Elke Pogge von Strandmann

University of Cologne, Köln, North Rhine-Westphalia, Germany

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Publications (43)277.23 Total impact

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    ABSTRACT: AFM13 is a bispecific, tetravalent chimeric antibody construct (TandA(®)) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this phase I dose escalation study 28 patients with heavily pre-treated relapsed or refractory Hodgkin lymphoma received AFM13 at doses of 0.01 to 7mg/kg body weight. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics (PK), anti-tumor activity and pharmacodynamics (PD). Adverse events were generally mild to moderate. The maximum tolerated dose was not reached. PK assessment revealed a half-life of up to 19 hours. Three of 26 evaluable patients achieved partial remission (11.5%) and 13 patients achieved stable disease (50%) with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin refractory patients. In 13 patients who received doses of ≥1.5mg/kg AFM13 the overall response rate was 23% and the disease control rate was 77%. AFM13 treatment resulted in a significant NK-cell activation and decrease of soluble CD30 in peripheral blood. In conclusion, AFM13 represents a well-tolerated, safe and active targeted immunotherapy of Hodgkin lymphoma. A phase II study is currently planned to optimize the dosing schedule in order to further improve the therapeutic efficacy. The phase I study is registered to www.clinicaltrials.gov as NCT01221571. Copyright © 2015 American Society of Hematology.
    Blood 04/2015; DOI:10.1182/blood-2014-12-614636 · 9.78 Impact Factor
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) is the most prominent B cell malignancy among adults in the Western world and characterized by a clonal expansion of B cells. The patients suffer from severe immune defects resulting in increased susceptibility to infections and failure to generate an antitumor immune response. Defects in both, DNA damage response (DDR) pathway and crosstalk with the tissue microenvironment have been reported to play a crucial role for the survival of CLL cells, therapy resistance and impaired immune response. To this end, major advances over the past years have highlighted several T cell immune evasion mechanisms in CLL. Here, we discuss the consequences of an impaired DDR pathway for detection and elimination of CLL cells by natural killer (NK) cells. NK cells are considered to be a major component of the immunosurveillance in leukemia but NK cell activity is impaired in CLL. Restoration of NK cell activity using immunoligands and immunoconstructs in combination with the conventional chemotherapy may provide a future perspective for CLL treatment.
    Frontiers in Genetics 02/2015; 6. DOI:10.3389/fgene.2015.00011
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    ABSTRACT: Genome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) influencing the risk of Hodgkin's lymphoma (HL) and demonstrated the association of common genetic variation for this type of cancer. Such evidence for inherited genetic risk is also provided by the family history and the very high concordance between monozygotic twins. However, little is known about the genetic and environmental contributions. A common measure for describing the phenotypic variation due to genetics is the heritability. Using GWAS data on 906 HL cases by considering all typed SNPs simultaneously, we have calculated that the common variance explained by SNPs accounts for >35% of the total variation on the liability scale in HL (95% confidence interval 6-62%). These findings are consistent with similar heritability estimates of ∼0.40 (95% confidence interval 0.17-0.58) based on Swedish population data. Our estimates support the underlying polygenic basis for susceptibility to HL, and show that heritability based on the population data is somehow larger than heritability based on the genomic data because of the possibility of some missing heritability in the GWAS data. Besides that there is still major evidence for multiple loci causing HL on chromosomes other than chromosome 6 that need to be detected. Because of limited findings in prior GWASs, it seems worth checking for more loci causing susceptibility to HL.European Journal of Human Genetics advance online publication, 17 September 2014; doi:10.1038/ejhg.2014.184.
