[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) is a clonal B cell malignancy characterized by proliferation of malignant plasma cells in the bone marrow. Despite high-dose melphalan therapy with autologous stem cell transplantation (ASCT) and the introduction of immunomodulatory drugs like bortezomib or lenalidomide, that have been associated with improved survival, MM is still incurable and new treatment options are needed. In B cell malignancies such as chronic lymphocytic leukaemia (CLL) or diffuse large B cell lymphoma (DLBCL), Syk (spleen tyrosine kinase) inhibitors have shown promising in vitro and first clinical results. In our study, we analyzed the potential of Syk as a target in MM.
The MM cell lines AMO-1, U266 and RPMI8226 and primary MM cells were treated with the Syk inhibitors BAY61-3606, R406 or Piceatannol and proliferation, migration and apoptosis induction were analyzed. Effects on involved intracellular signaling cascades were determined by Western blotting. Furthermore, we analyzed synergistic and additive effects of Syk inhibitors in combination with established anti-myeloma drugs and experimental inhibitors (e.g. PI-3-Kinase inhibitor NVP-BEZ235).
Incubation of MM cell lines as well as primary MM cells with Syk inhibitors resulted in a reduced proliferation and stromal cell-derived factor-1 alpha (SDF-1 alpha) induced migration that was accompanied by a concentration dependent inhibition of the MAP-Kinase, characterized by reduced phosphorylation of ERK an p38 molecules, and NF-kappaB signalling pathways. Furthermore, Syk inhibition induced apoptosis in MM cells in a dose-dependent manner, characterized by reduced expression of pro-caspase 3, increased PARP-1 cleavage and enhanced release of cytochrome c. In addition combined treatment of MM cells with Syk inhibitors and NVP-BEZ235 (dual PI3-kinase/mTOR inhibitor) or MAPK inhibitors (PD98059, SP600125, U0126, SB203580) resulted in increased apoptotic activity of the drugs.
Our results show that Syk inhibition might represent a promising new treatment option in MM with an increased efficacy when combined with MAP kinase inhibitors. Furthermore, our study strongly underlines the potency of Syk inhibitors as a potential therapeutic treatment option for MM patients.
[Show abstract][Hide abstract] ABSTRACT: Inhibitors of VEGF receptor (VEGFR) signaling such as sorafenib and sunitinib that are currently used in the treatment of malignant diseases have been shown to affect immunological responses by inhibition of the function of antigen presenting cells and T lymphocytes. The VEGFR-inhibitor axitinib has recently been approved for second line therapy of metastatic renal cell carcinoma. While there is some evidence that axitinib might interfere with the activation of T cells, not much is known about the effects of axitinib on dendritic cell (DC) phenotype and function. We here show that the addition of axitinib during the final Toll-like receptor-4-induced maturation step of monocyte-derived human DCs results in a reduced DC activation characterized by impaired expression of activation markers and co-stimulatory molecules such as CD80, CD83 and CD86. We further found a decreased secretion of interleukin-12 which was accompanied by reduced nuclear expression of the transcription factor cRel. In addition, we found a dose-dependent reduced activation of p38 and STAT3 in axitinib-exposed DCs, whereas the expression was not affected. The dysfunction of axitinib-exposed DCs was further underlined by their impaired induction of allogeneic T cell proliferation in a mixed lymphocyte reaction assay and inhibition of DC migration. Our results demonstrate that axitinib significantly affects DC differentiation and function primarily via the inhibition of the nuclear factor kappa B signaling pathway leading to impaired T cell activation. This will be of importance for the design of future vaccination protocols and therapeutic approaches aiming at combining different treatment strategies, eg such as programmed death-1 inhibitors with axitinib.
PLoS ONE 06/2015; 10(6):e0128897. DOI:10.1371/journal.pone.0128897 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this issue of Blood, Schneidawind et al demonstrate that the adoptive transfer of CD4+ invariant natural killer T (iNKT) cells from third-party mice protects from lethal graft-versus-host disease (GVHD) through expansion of donor regulatory T cells (Tregs) in a murine model of allogeneic hematopoietic cell transplantation (HCT).
