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Adrian Wiestner

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https://www.readbyqxmd.com/read/30498085/tlr-signaling-is-activated-in-lymph-node-resident-cll-cells-and-is-only-partially-inhibited-by-ibrutinib
#1
Eman L Dadashian, Erin M McAuley, Delong Liu, Arthur L Shaffer, Ryan M Young, Jessica R Iyer, Michael J Kruhlak, Louis M Staudt, Adrian Wiestner, Sarah E M Herman
Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells driven by B-cell receptor (BCR) signaling and activated primarily in the lymph node. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib effectively inhibits BCR-dependent proliferation and survival signals and has emerged as a breakthrough therapy for CLL. However, complete remissions are uncommon and are achieved only after years of continuous therapy. We hypothesized that other signaling pathways that sustain CLL cell survival are only partially inhibited by ibrutinib...
November 29, 2018: Cancer Research
https://www.readbyqxmd.com/read/30104242/activation-of-th1-immunity-within-the-tumor-microenvironment-is-associated-with-clinical-response-to-lenalidomide-in-chronic-lymphocytic-leukemia
#2
Georg Aue, Clare Sun, Delong Liu, Jae-Hyun Park, Stefania Pittaluga, Xin Tian, Elinor Lee, Susan Soto, Janet Valdez, Irina Maric, Maryalice Stetler-Stevenson, Constance Yuan, Yusuke Nakamura, Pawel Muranski, Adrian Wiestner
Immune stimulation contributes to lenalidomide's antitumor activity. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature, autoreactive B cells in secondary lymphoid tissues, blood, and bone marrow and progressive immune dysfunction. Previous studies in CLL indicated that lenalidomide can repair defective T cell function in vitro. Whether T cell activation is required for clinical response to lenalidomide remains unclear. In this study, we report changes in the immune microenvironment in patients with CLL treated with single-agent lenalidomide and associate the immunologic effects of lenalidomide with antitumor response...
October 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29980538/siglec-6-on-chronic-lymphocytic-leukemia-cells-is-a-target-for-post-allogeneic-hematopoietic-stem-cell-transplantation-antibodies
#3
Jing Chang, Haiyong Peng, Brian C Shaffer, Sivasubramanian Baskar, Ina C Wecken, Matthew G Cyr, Gustavo J Martinez, Jo Soden, Jim Freeth, Adrian Wiestner, Christoph Rader
Although the 5-year survival rate of chronic lymphocytic leukemia (CLL) patients has risen to >80%, the only potentially curative treatment is allogeneic hematopoietic stem cell transplantation (alloHSCT). To identify possible new monoclonal antibody (mAb) drugs and targets for CLL, we previously developed a phage display-based human mAb platform to mine the antibody repertoire of patients who responded to alloHSCT. We had selected a group of highly homologous post-alloHSCT mAbs that bound to an unknown CLL cell surface antigen...
September 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29978754/richter-transformation-to-hodgkin-lymphoma-on-bruton-s-tyrosine-kinase-inhibitor-therapy
#4
Alankrita Taneja, Jade Jones, Stefania Pittaluga, Irina Maric, Mohammed Farooqui, Inhye E Ahn, Adrian Wiestner, Clare Sun
No abstract text is available yet for this article.
July 6, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29844189/potent-and-selective-antitumor-activity-of-a-t-cell-engaging-bispecific-antibody-targeting-a-membrane-proximal-epitope-of-ror1
#5
Junpeng Qi, Xiuling Li, Haiyong Peng, Erika M Cook, Eman L Dadashian, Adrian Wiestner, HaJeung Park, Christoph Rader
T cell-engaging bispecific antibodies (biAbs) present a promising strategy for cancer immunotherapy, and numerous bispecific formats have been developed for retargeting cytolytic T cells toward tumor cells. To explore the therapeutic utility of T cell-engaging biAbs targeting the receptor tyrosine kinase ROR1, which is expressed by tumor cells of various hematologic and solid malignancies, we used a bispecific ROR1 × CD3 scFv-Fc format based on a heterodimeric and aglycosylated Fc domain designed for extended circulatory t 1/2 and diminished systemic T cell activation...