    European journal of human genetics: EJHG 09/2014; DOI:10.1038/ejhg.2014.184 · 4.23 Impact Factor
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    ABSTRACT: NKG2D, an activating receptor expressed on NK cells and T cells, is critically involved in tumor immunosurveillance. In this study, we explored the potential therapeutic utility of the NKG2D ligand ULBP2 for the treatment of colon carcinoma. To this end we designed a fusion protein consisting of human ULBP2 and an antibody-derived single chain targeting the tumor carcinoembryonic antigen (CEA). The bispecific recombinant fusion protein re-directed NK cells towards malignant cells by binding to both, tumor cells and NK cells, and triggered NK cell-mediated target cell killing in vitro. Moreover, tumor growth was significantly delayed in a syngeneic colon carcinoma mouse model in response to immunoligand treatment. The anti-tumor activity could be attributed to the stimulation of immune cells with an elevated expression of the activation marker CD69 on NK, T and NKT cells and the infiltration of CD45+ immune cells into the solid tumor. In summary, it was demonstrated that immunoligands provide specific tumor targeting by NK cells and exert anti-tumor activity in vitro and in vivo. This technology represents a novel immunotherapeutic strategy for solid tumors with the potential to be further developed for clinical applications. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 06/2014; 134(12). DOI:10.1002/ijc.28609 · 5.01 Impact Factor
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    ABSTRACT: Natural killer (NK) cells are potent immune effector cells capable of mediating antitumor responses. Thus, during immunoediting tumor cell populations evolve strategies to escape NK cell-mediated recognition. In this study, we report a novel mechanism of immune escape involving tumor cell shedding of B7-H6, a ligand for the activating receptor NKp30 that mediates NK cell binding and NK cell-mediated killing, Tumor cells from different cancer entities released B7-H6 by ectodomain shedding mediated by the cell surface proteases ADAM-10 and ADAM-17, as demonstrated through the use of pharmacological inhibitors or siRNA-mediated gene attenuation. Inhibiting this proteolytic shedding process increased the levels of B7-H6 expressed on the surface of tumor cells, enhancing NKp30-mediated activation of NK cells. Notably, we documented elevated levels of soluble B7-H6 levels in blood sera obtained from a subset of malignant melanoma patients, compared to healthy control individuals, along with evidence of elevated B7-H6 expression in melanoma specimens in situ. Taken together, our results illustrated a novel mechanism of immune escape in which tumor cells impede NK-mediated recognition by metalloprotease-mediated shedding of B7-H6. One implication of our findings is that therapeutic inhibition of specific metalloproteases may help support NK cell-based cancer therapy.
    Cancer Research 04/2014; 74(13). DOI:10.1158/0008-5472.CAN-13-3017 · 9.28 Impact Factor
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    Katrin S Reiners, Juliane Dassler, Christoph Coch, Elke Pogge von Strandmann
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    ABSTRACT: Exosomes are endosomal-derived nanovesicles released by normal and tumor cells, which transfer functionally active proteins, lipids, and nucleic acids between cells. They are important mediators of intercellular communication and act on the adjacent stroma as well as in the periphery. Recently, exosomes have been recognized to play a pathophysiological role in various diseases such as cancer or infectious diseases. Tumor cell-derived exosomes (Tex) have been shown to act as tumor promotors by educating non-malignant cells to provide a tumor supporting microenvironment, which helps to circumvent immune detection by the host and supports metastasis. However, Tex with anti-tumor, immune-activating properties were also described reflecting the complexity of exosomes. Here, we assess the role of extracellular microvesicles/exosomes as messengers affecting NK cell function in health and disease and discuss the molecular basis for the differential impact of exosomes on NK cell activity. The molecular composition/load of exosomes and the mechanisms regulating their release remain unclear and need to be further analyzed to facilitate the development of new treatment options targeting the exosomal machinery.
