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https://www.readbyqxmd.com/read/27908880/an-anti-cd3-anti-cll-1-bispecific-antibody-for-the-treatment-of-acute-myeloid-leukemia
#1
Steven R Leong, Siddharth Sukumaran, Maria Hristopoulos, Klara Totpal, Shannon Stainton, Elizabeth Lu, Alfred Wong, Lucinda Tam, Robert Newman, Brian R Vuillemenot, Diego Ellerman, Chen Gu, Mary Mathieu, Mark S Dennis, Allen Nguyen, Bing Zheng, Crystal Zhang, Genee Lee, Yu-Waye Chu, Rodney A Prell, Kedan Lin, Steven T Laing, Andrew G Polson
Acute myeloid leukemia (AML) is major unmet medical need. Most patients have poor long-term survival and treatment has not significantly changed in 40 years. Recently, bispecific antibodies that redirect the cytotoxic activity of effector T-cells by binding to CD3, the signaling component of the T-cell receptor, and a tumor target have shown clinical activity. Notably, blinatumomab is approved to treat relapsed/refractory acute lymphoid leukemia. Here we describe the design, discovery, pharmacological activity, pharmacokinetics, and safety of a CD3 T-cell-dependent bispecific (TDB) full-length human IgG1 therapeutic antibody targeting CLL-1 that could potentially be used in humans to treat AML...
December 1, 2016: Blood
https://www.readbyqxmd.com/read/27904140/restrictions-in-the-t-cell-repertoire-of-chronic-lymphocytic-leukemia-high-throughput-immunoprofiling-supports-selection-by-shared-antigenic-elements
#2
A Vardi, E Vlachonikola, M Karypidou, E Stalika, V Bikos, K Gemenetzi, C Maramis, A Siorenta, A Anagnostopoulos, S Pospisilova, N Maglaveras, I Chouvarda, K Stamatopoulos, A Hadzidimitriou
Immunoglobulin (IG) gene repertoire restrictions strongly support antigen selection in the pathogenesis of chronic lymphocytic leukemia (CLL). Given the emerging multifarious interactions between CLL and bystander T cells, we sought to determine whether antigen(s) are also selecting T cells in CLL. We performed a large-scale, next-generation sequencing (NGS) study of the T-cell repertoire, focusing on major stereotyped subsets representing CLL subgroups with undisputed antigenic drive, but also included patients carrying non-subset IG rearrangements to seek for T-cell immunogenetic signatures ubiquitous in CLL...
December 1, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27904138/cirmtuzumab-inhibits-wnt5a-induced-rac1-activation-in-chronic-lymphocytic-leukemia-treated-with-ibrutinib
#3
J Yu, L Chen, B Cui, C Wu, M Y Choi, Y Chen, L Zhang, L Z Rassenti, G F Widhopf, T J Kipps
Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival...
December 1, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27890932/il-10-production-by-cll-cells-is-enhanced-in-the-anergic-ighv-mutated-subset-and-associates-with-reduced-dna-methylation-of-the-il10-locus
#4
S Drennan, A D'Avola, Y Gao, C Weigel, E Chrysostomou, A J Steele, T Zenz, C Plass, P W Johnson, A P Williams, G Packham, F K Stevenson, C C Oakes, F Forconi
Chronic lymphocytic leukemias (CLL) with unmutated (U-CLL) or mutated (M-CLL) IGHV have variable features of immunosuppression, possibly influenced by those CLL cells activated to produce IL-10. The two subsets differ in their levels of anergy, defined by low surface IgM levels/signaling capacity, and in their DNA methylation profile, particularly variable in M-CLL. We have now found that levels of IL-10 produced by activated CLL cells were highly variable. Levels were higher in M-CLL than in U-CLL and correlated with anergy...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27890931/a-tlr7-agonist-enhances-the-anti-tumor-efficacy-of-obinutuzumab-in-murine-lymphoma-models-via-nk-cells-and-cd4-t-cells
#5
E J Cheadle, G Lipowska-Bhalla, S J Dovedi, E Fagnano, C Klein, J Honeychurch, T M Illidge
Anti-CD20 mAb such as rituximab have proven highly effective at improving outcome in B-cell malignancies. However, many patients ultimately relapse and become refractory to treatment. The glycoengineered anti-CD20 mAb obinutuzumab was developed to induce enhanced antibody dependent cellular cytotoxicity, antibody dependent phagocytosis and direct cell death and was shown to lead to improved outcomes in a randomized study in B-chronic lymphocytic leukemia (B-CLL). We hypothesized that immune stimulation through TLR7 agonism in combination with obinutuzumab would further enhance lymphoma clearance and the generation of long-term anti-tumor immune responses...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27888629/inhibition-of-bcr-signaling-using-the-syk-inhibitor-tak-659-prevents-stroma-mediated-signaling-in-chronic-lymphocytic-leukemia-cells
#6
Noelia Purroy, Júlia Carabia, Pau Abrisqueta, Leire Egia, Meritxell Aguiló, Cecilia Carpio, Carles Palacio, Marta Crespo, Francesc Bosch
Proliferation and survival of chronic lymphocytic leukemia (CLL) cells depend on microenvironmental signals coming from lymphoid organs. One of the key players involved in the crosstalk between CLL cells and the microenvironment is the B-cell receptor (BCR). Syk protein, a tyrosine kinase essential for BCR signaling, is therefore a rational candidate for targeted therapy in CLL. Against this background, we tested the efficacy of the highly specific Syk inhibitor TAK-659 in suppressing the favorable signaling derived from the microenvironment...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27875673/recent-advances-in-engineered-t-cell-therapies-targeting-b-cell-malignancies
#7
Nathan Singh
Immunotherapy using engineered autologous T cells has been attempted for decades, but clinical trials have only recently demonstrated efficacy. The combination of enhanced manufacturing techniques, highly efficient engineering, appropriate target selection and synthetic receptors with potent T cell activating domains has led to the development of highly-active cellular therapy products. B-cell malignancies have served as the paradigmatic diseases to initially evaluate and subsequently hone engineered T cells targeting cancer...
October 2016: Discovery Medicine
https://www.readbyqxmd.com/read/27861596/pd-l1-status-in-refractory-lymphomas
#8
Semir Vranic, Nilanjan Ghosh, Jeffery Kimbrough, Nurija Bilalovic, Ryan Bender, David Arguello, Yvonne Veloso, Aida Dizdarevic, Zoran Gatalica
Targeted immunotherapy based on PD-1/PD-L1 suppression has revolutionized the treatment of various solid tumors. A remarkable improvement has also been observed in the treatment of patients with refractory/relapsing classical Hodgkin lymphoma (cHL). We investigated PD-L1 status in a variety of treatment resistant lymphomas. Tumor samples from 78 patients with therapy resistant lymphomas were immunohistochemically (IHC) investigated for the expression of PD-L1 using two antibody clones (SP142 and SP263, Ventana)...
2016: PloS One
https://www.readbyqxmd.com/read/27855324/green-tea-polyphenol-epigallocatechin-3-gallate-differentially-induces-apoptosis-in-cll-b-and-t-cells-but-not-in-healthy-b-and-t-cells-in-a-dose-dependant-manner
#9
Scott Cornwall, Gavin Cull, David Joske, Reza Ghassemifar
B-cell chronic lymphocytic leukaemia (CLL) is characterized by an accumulation of CD5-positive monoclonal B-cells due in large part to a failure of apoptosis. The ability to study CLL B-cells in vitro has always been a challenge and hampered by the low viability of the CLL B-cells in cell culture systems. In this study, we present a multicellular cell culture system to maintain CLL B-cells viable in culture for 60h in the presence of a stromal cell feeder layer in combination with a whole white blood cell preparation...
November 2, 2016: Leukemia Research
https://www.readbyqxmd.com/read/27853650/therapeutic-cd94-nkg2a-blockade-improves-natural-killer-cell-dysfunction-in-chronic-lymphocytic-leukemia
#10
Emily M McWilliams, Jennifer M Mele, Carolyn Cheney, Elizabeth A Timmerman, Faraz Fiazuddin, Ethan J Strattan, Xiaokui Mo, John C Byrd, Natarajan Muthusamy, Farrukh T Awan
Natural killer (NK)-cell count is predictive of chronic lymphoid leukemia (CLL) disease progression and their dysfunction is well documented, but the etiology of this is currently lacking. CLL cells have been shown to over-express HLA-E, the natural ligand for NKG2A expressed on NK-cells that generates a distinct negative signal relative to direct NK-cell cytotoxicity in other disease models. Utilizing a novel anti-NKG2A monoclonal blocking antibody (mAb), monalizumab, we explored the in vitro preclinical activity of targeting the NKG2A receptor, and the NKG2A/HLA-E interaction as a mechanism of tumor evasion in CLL patients...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27846451/sar-study-of-5-alkynyl-substituted-quinazolin-4-3h-ones-as-phosphoinositide-3-kinase-delta-pi3k%C3%AE-inhibitors
#11
Manman Wei, Xi Zhang, Xiang Wang, Zilan Song, Jian Ding, Ling-Hua Meng, Ao Zhang
PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7...
November 9, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27815572/phase-i-ii-study-of-lenalidomide-and-alemtuzumab-in-refractory-chronic-lymphocytic-leukemia-cll-effects-on-t-cells-and-immune-checkpoints
#12
Maria Winqvist, Fariba Mozaffari, Marzia Palma, Sandra Eketorp Sylvan, Lotta Hansson, Håkan Mellstedt, Anders Österborg, Jeanette Lundin
This phase I-II study explored safety, immunomodulatory and clinical effects of lenalidomide (weeks 1-16) and alemtuzumab (weeks 5-16) in 23 patients with refractory chronic lymphocytic leukemia. Most patients had Rai stage III/IV disease and were heavily pretreated (median 4 prior therapies), and 61% had del(17p)/del(11q). Eleven of 19 evaluable patients (58%) responded, with a median response duration of 12 months (1-29+); time to progression was short in non-responders. Lenalidomide had a narrow therapeutic dose range, 2...
November 4, 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/27802969/ibrutinib-efficacy-and-tolerability-in-patients-with-relapsed-chronic-lymphocytic-leukemia-following-allogeneic-hct
#13
Christine E Ryan, Bita Sahaf, Aaron C Logan, Susan O'Brien, John C Byrd, Peter Hillmen, Jennifer R Brown, Martin J S Dyer, Anthony R Mato, Michael J Keating, Samantha Jaglowski, Fong Clow, Andrew R Rezvani, Lori Styles, Steven E Coutre, David B Miklos
Ibrutinib, a potent and irreversible small molecule inhibitor of both Bruton's tyrosine kinase (BTK) and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplantation who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87...
November 1, 2016: Blood
https://www.readbyqxmd.com/read/27795555/targeted-deep-sequencing-reveals-clinically-relevant-subclonal-ighv-rearrangements-in-chronic-lymphocytic-leukemia
#14
B Stamatopoulos, A Timbs, D Bruce, T Smith, R Clifford, P Robbe, A Burns, D V Vavoulis, L Lopez, P Antoniou, J Mason, H Dreau, A Schuh
The immunoglobulin heavy-chain variable region gene (IgHV) mutational status is considered the gold standard of prognostication in Chronic Lymphocytic Leukemia (CLL) and is currently determined by Sanger sequencing that allows the analysis of the major clone. Using next generation sequencing (NGS), we sequenced the IgHV gene from 2 independent cohorts:(A) 270 consecutive patient samples obtained at diagnosis and (B) 227 patients from the UK ARCTIC-AdMIRe clinical trials. Using cDNA from purified CD19+CD5+ cells, we demonstrate the presence of multiple rearrangements in independent experiments and showed that 24...
October 31, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27791448/the-shrinking-role-of-chemotherapy-in-the-treatment-of-chronic-lymphocytic-leukemia
#15
Ryan W Jacobs, Farrukh T Awan, Lori A Leslie, Saad Z Usmani, Nilanjan Ghosh
The therapeutic landscape of chronic lymphocytic leukemia (CLL) has changed significantly since the first targeted therapy, rituximab, was approved for the treatment of symptomatic patients. Areas covered: Multiple monoclonal antibodies (mAbs) and small molecule inhibitors (SMIs) that target the B-cell receptor (BCR) and BCL-2 pathways are now approved treatments for CLL patients. Recent and emerging clinical data investigating the use of targeted therapies in the treatment of CLL patients will be reviewed...
