonal Gammopathy of Undetermined Significance (MGUS) to Multiple Myeloma (MM) and in the MM pathogenesis, we used SEREX and screened serum of MGUS and MM patients with a MM cDNA library. We identified 10 novel antigens and focused our attention on...

Uncontrolled proliferation and development of drug resistance in multiple myeloma (MM) cells are consequences of the numerous genetic aberrations which are further stimulated in the context of bone marrow microenvironment. Thus, inhibition of complementary pro-survival signaling and transcriptional networks rather than individual pathway is require...

Understanding the elusive mechanisms of tumor-driven immune evasion will aid the refinement of existing cancer immunotherapy strategies and identify novel treatments. To date, pre-clinical animal models that closely model human cancer, including the immune suppressive mechanisms utilized by cancer cells, have been under-characterized. The identific...

Cyclin dependent kinases (CDKs) and their cyclin complexes play a crucial role in cell cycle control and transcriptional regulation. In multiple myeloma (MM), the abnormal activation of different CDKs and their cyclin partners, especially CDK4/cyclin D1 and CDK6/Cyclin D2, mediate uncontrolled cell cycle progression. Therefore CDKs represent promis...

Numerous methods for selectively depleting or manipulating alloantigen (alloAg) specific CD4 T cells (CD4 T) are being studied for their potential in improving transplant outcomes by limiting GVHD or graft rejection. Although some methods target specific molecules (e.g. costimulatory receptors and ligands, activation antigens), the effects of these...

Retention of antigen (Ag) specific immunity to pathogens and tumor cells in the context of adequate control of alloreactivity remains a challenge for allogeneic hematopoietic stem cell transplantation (HSCT). Global or subset depletion of T cells achieves control of alloreactivity at the cost of loss of non-allospecific repertoire. Induction of Ag...

Control of alloreactivity without loss of immunity to pathogens and tumor antigens remains the major challenge in allogeneic hematopoietic stem cell transplantation (AHSCT). One platform for achieving this objective has been based upon the methodologies of stimulating donor T cells with recipient alloantigens and destroying, removing, and/or inacti...

Deregulation of the TCL1 pathway plays a crucial role in B-CLL pathogenesis and targeted expression of TCL1 results in the development in older mice of a B cell lymphoproliferative disorder resembling human B-CLL. CLL patients develop progressively impaired immunity and gene expression profiling of CD4 and CD8 T cells in B-CLL patients revealed def...

Following allogeneic stem cell transplantation there is evidence of a graft versus leukemia effect (GVL). Whether this is mediated by an immune response against histocompatibility antigens also expressed on the tumor cells, i.e. by graft versus host disease (GVHD) or might be contributed to by response against specific tumor associated antigens (TA...

Targeting immunoglobulin (Ig) framework region (FR) derived peptides offers the advantage of a less patient specific immunotherapeutic strategy in B-cell malignancies. A major limitation of this method is the generally low immunogenicity and low binding affinity of these peptides to MHC class I and class II molecules. Heteroclitic peptide modificat...

Both host and viral factors play an important role in the pathogenesis of human immunodeficiency virus (HIV)-associated bran injury. In this study, the authors examined the interactions between tumor necrosis factor (TNF)-alpha, CXCR4, the alpha chemokine receptor, and three HIV isolates, including the T-tropic viruses, HIV-1(MN) and HIV-1(IIIB), a...

To examine the impact of tumors on the immune system, we compared global gene expression profiles of peripheral blood T cells from previously untreated patients with B cell chronic lymphocytic leukemia (CLL) with those from age-matched healthy donors. Although the cells analyzed were not part of the malignant clone, analysis revealed differentially...

The mutational status of the variable region of the immunoglobulin heavy chain gene (IgV(H)) is an important prognostic marker in B-cell chronic lymphocytic leukaemia (B-CLL), with mutated patients having improved outcome. To examine the impact of mutational status on V(H), D(H), and J(H) gene segment location and immunogenicity, we analysed 375 Ig...

It is possible to differentiate malignant from healthy cells and to classify diseases based on identification of specific gene expression profiles. We hypothesized that gene expression profiling could also be used to identify differential activation of healthy and malignant cells, and as a model for this, we examined the molecular sequelae of CD40...

The TCL1 gene at 14q32.1 is involved in chromosomal translocations and inversions in T cell leukemias, but targeted expression of the TCL1 gene in mice results in the development of a CLL like disorder in older mice resembling human B-CLL, so that deregulation of the TCL1 pathway proved to play a crucial role in CLL pathogenesis in mice. Developmen...

Previous studies have suggested that the development and progression of B cell CLL is dependent on interactions between malignant cells and normal components of the immune system. Although the T cell count may be normal or even increased, T cell dysfunction is a feature of CLL, with abnormal CD4/CD8 ratio, impaired mitogen response, and altered exp...

In B cell chronic lymphocytic leukemia (B-CLL) somatic hypermutation in the immunoglobulin variable heavy chain (IgVH) identifies two distinct prognostic variants with mutated (M) patients having better survival. Ig recombination in this disease demonstrates biased V, D and J gene usage. To determine features of VDJ recombination associated with ch...

In all, 55 patients at high risk or ineligible for a conventional allogeneic hematopoietic stem cell transplant (HSCT) received a regimen consisting of extracorporeal photopheresis, pentostatin, and reduced dose total body irradiation. The median age was 49 years (18-70 years); 44 received a sibling and 11 an unrelated HSCT; 44% were over the age o...

Graft-versus-host disease (GVHD) causes significant morbidity and mortality in patients undergoing allogeneic bone marrow transplantation following either a conventional or reduced-intensity preparative regimen. In a murine model, inactivation of host dendritic cells (DCs) was associated with a significant reduction in acute GVHD, suggesting that h...

DAB(389)IL-2 (ONTAK) is a fusion protein consisting of the ADP-ribosyltransferase and membrane translocating domains of native diphtheria toxin and the full-length sequence for interleukin-2 (IL-2) gene. In vitro data demonstrates that DAB(389)IL-2 is cytotoxic to cells expressing the high affinity IL-2 receptor (IL-2R). In Phases I and II clinical...