    Frontiers in Immunology 03/2014; 5:91. DOI:10.3389/fimmu.2014.00091
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    ABSTRACT: Classical Hodgkin's lymphoma (cHL)-affected lymphoid tissue contains only a few malignant Hodgkin and Reed-Sternberg (HRS) cells, which are disseminated within a massive infiltrate of reactive cells. In particular, the innate immune infiltrate is deemed to support tumour growth by direct cell-cell interaction. Since they are rarely found in close proximity to the malignant cells in situ, we investigated whether cHL-derived extracellular vesicles might substitute for a direct cell-cell contact. We studied the crosstalk of the transmembrane proteins CD30 and CD30 ligand (CD30L) because they are selectively expressed on HRS and innate immune cells, respectively. Here, we showed that HRS cells released both the ectodomain as a soluble molecule (sCD30) and the entire receptor on the surface of extracellular vesicles. The vesicle diameter was 40-800 nm, as determined by cryo- and immune electron microscopy. In addition to CD30, typical extracellular vesicle markers were detected by mass spectrometry and flow cytometry, including tetraspanins, flotillins, heat shock proteins and adhesion molecules. In contrast to sCD30, vesicles caused a CD30-dependent release of interleukin-8 in CD30L(+) eosinophil-like EoL-1 cells and primary granulocytes from healthy donors, underscoring the functionality of CD30 on vesicles. In extracellular matrix (ECM)-embedded culture of HRS cells, a network of actin and tubulin-based protrusions guided CD30(+) vesicles into the micro-environment. This network targeted CD30(+) vesicles towards distant immune cells and caused a robust polarization of CD30L. Confocal laser scanning microscopy of 30 µm sections showed a CD30 vesicle-containing network also in cHL-affected lymphoid tissue of both mixed-cellularity and nodular sclerosing subtypes. This network might facilitate the communication between distant cell types in cHL tissue and allow a functional CD30-CD30L interaction in trans. The tubulin backbone of the network may provide a target for the therapy of cHL with antitubulin-based CD30 antibody constructs. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    The Journal of Pathology 03/2014; 232(4):405-14. DOI:10.1002/path.4306 · 7.33 Impact Factor
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    ABSTRACT: Epigenetic changes have been implicated in the malignant phenotype of Hodgkin Reed Sternberg (HRS) cells in Hodgkin lymphoma (HL), where HRS survival and proliferation depends on the microenvironment. The histone-deacetylase (HDAC) inhibitor LBH589 (panobinostat) showed clinical efficacy but its impact on the HRS microenvironment is unclear. Hence, we analysed the effects of LBH589 on lymphocytes and also potential combination therapies. In lymphocyte-target cell killing assays, LBH589-treatment triggered an enhanced lymphocyte-dependent lysis of HL cells despite of mild lymphocytopenic effects. In co-culture experiments of lymphocytes with HL cells, LBH589 suppressed the IFNgamma-release but increased the TNFalpha secretion. Recombinant TNFalpha boosted the lymphocyte-dependent lysis of HL target cells. In HL cell lines, LBH589 induced cell death, autophagy, and an increase of MICA/B that are ligands to natural killer cell receptors. The combination of LBH589 with Brentuximab Vedotin was inefficient due to down-regulation of CD30 as a target. Combination with gemcitabine revealed highly significant effects, suggesting a potential combination for future therapy. Based on these data we suggest that LBH589 favourably modulates the cytokine network and lymphocyte activity in the HL microenvironment.
    PLoS ONE 11/2013; 8(11):e79502. DOI:10.1371/journal.pone.0079502 · 3.53 Impact Factor
  • Maulik Vyas, Ulrike Koehl, Michael Hallek, Elke Pogge von Strandmann
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    ABSTRACT: The insight that the immune system is able to eradicate tumor cells inspired the development of targeted immunotherapies. These novel approaches aim to trigger immune molecules and receptors, including CD3 on T cells and NKG2D and NKp30 on natural killer (NK) cells, to harness the immune system against cancer. In cancer patients, overcoming immune suppression induced by malignant cells or by the tumor microenvironment remains the major challenge to the clinical efficacy of immunotherapies. Recombinant constructs have been developed in various formats either utilizing natural ligands (immunoligands) or antibody-derived components (immunoconstructs) to circumvent mechanisms that counteract an effective antitumor immune response.
    Trends in Molecular Medicine 11/2013; 20(2). DOI:10.1016/j.molmed.2013.10.006 · 10.11 Impact Factor
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    ABSTRACT: In addition to HLA, recent genome-wide association studies (GWASs) of Hodgkin's lymphoma (HL) have identified susceptibility loci for HL at 2p16.1, 8q24.21 and 10p14. In this study, we perform a GWAS meta-analysis with published GWAS (totalling 1,465 cases and 6,417 controls of European background), and follow-up the most significant association signals in 2,024 cases and 1,853 controls. A combined analysis identifies new HL susceptibility loci mapping to 3p24.1 (rs3806624; P=1.14 × 10(-12), odds ratio (OR)=1.26) and 6q23.3 (rs7745098; P=3.42 × 10(-9), OR=1.21). rs3806624 localizes 5' to the EOMES (eomesodermin) gene within a p53 response element affecting p53 binding. rs7745098 maps intergenic to HBS1L and MYB, a region previously associated with haematopoiesis. These findings provide further insight into the genetic and biological basis of inherited susceptibility to HL.