June 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29764250/immunological-changes-with-kinase-inhibitor-therapy-for-chronic-lymphocytic-leukemia
#6
Christopher Pleyer, Adrian Wiestner, Clare Sun
Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib...
May 15, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29743179/a-cd19-cd3-bispecific-antibody-for-effective-immunotherapy-of-chronic-lymphocytic-leukemia-in-the-ibrutinib-era
#7
Hannah R Robinson, Junpeng Qi, Erika M Cook, Cydney Nichols, Eman L Dadashian, Chingiz Underbayev, Sarah E M Herman, Nakhle S Saba, Keyvan Keyvanfar, Clare Sun, Inhye E Ahn, Sivasubramanian Baskar, Christoph Rader, Adrian Wiestner
The Bruton tyrosine kinase inhibitor ibrutinib induces high rates of clinical response in chronic lymphocytic leukemia (CLL). However, there remains a need for adjunct treatments to deepen response and to overcome drug resistance. Blinatumomab, a CD19/CD3 bispecific antibody (bsAb) designed in the BiTE (bispecific T-cell engager) format, is approved by the US Food and Drug Administration for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Because of its short half-life of 2...
August 2, 2018: Blood
https://www.readbyqxmd.com/read/29741135/polyreactive-antibodies-in-cll-correlate-with-the-level-of-immunoglobulins-not-the-number-of-b-lymphocytes
#8
Sreenivasulu Gunti, Sarah E M Herman, Raju V S R K Gottumukkala, Ying Xiong, Clare Sun, Gilberto N Carmona, Adrian Wiestner, Abner L Notkins
No abstract text is available yet for this article.
May 9, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29483101/depth-and-durability-of-response-to-ibrutinib-in-cll-5-year-follow-up-of-a-phase-2-study
#9
Inhye E Ahn, Mohammed Z H Farooqui, Xin Tian, Janet Valdez, Clare Sun, Susan Soto, Jennifer Lotter, Stephanie Housel, Maryalice Stetler-Stevenson, Constance M Yuan, Irina Maric, Katherine R Calvo, Pia Nierman, Thomas E Hughes, Nakhle S Saba, Gerald E Marti, Stefania Pittaluga, Sarah E M Herman, Carsten U Niemann, Lone B Pedersen, Christian H Geisler, Richard Childs, Georg Aue, Adrian Wiestner
The safety and efficacy of ibrutinib (420 mg) in chronic lymphocytic leukemia (CLL) were evaluated in a phase 2 study; 51 patients had TP53 aberration (TP53 cohort) and 35 were enrolled because of age 65 years or older (elderly cohort). Both cohorts included patients with treatment-naive (TN) and relapsed/refractory (RR) CLL. With the median follow-up of 4.8 years, 49 (57.0%) of 86 patients remain on study. Treatment was discontinued for progressive disease in 20 (23.3%) patients and for adverse events in 5 (5...
May 24, 2018: Blood
https://www.readbyqxmd.com/read/29348577/targeting-b-cell-receptor-signalling-in-cancer-preclinical-and-clinical-advances
#10
REVIEW
Jan A Burger, Adrian Wiestner
B cell receptor (BCR) signalling is crucial for normal B cell development and adaptive immunity. BCR signalling also supports the survival and growth of malignant B cells in patients with B cell leukaemias or lymphomas. The mechanism of BCR pathway activation in these diseases includes continuous BCR stimulation by microbial antigens or autoantigens present in the tissue microenvironment, activating mutations within the BCR complex or downstream signalling components and ligand-independent tonic BCR signalling...
March 2018: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/29301866/functional-and-clinical-relevance-of-vla-4-cd49d-cd29-in-ibrutinib-treated-chronic-lymphocytic-leukemia
#11
Erika Tissino, Dania Benedetti, Sarah E M Herman, Elisa Ten Hacken, Inhye E Ahn, Kari G Chaffee, Francesca Maria Rossi, Michele Dal Bo, Pietro Bulian, Riccardo Bomben, Elisabeth Bayer, Andrea Härzschel, Julia Christine Gutjahr, Massimiliano Postorino, Enrico Santinelli, Ayed Ayed, Francesco Zaja, Annalisa Chiarenza, Gabriele Pozzato, Alexandre Chigaev, Larry A Sklar, Jan A Burger, Alessandra Ferrajoli, Tait D Shanafelt, Adrian Wiestner, Giovanni Del Poeta, Tanja Nicole Hartmann, Valter Gattei, Antonella Zucchetto
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells...
February 5, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29259203/the-evolutionary-landscape-of-chronic-lymphocytic-leukemia-treated-with-ibrutinib-targeted-therapy
#12
RANDOMIZED CONTROLLED TRIAL
Dan A Landau, Clare Sun, Daniel Rosebrock, Sarah E M Herman, Joshua Fein, Mariela Sivina, Chingiz Underbayev, Delong Liu, Julia Hoellenriegel, Sarangan Ravichandran, Mohammed Z H Farooqui, Wandi Zhang, Carrie Cibulskis, Asaf Zviran, Donna S Neuberg, Dimitri Livitz, Ivana Bozic, Ignaty Leshchiner, Gad Getz, Jan A Burger, Adrian Wiestner, Catherine J Wu
Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo-immunotherapy to targeted agents. To define the evolutionary dynamics induced by targeted therapy in CLL, we perform serial exome and transcriptome sequencing for 61 ibrutinib-treated CLLs. Here, we report clonal shifts (change >0.1 in clonal cancer cell fraction, Q < 0.1) in 31% of patients during the first year of therapy, associated with adverse outcome. We also observe transcriptional downregulation of pathways mediating energy metabolism, cell cycle, and B cell receptor signaling...
December 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/29156668/cll-kinetics-in-the-tumor-microenvironment
#13
EDITORIAL
Clare Sun, Adrian Wiestner
No abstract text is available yet for this article.
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28993409/malt1-inhibition-is-efficacious-in-both-na%C3%A3-ve-and-ibrutinib-resistant-chronic-lymphocytic-leukemia
#14
Nakhle S Saba, Deanna H Wong, Georges Tanios, Jessica R Iyer, Patricia Lobelle-Rich, Eman L Dadashian, Delong Liu, Lorena Fontan, Erik K Flemington, Cydney M Nichols, Chingiz Underbayev, Hana Safah, Ari Melnick, Adrian Wiestner, Sarah E M Herman
The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2 , a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma...
December 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28645939/combined-btk-and-pi3k%C3%AE-inhibition-with-acalabrutinib-and-acp-319-improves-survival-and-tumor-control-in-cll-mouse-model
#15
Carsten U Niemann, Helena I Mora-Jensen, Eman L Dadashian, Fanny Krantz, Todd Covey, Shih-Shih Chen, Nicholas Chiorazzi, Raquel Izumi, Roger Ulrich, Brian J Lannutti, Adrian Wiestner, Sarah E M Herman
Purpose: Targeting the B-cell receptor (BCR) pathway with inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon, and drug resistance with single-agent therapy can occur. In vitro studies support the effectiveness of combing PI3Kδ and BTK inhibitors. Experimental Design: As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3Kδ inhibitor ACP-319 in vivo We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL...
October 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28522579/improved-classification-of-leukemic-b-cell-lymphoproliferative-disorders-using-a-transcriptional-and-genetic-classifier
#16
LETTER
Alba Navarro, Guillem Clot, Alejandra Martínez-Trillos, Magda Pinyol, Pedro Jares, Blanca González-Farré, Daniel Martínez, Nicola Trim, Verónica Fernández, Neus Villamor, Dolors Colomer, Dolors Costa, Itziar Salaverria, David Martín-Garcia, Wendy Erber, Cristina López, Sandrine Jayne, Reiner Siebert, Martin J S Dyer, Adrian Wiestner, Wyndham H Wilson, Marta Aymerich, Armando López-Guillermo, Àlex Sánchez, Elías Campo, Estella Matutes, Sílvia Beà
No abstract text is available yet for this article.
September 2017: Haematologica
https://www.readbyqxmd.com/read/28278728/soluble-cd52-is-an-indicator-of-disease-activity-in-chronic-lymphocytic-leukemia
#17
Fie J Vojdeman, Sarah E M Herman, Nikolai Kirkby, Adrian Wiestner, Mars B van T' Veer, Geir E Tjønnfjord, Maija A Itälä-Remes, Eva Kimby, Mohammed Z Farooqui, Aaron Polliack, Ka Lung Wu, Jeanette K Doorduijn, Wendimagegn G Alemayehu, Shulamiet Wittebol, Tomas Kozak, Jan Walewski, Martine C J Abrahamse-Testroote, Marinus H J van Oers, Christian H Geisler, Carsten U Niemann
CD52 is a glycoprotein expressed on normal as well as leukemic immune cells and shed as soluble CD52 (sCD52). We studied sCD52 levels in three CLL cohorts: the 'early', the 'high-risk', and the 'ibrutinib-treated'. The 'high-risk' patients had significantly higher sCD52 levels than the 'early' patients. For the 'early' patients, high sCD52 levels were associated with a significantly shorter time to first treatment. Regarding prognostic factors, no clear correlations with stage, IGHV, or beta-2-microglobulin were found; in a cox multivariate analysis of the 'early' patients, sCD52 and IGHV both had independent prognostic value...
February 7, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28212557/using-high-sensitivity-sequencing-for-the-detection-of-mutations-in-btk-and-plc%C3%AE-2-genes-in-cellular-and-cell-free-dna-and-correlation-with-progression-in-patients-treated-with-btk-inhibitors
#18
Adam Albitar, Wanlong Ma, Ivan DeDios, Jeffrey Estella, Inhye Ahn, Mohammed Farooqui, Adrian Wiestner, Maher Albitar
Patients with chronic lymphocytic leukemia (CLL) that develop resistance to Bruton tyrosine kinase (BTK) inhibitors are typically positive for mutations in BTK or phospholipase c gamma 2 (PLCγ2). We developed a high sensitivity (HS) assay utilizing wild-type blocking polymerase chain reaction achieved via bridged and locked nucleic acids. We used this high sensitivity assay in combination with Sanger sequencing and next generation sequencing (NGS) and tested cellular DNA and cell-free DNA (cfDNA) from patients with CLL treated with the BTK inhibitor, ibrutinib...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28199309/phosphatidylinositol-3-kinase-%C3%AE-blockade-increases-genomic-instability-in-b-cells
#19
Mara Compagno, Qi Wang, Chiara Pighi, Taek-Chin Cheong, Fei-Long Meng, Teresa Poggio, Leng-Siew Yeap, Elif Karaca, Rafael B Blasco, Fernanda Langellotto, Chiara Ambrogio, Claudia Voena, Adrian Wiestner, Siddha N Kasar, Jennifer R Brown, Jing Sun, Catherine J Wu, Monica Gostissa, Frederick W Alt, Roberto Chiarle
Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation...
February 23, 2017: Nature
https://www.readbyqxmd.com/read/28154084/lymphocyte-activation-gene-3-a-novel-therapeutic-target-in-chronic-lymphocytic-leukemia
#20
Mika Shapiro, Yair Herishanu, Ben-Zion Katz, Nili Dezorella, Clare Sun, Sigi Kay, Aaron Polliack, Irit Avivi, Adrian Wiestner, Chava Perry
A novel therapeutic approach in cancer, attempting to stimulate host anti-tumor immunity, involves blocking of immune checkpoints. Lymphocyte activation gene 3 (LAG3) is an immune checkpoint receptor expressed on activated/exhausted T cells. When engaged by the major histocompatibility complex (MHC) class II molecules, LAG3 negatively regulates T-cell function, thereby contributing to tumor escape. Intriguingly, a soluble LAG3 variant activates both immune and malignant MHC class II-presenting cells. In the study herein, we examined the role of LAG3 in the pathogenesis of chronic lymphocytic leukemia, an MHC class II-presenting malignancy, and show that chronic lymphocytic leukemia cells express and secrete LAG3...
May 2017: Haematologica
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