[Show abstract][Hide abstract] ABSTRACT: Intensive therapy regimens in patients with acute myeloid leukemia (AML) frequently result in sepsis and septic shock. In this study, we investigated the prognostic outcome of AML patients requiring intensive care treatment due to severe sepsis or septic shock.
We present a retrospective cohort study in a medical intensive care unit (ICU) of a university hospital that serves as a tertiary care center.
Here we present data from 44 AML patients of our ICU with 29 requiring invasive mechanical ventilation due to sepsis and compared multiple clinical and laboratory parameters of ICU survivors and non-survivors.
Mean age was 59.5 years, the overall mortality rate was 41 % (18/44), and the mortality rate among patients who received mechanical ventilation was 55 % (16/29). The mortality rate among younger patients (aged 60 years or less) was 17 % (3/18), while 58 % of the older patients died (15/26). The mortality rate among younger patients who received mechanical ventilation was 23 % (3/13) compared with 81 % (13/16) of the older patients. The mean invasive ventilation time was 415 h in non-survivors compared with 667 h in survivors. No differences could be identified between survivors and non-survivors, concerning multiple laboratory parameters or AML prognostic and therapeutic parameters; our analysis, however, confirmed a statistically significant difference in the patients' age.
In previous studies, age was one of the most important prognostic factors in AML patients receiving mechanical ventilation due to severe sepsis or septic shock. In spite of improvements in diagnostic and treatment over the last couple of years, our study indicates that this fact still is true. However, the overall outcome has improved over the years due to improvements in intensive care medicine.
Journal of Cancer Research and Clinical Oncology 03/2015; 141(9). DOI:10.1007/s00432-015-1955-9 · 3.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent meta-analyses showed that antibiotic prophylaxis in patients with neutropenia after chemotherapy reduced the incidence of fever and mortality rate. Fluoroquinolones appear to be most effective and well tolerated. Thus, in April 2008, we changed our antibiotic prophylaxis regimen from cotrimoxazole/colistin (COT/COL) to the fluoroquinolone ciprofloxacin (CIP) in patients with acute myeloid leukemia (AML). The aim of this retrospective study was to compare efficacy and development of bacterial resistance with two different prophylaxis regimens over a time period of more than 4 years.
Induction chemotherapy courses given for AML during the antibiotic prophylaxis period with COT/COL (01/2006-04/2008) and CIP (04/2008-06/2010) were retrospectively analyzed with a standard questionnaire.
Eighty-five courses in the COT/COL group and 105 in the CIP group were analyzed. The incidence of fever was not significantly different (COT/COL 80 % vs CIP 77 %; p = 0.724). Also, the rate of microbiologically documented infections was nearly the same (29 vs 26 %; p = 0.625). In addition, there was no significant difference in the incidence of clinically documented infections (11 vs 19 %; p = 0.155) or in the rates of detected gram-positive and gram-negative bacteria. Of note, there was no increase in resistance rates or cases with Clostridium difficile-associated diarrhea in the CIP group.
The antibiotic prophylaxis with CIP compared to COT/COL in AML was similarly effective with no increase in bacterial resistance. COT/COL may have the advantages of providing additional prophylaxis against Pneumocystis jirovecii pneumonia and leaving fluoroquinolones as an additional option for treatment of febrile neutropenia.
Supportive Care Cancer 01/2015; 23(5). DOI:10.1007/s00520-015-2621-0 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Specialized blood cells are generated through the entire life of an organism by differentiation of a small number of hematopoietic stem cells (HSC). There are strictly regulated mechanisms assuring a constant and controlled production of mature blood cells. Although such mechanisms are not completely understood, some factors regulating cell cycle and differentiation have been identified. We have previously shown that Caspase-3 is an important regulator of HSC homeostasis and cytokine responsiveness. p21cip1/waf1 is a known cell cycle regulator, however its role in stem cell homeostasis seems to be limited. Several reports indicate interactions between p21cip1/waf1 and Caspase-3 in a cell type dependent manner. Here we studied the impact of simultaneous depletion of both factors on HSC homeostasis. Depletion of both Caspase-3 and p21cip1/waf1 resulted in an even more pronounced increase in the frequency of hematopoietic stem and progenitor cells. In addition, simultaneous deletion of both genes revealed a further increase of cell proliferation compared to single knock-outs and WT control mice, while apoptosis or self-renewal ability were not affected in any of the genotypes. Upon transplantation, p21cip1/waf1-/- bone marrow did not reveal significant alterations in engraftment of lethally irradiated mice, while Caspase-3 deficient HSPC displayed a significant reduction of blood cell production. However, when both p21cip1/waf1 and Caspase-3 were eliminated this differentiation defect caused by Caspase-3 deficiency was abrogated.