    Nature Communications 10/2013; 4:2549. DOI:10.1038/ncomms3549 · 10.74 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):4572-4572. DOI:10.1158/1538-7445.AM2013-4572 · 9.28 Impact Factor
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    ABSTRACT: Abstract Evasion of apoptosis is a hallmark of cancer cells. Inhibitor of apoptosis proteins (IAPs) act as endogenous inhibitors of programmed cell death and are overexpressed in several tumors including Hodgkin lymphoma (HL). Preclinical studies indicate antitumor activity of IAP antagonists and clinical studies in hematological malignancies are underway. Here, we investigate the impact of the small molecule IAP antagonist LCL161 on HL cell lines. Although the antagonist caused rapid degradation of cIAP1 leading to TNFα secretion, LCL161 did not promote apoptosis significantly. However, LCL161 induced expression of MICA and MICB, ligands for the activating immune receptor NKG2D, and enhanced the susceptibility of HL cells to NKG2D-dependent lysis by NK cells. MICA/B upregulation was dependent on activation of the DNA damage response upon LCL161 treatment. Taken together, we demonstrate a novel link between IAP inhibition, DNA damage and immune recognition.
    Biological Chemistry 06/2013; 394(10). DOI:10.1515/hsz-2013-0161 · 2.69 Impact Factor
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    ABSTRACT: Natural killer (NK) cells are able to lyse infected and tumor cells while sparing healthy cells. Recognition of diseased cells by NK cells is governed by several activating and inhibitory receptors. We review numerous pathways that have been implicated in the regulation of self-ligands for activating receptors, including NKG2D, DNAM-1, LFA-1, NKp30, NKp44, NKp46, NKp65, and NKp80 found on NK cells and some T cells. Understanding how the regulation of self-encoded ligand expression is regulated may provide novel avenues for future therapeutic approaches to infections and cancer.
    Annals of Medicine 05/2013; DOI:10.3109/07853890.2013.792495 · 4.73 Impact Factor
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    ABSTRACT: Natural killer (NK) cells are a major component of the anti-tumor immune response. NK cell dysfunctions have been reported in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here we investigated the role of tumor cell-released soluble and exosomal ligands for NK cell receptors that modulate NK cell activity. Soluble CLL plasma factors suppressed NK cell cytotoxicity and down-regulated the surface receptors CD16 and CD56 on NK cells of healthy donors. The inhibition of NK cell cytotoxicity was attributed to the soluble ligand BAG6/BAT3 that engages the activating receptor NKp30 expressed on NK cells. Soluble BAG6 was detectable in the plasma of CLL patients, with the highest levels at the advanced disease stages. In contrast, NK cells were activated when BAG6 was presented on the surface of exosomes. The latter form was induced in non-CLL cells by cellular stress via an nSmase2-dependent pathway. Such cells were eliminated by lymphocytes in a xenograft tumor model in vivo. Here, exosomal BAG6 was essential for tumor cell killing because BAG6-deficient cells evaded immune detection. Taken together, the findings show that the dysregulated balance of exosomal vs soluble BAG6 expression may cause immune evasion of CLL cells.
    Blood 03/2013; 121(18). DOI:10.1182/blood-2013-01-476606 · 9.78 Impact Factor
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    ABSTRACT: Natural killer (NK) cells represent a key component of the innate immune system against cancer. Nevertheless, malignant diseases arise in immunocompetent individuals despite tumor immunosurveillance. Hodgkin lymphoma (HL) is characterized by CD30+ tumor cells and a massive infiltration of immune effector cells in affected lymph nodes. The latter obviously fail to eliminate the malignant cell population. Here, we tested for functional NK cell defects in HL and suggest an improvement of NK function by therapeutic means. We demonstrate that peripheral NK cells (pNK) from patients with HL fail to eliminate HL cell lines in ex vivo killing assays. Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors NKp30 (BAG6/BAT3) and NKG2D (MICA), factors known to constrict NK cell function. In vitro, NK cell cytotoxicity could be restored by an NKG2D/NKp30-independent bispecific antibody construct (CD30xCD16A). It artificially links the tumor receptor CD30 with the cytotoxicity NK cell receptor CD16A. Moreover, we observed that NK cells from patients treated with this construct were generally activated and displayed a restored cytotoxicity against HL target cells. These data suggest that reversible suppression of NK cell activity contributes to immune evasion in HL and can be antagonized therapeutically.Molecular Therapy (2013); doi:10.1038/mt.2013.14.