December 2016: Expert Review of Hematology
https://www.readbyqxmd.com/read/27766121/transformation-of-cll-to-alcl-the-role-of-clonality-studies-in-diagnostic-molecular-haematopathology
#16
Richard Colling, Daniel Royston, Elizabeth Soilleux
Clonality studies greatly assist in the diagnosis of challenging haematopathology cases. These robust and standardised tests aid the detection of clonal lymphoid populations and may assist in lymphocyte subtyping. In this case report, a gentleman presented with a high-grade transformation of a B cell neoplasm which histologically and immunophenotypically mimicked a T cell anaplastic large-cell lymphoma. With the aid of T cell and B cell receptor clonality studies, it was demonstrated that this tumour was in fact of B cell lineage...
September 2016: Journal of Hematopathology
https://www.readbyqxmd.com/read/27757305/mono-and-dual-targeting-triplebodies-activate-natural-killer-cells-and-have-anti-tumor-activity-in-vitro-and-in-vivo-against-chronic-lymphocytic-leukemia
#17
Maulik Vyas, Ann-Charlott Schneider, Olga Shatnyeva, Katrin S Reiners, Samir Tawadros, Stephan Kloess, Ulrike Köhl, Michael Hallek, Hinrich P Hansen, Elke Pogge von Strandmann
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia that affects B lymphocytes in adults. Natural killer (NK) cells in CLL patients are intrinsically potent but display poor in situ effector functions. NKG2D is an activating receptor found on NK and CD8(+) T cells and plays a role in immunosurveillance of CLL. In this study, we developed mono- and dual-targeting triplebodies utilizing a natural ligand for human NKG2D receptor (ULBP2) to retarget NK cells against tumor cells. Triplebodies in both formats showed better ability to induce NK-cell-dependent killing of target cells compared to bispecific counterparts...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27746042/rituximab-in-lymphoma-and-chronic-lymphocytic-leukaemia-a-practice-guideline
#18
A Prica, F Baldassarre, L K Hicks, K Imrie, T Kouroukis, M Cheung
Rituximab is the first monoclonal antibody to be approved for use by the US Food and Drug Administration in cancer. Its role in the treatment of non-Hodgkin lymphoma, including chronic lymphocytic leukaemia (CLL), has evolved significantly. We aimed to systematically review and update the literature on rituximab in lymphoma and CLL, and provide evidence-based consensus guidelines for its rational use. Validated methodology from the Cancer Care Ontario Program in Evidence-based Care was used. A comprehensive literature search was completed by a methodologist from the Hematology Disease Site Group of Cancer Care Ontario...
October 13, 2016: Clinical Oncology: a Journal of the Royal College of Radiologists
https://www.readbyqxmd.com/read/27742072/current-state-of-hematopoietic-cell-transplantation-in-cll-as-smart-therapies-emerge
#19
Mohamed A Kharfan-Dabaja, Jessica El-Asmar, Farrukh T Awan, Mehdi Hamadani, Ernesto Ayala
Novel therapies targeting various kinases downstream of the B-cell receptor have emerged along with monoclonal antibodies and BCL-2 antagonists, and are changing the therapeutic landscape of chronic lymphocytic leukemia. However, cure remains unattainable unless eligible patients are offered an allogeneic hematopoietic cell transplant. Access to allogeneic hematopoietic cell transplantation has expanded considerably with availability of reduced intensity conditioning regimens which is capable offering durable remissions even in poor-risk disease...
March 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27742064/present-and-future-of-personalized-medicine-in-cll
#20
Emili Montserrat, Tycho Bauman, Julio Delgado
Medicine has been 'personalized' (i.e. centred in persons) since its foundation. Recently, however, the term 'personalized medicine' (or, better, 'precision medicine') has been introduced to define 'a form of medicine that uses information about a person's genes, proteins, and environment to prevent, diagnose, and treat disease'. This concept has gained momentum thanks to next-generation-sequencing (NGS) techniques that allow identification of molecular characteristics unique to the patient and to the tumour...
March 2016: Best Practice & Research. Clinical Haematology
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