PLoS ONE 10/2014; 9(10):e109266. DOI:10.1371/journal.pone.0109266 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITD), as well as concurrent gene mutations with regard to postremission therapy in 323 patients with FLT3-ITD positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (p=0.004) and IS in the tyrosine kinase domain 1 (TKD1, p=0.06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (CTX, n=121) or autologous hematopoietic stem cell transplantation (HSCT, n=17), an allelic ratio ≥0.51 was associated with an unfavorable relapse-free (RFS, p=0.0008) and overall survival (OS, p=0.004); after allogeneic HSCT (n=93), outcome was significantly improved in patients with a high allelic ratio (RFS, p=0.02; OS, p=0.03), whereas no benefit was seen in patients with low allelic ratio (RFS, p=0.38; OS, p=0.64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AML HD93, reference 29; AML HD98A, reference 30; AMLSG 07-04, ClinicalTrials.gov identifier: NCT00151242.
[Show abstract][Hide abstract] ABSTRACT: Outcome of AML patients older than 60 years has remained poor due to unfavorable disease characteristics and patient-related factors. The randomized AMLSG 06-04 protocol was designed based on in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid (ATRA) with chemotherapy. Between 2004 and 2006, 186 patients were randomized to receive 2 induction cycles with idarubicin, cytarabine and ATRA with VPA (VPA) or without (STANDARD). In all patients consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared to STANDARD (40% vs. 52%; p=0.14) due to a higher early death rate (26% vs. 14%; p=0.06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the two arms (p=0.95 and p=0.57, respectively). However, relapse-free-survival was significantly superior in VPA compared to STANDARD (24.4% vs. 6.4% at 5 years, p=0.02). Explorative subset analyses revealed that AML with mutated NPM1 may particularly benefit from VPA. This study was registered at clinicaltrials.gov, identifier: NCT00151255.
[Show abstract][Hide abstract] ABSTRACT: Lenalidomide activates the immune system, but the exact immunomodulatory mechanisms of lenalidomide in vivo are poorly defined. In an observational study we assessed the impact of lenalidomide on different populations of immune cells in multiple myeloma patients. Lenalidomide therapy was associated with increased amounts of a CD8+ T cell subset, phenotypically staged between classical central memory T cells (TCM) and effector memory T cells (TEM), consequently termed TCM/TEM. The moderate expression of perforin/granzyme and phenotypic profile of these cells identifies them as not yet terminally differentiated, which makes them promising candidates for the anti-tumor response. In addition, lenalidomide-treated patients showed higher abundance of CD14+ myeloid cells co-expressing CD15. This population was able to inhibit both CD4+ and CD8+ T cell proliferation in vitro and could thus be defined as a yet undescribed novel myeloid-derived suppressor cell (MDSC) subtype. We observed a striking correlation between levels of TCM/TEM, mature Tregs and CD14+CD15+ MDSCs. In summary, lenalidomide induces both activating and inhibitory components of the immune system, indicating the existence of potential counter-regulatory mechanisms. These findings provide new insights into the immunomodulatory action of lenalidomide.
[Show abstract][Hide abstract] ABSTRACT: Recent work has identified dysfunctional Hippo signaling to be involved in maintenance and progression of various human cancers, although data on clear cell renal cell carcinoma (ccRCC) have been limited. Here, we provide evidence implicating aberrant Hippo signaling in ccRCC proliferation, invasiveness, and metastatic potential. Nuclear overexpression of the Hippo target Yes-associated protein (YAP) was found in a subset of patients with ccRCC. Immunostaining was particularly prominent at the tumor margins and highlighted neoplastic cells invading the tumor-adjacent stroma. Short hairpin RNA-mediated knockdown of YAP significantly inhibited proliferation, migration, and anchorage-independent growth of ccRCC cells in soft agar and led to significantly reduced murine xenograft growth. Microarray analysis of YAP knockdown versus mock-transduced ccRCC cells revealed down-regulation of endothelin 1, endothelin 2, cysteine-rich, angiogenic inducer, 61 (CYR61), and c-Myc in ccRCC cells as well as up-regulation of the cell adhesion molecule cadherin 6. Signaling pathway impact analysis revealed activation of the p53 signaling and cell cycle pathways as well as inhibition of mitogen-activated protein kinase signaling on YAP down-regulation. Our data suggest CYR61 and c-Myc as well as signaling through the endothelin axis as bona fide downstream effectors of YAP and establish aberrant Hippo signaling as a potential therapeutic target in ccRCC.
[Show abstract][Hide abstract] ABSTRACT: Die Behandlung mit monoklonalen Antikörpern stellt eine zentrale Säule in der modernen Krebstherapie dar. In Deutschland sind derzeit 11 unkonjugierte Antikörper (Catumaxomab, Rituximab, Cetuximab, Bevacizumab, Eculizumab, Alemtuzumab, Trastuzumab, Pertuzumab, Ofatumumab, Panitumumab und Ipilimumab) sowie 2 konjugierte monoklonale Antikörper (90Yttrium-Ibritumomab-Tiuxetan und Brentuximab Vedotin) zur antitumoralen Immuntherapie zugelassen. Eine bemerkenswerte Entwicklung in der spezifischen Antitumorimmuntherapie stellen immunmodulatorische (Checkpoint-)Antikörper dar, wie z. B. Anti-CTLA-4- und Anti-PD-1- bzw. Anti-PD-L1-Antikörper, die vielversprechende klinische Erfolge verzeichnen.
In current treatment strategies for patients with hematological malignancies and solid tumors, monoclonal antibody therapy has evolved into one of the most successful and most important therapeutic concepts. To date 11 unconjugated monoclonal antibodies (catumaxomab, rituximab, cetuximab, bevacizumab, eculizumab, alemtuzumab, trastuzumab, pertuzumab, ofatumumab, panitumumab and ipilimumab) and 2 conjugated monoclonal antibodies (90Yttrium-ibritumomab tiuxetan and brentuximab vedontin) are currently approved for anti-tumor immunotherapy in Germany. The remarkable development of immunomodulatory (checkpoint) antibodies, such as anti-CTLA-4, anti-PD1 and anti-PD-LA has recently achieved very promising clinical success.
[Show abstract][Hide abstract] ABSTRACT: Harnessing the host immune system to eradicate cancer has a high therapeutic potential. One paradigm of anticancer immunotherapy is represented by allogeneic stem cell transplantation. In this setting, the host must be conditioned prior to transplantation, allowing for engraftment and subsequent graft-vs.-tumor reactivity. Conditioning may also be a prerequisite for the efficacy of other immunotherapeutic regimens. In particular, tumor debulking followed by conditioning (aimed at blocking endogenous inhibitory stimuli, for instance upon the depletion of regulatory T cells or the inhibition of immune checkpoints) and subsequent immunization (for instance by means of patient-tailored vaccines) based on innovative adjuvants (such as RIG-I ligands) may allow for the elicitation of superior antitumor immune responses. Repetitive boosting might then maintain immunosurveillance. An intense wave of investigation on the optimal timing of immunostimulatory interventions with respect to the administration of immunogenic chemotherapeutics and on the use of small drugs that promote efficient antitumor immune responses will end up in the generation of highly effective immunotherapeutic anticancer regimens.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to evaluate the diagnostic benefit of an intravoxel incoherent motion (IVIM) model-based characterization of pancreatic masses from diffusion-weighted imaging (DWI) with 3 b values.
This retrospective study had an approval from the institutional review board, and informed patient consent was waived. The 1.5-T DWI data of 42 patients with or without pancreatic disease, acquired by a respiratory-gated spin-echo echo-planar imaging sequence with 3 b values (0, 50, 800 s/mm), were retrospectively analyzed. The IVIM-related parameters D', which is the apparent diffusion coefficient [ADC(50,800)], and f', as well as ADC(0,50), and conventional ADC(0,800) were calculated voxelwise. Regions of interest were analyzed in pancreatic adenocarcinomas (CAs, n = 12), neuroendocrine pancreatic tumors (NETs, n = 9), and chronic pancreatitis (CPs, n = 11), not affected tissue of each pathologic group, and in the head, body, and tail of the healthy pancreas (n = 10).
By ADC(0,800) and D', CAs could hardly be distinguished from neuroendocrine pancreatic tumors and chronic pancreatitis. However, CAs revealed very low ADC(0,50) and f' values, which differed significantly from all other groups. In the healthy pancreas, ADC(0,800) and D' values were significantly higher for the head than for the body and tail, but no significant differences were found for ADC(0,50) and f'.
The determination of IVIM-based microcirculation-sensitive parameter maps from DWI with 3 b values significantly improved the discrimination of CAs from NETs, CPs, and the healthy tissue.
[Show abstract][Hide abstract] ABSTRACT: Tigecycline (TGC) is a first-in-class glycylcycline with an expanded spectrum of activity. Although TGC has not been prospectively studied in febrile neutropenia (FN), we observed that occasionally critically ill neutropenic patients unresponsive to other antibiotics were treated with TGC in our departments. The aim of our study was to analyse effectiveness and toxicity of TGC in FN.
Data of infectious episodes treated with TGC were retrospectively collected. Baseline data of patients, haematological malignancy, infection and adverse events were documented. Success was defined as defervescence (≥7 days) in the absence of any sign of persistent infection.
Data of 35 patients with haematological malignancies and FN were evaluated. Median duration of neutropenia was 25 days (range 6-69 days). The type of infection was pneumonia in 24 patients, four microbiologically documented infections, three clinically documented infections and four with fever of unknown origin. The TGC was administered after a median of two (range 1-5) prior antibiotic regimens. Treatment was successful in 15 (43 %) patients. In patients with prolonged neutropenia (≥28 days), response was significantly lower (13 vs. 79 %; p = 0.001). Eight (23 %) patients died during the fever episode. Grade 3-4 toxicity occurred in five (14 %) patients.
Our results showed promising response rates to TGC and very low toxicity rates compared to the generally low response rate of third-line antibiotic therapies, indicating that TGC may be a successful alternative for salvage treatment of febrile neutropenia, but further study is needed.
[Show abstract][Hide abstract] ABSTRACT: Tyrosine kinase inhibitors induce sustained disease remissions in chronic myeloid leukemia by exploiting the addiction of this type of leukemia to the activity of the fusion oncogene BCR-ABL. However, these agents fail to eradicate CML stem cells which are ultimately responsible for disease relapses upon treatment discontinuation. Evidence that the immune system can effectively reject CML stem cells potentially leading to patient cure is provided by the experience with patients receiving allogeneic bone marrow transplantations. Compelling evidence indicates that more modern, antigen-specific immunotherapeutic approaches are also feasible and hold strong potential to be clinically effective. Amongst these, particularly promising is the use of autologous dendritic cells pulsed with antigens or direct application of in vitro transcribed RNA encoding for leukemia-associated antigens, since this approach allows to circumvent HLA-restriction of the leukemia-associated T cell epitopes that have been eventually identified. Combining these strategies with monoclonal antibodies, such as anti-CTLA-4 or anti-PD-1, may help to obtain even stronger immune responses and better clinical results. This narrative review addresses this topic by focusing in particular on the cell-based immunotherapeutic strategies for CML and on the issue of the leukemia-associated antigens to be selected for targeting.
Current cancer drug targets 07/2013; 13(7). DOI:10.2174/15680096113139990086 · 3.52 Impact Factor