    Molecular Therapy 03/2013; 21(4). DOI:10.1038/mt.2013.14 · 6.43 Impact Factor
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    ABSTRACT: Natural killer (NK) cells are a major component of the antitumor immune response. NK cell dysfunctions have been reported in various hematological malignancies, including chronic lymphocytic leukemia (CLL). Here we investigated the role of tumor cell-released soluble and exosomal ligands for NK cell receptors that modulate NK cell activity. Soluble CLL plasma factors suppressed NK cell cytotoxicity and down-regulated the surface receptors CD16 and CD56 on NK cells of healthy donors. The inhibition of NK cell cytotoxicity was attributed to the soluble NKp30 ligand BAG6/BAT3, detectable in the plasma of CLL patients, with the highest levels at advanced disease stages. In contrast, NK cells were activated by BAG6 expressed on exosomes. Exosomal BAG6 expression was induced by cellular stress via an nSMase2-dependent pathway. Finally, cells releasing exosomal BAG6 were eliminated by lymphocytes in a xenograft tumor model in vivo; in marked contrast BAG6-deficient cells that failed to produce exosomal BAG6 evaded immune detection. Taken together, the findings show that the dysregulated balance of exosomal versus soluble BAG6 expression may causes immune evasion of CLL cells.
    Blood 02/2013; · 9.78 Impact Factor
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    ABSTRACT: Galectin-1 (Gal1) is a member of a highly conserved family of carbohydrate-binding proteins that modulates innate and adaptive immune responses and fosters tumor-immune escape. Hodgkin lymphoma (HL) Reed-Sternberg (RS) cells overexpress and secrete Gal1, which selectively kills Th1, Th17 and cytotoxic T cells and promotes the immunosuppressive Th2/Treg-predominant HL microenvironment. We developed a sandwich ELISA and assessed serum Gal1 levels in 293 newly diagnosed, previously untreated classical HL (cHL) patients enrolled on 3 risk-adapted clinical trials. Serum Gal1 levels were significantly higher in cHL patients than in normal controls (p < .0001). Gal1 serum levels also increased with Ann Arbor stage (p = .012), areas of nodal involvement (p < .0001) and the International Prognostic Score (IPS) (2-7, p = .019). We conclude that Gal1 serum levels are significantly associated with tumor burden and associated clinical features in newly diagnosed cHL patients.
    Blood 02/2013; 121(17). DOI:10.1182/blood-2012-12-474569 · 9.78 Impact Factor
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    ABSTRACT: Hodgkin lymphoma (HL) has become one of the best curable cancers. However, better biomarkers are needed for outcome prediction that would allow protecting patients from over- or under-dosing of treatment. Thymus and activation-regulated chemokine/CCL17 (TARC) is highly and specifically elevated in this disease and has been proposed as possible biomarker in HL patients. In this study, we show that pretreatment TARC levels were associated with established clinical risk factors and predictive for response to treatment in a large cohort of HL patients treated in clinical trials by the German Hodgkin Study Group. Moreover, TARC levels also significantly contributed to a novel multivariate model predicting treatment response. These data clearly suggest an important role for this chemokine as biomarker in HL. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.
    American Journal of Hematology 11/2012; 88(2). DOI:10.1002/ajh.23361 · 3.48 Impact Factor

Publication Stats

699 Citations
277.23 Total Impact Points

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Institutions

  • 2004–2015
    • University of Cologne
      • Department of Internal Medicine
      Köln, North Rhine-Westphalia, Germany
  • 2007
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia