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CLL, Immunology

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https://www.readbyqxmd.com/read/28494631/learning-from-the-failures-of-drug-discovery-in-b-cell-non-hodgkin-lymphomas-and-perspectives-for-the-future-chronic-lymphocytic-leukemia-and-diffuse-large-b-cell-lymphoma-as-two-ends-of-a-spectrum-in-drug-development
#1
Boris Kubuschok, Martin Trepel
Despite substantial recent advances, there is still an unmet need for better therapies in B-cell non Hodgkin lymphomas (B-NHL), especially in relapsed or refractory disease. Many novel targeted drugs have been developed based on a better molecular understanding of B-NHL. Areas covered: This article focuses on chronic lymphocytic leukemia (CLL) as a representative for indolent lymphomas and paradigmatic for the tremendous progress in treating B-NHL on the one hand and diffuse large B-cell lymphoma (DLBCL) as a representative for aggressive lymphomas and paradigmatic for many unsolved problems in lymphoma treatment on the other hand...
May 12, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28295181/long-term-follow-up-of-patients-receiving-allogeneic-stem-cell-transplant-for-chronic-lymphocytic-leukaemia-mixed-t-cell-chimerism-is-associated-with-high-relapse-risk-and-inferior-survival
#2
Philip A Thompson, Francesco Stingo, Michael J Keating, William G Wierda, Susan M O'Brien, Zeev Estrov, Celina Ledesma, Katayoun Rezvani, Muzaffar Qazilbash, Nina Shah, Simrit Parmar, Uday Popat, Paolo Anderlini, Nieto Yago, Stefan O Ciurea, Partow Kebriaei, Richard Champlin, Elizabeth J Shpall, Chitra M Hosing
There is limited information regarding the immunological predictors of post-allogeneic stem cell transplant (alloSCT) outcome in chronic lymphocytic leukaemia (CLL), such as mixed T-cell chimerism. We analysed 143 consecutive patients with relapsed/refractory CLL, transplanted between 2000 and 2012, to determine the prognostic relevance of mixed chimerism post-alloSCT and the ability of post-transplant immunomodulation to treat relapse. Mixed T-cell chimerism occurred in 50% of patients at 3 months and 43% at 6 months post-alloSCT; upon 3- and 6-month landmark analysis, this was associated with inferior progression-free survival (PFS) [Hazard ratio (HR) 1·93, P = 0·003 and HR 2·58, P < 0·001] and survival (HR 1·66, P = 0·05 and HR 2·17, P < 0·001), independent of baseline patient characteristics, and a lower rate of grade II-IV acute graft-versus-host disease (GHVD) (16% vs...
March 14, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28096240/coevolution-of-leukemia-and-host-immune-cells-in-chronic-lymphocytic-leukemia
#3
REVIEW
Noelia Purroy, Catherine J Wu
Cumulative studies on the dissection of changes in driver genetic lesions in cancer across the course of the disease have provided powerful insights into the adaptive mechanisms of tumors in response to the selective pressures of therapy and environmental changes. In particular, the advent of next-generation-sequencing (NGS)-based technologies and its implementation for the large-scale comprehensive analyses of cancers have greatly advanced our understanding of cancer as a complex dynamic system wherein genetically distinct subclones interact and compete during tumor evolution...
April 3, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28067179/cd20-based-immunotherapy-of-b-cell-derived-hematologic-malignancies
#4
Dariush Shanehbandi, Jafar Majidi, Tohid Kazemi, Behzad Baradaran, Leili Aghebati-Maleki
CD20 is a surface antigen which is expressed at certain stages of B-cell differentiation. Targeting the CD20-positive B-cells with therapeutic monoclonal antibodies (MAbs) has been an effectual strategy in the treatment of hematologic malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Initial success with Rituximab (RTX) has encouraged the creation and development of more effective CD20 based therapeutics. However, treatment with conventional MAbs has not been adequate to overcome the problems such as refractory/relapsed disease...
January 9, 2017: Current Cancer Drug Targets
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
#5
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 (CLLs) with unmutated (U-CLL) or mutated (M-CLL) IGHV have variable features of immunosuppression, possibly influenced by those CLL cells activated to produce interleukin 10 (IL-10). The two subsets differ in their levels of anergy, defined by low surface immunoglobulin M 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...
January 3, 2017: 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-antitumor-efficacy-of-obinutuzumab-in-murine-lymphoma-models-via-nk-cells-and-cd4-t-cells
#6
E J Cheadle, G Lipowska-Bhalla, S J Dovedi, E Fagnano, C Klein, J Honeychurch, T M Illidge
Anti-CD20 monoclonal antibodies (mAb) such as rituximab have been proven to be 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-CLL. We hypothesized that immune stimulation through Toll-like receptor 7 (TLR7) agonism in combination with obinutuzumab would further enhance lymphoma clearance and the generation of long-term antitumor immune responses...
January 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27643996/simultaneous-existence-of-acute-myeloid-leukemia-and-chronic-lymphocytic-leukemia-a-case-report
#7
Eman Al Mussaed, Hani Osman, Ghaleb Elyamany
BACKGROUND: The simultaneous Occurrence of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) has been rarely reported. Most of these cases have been occurring more frequently as a secondary event in patients receiving chemotherapeutic agents for CLL. CASE PRESENTATION: We describe a case of a 77-year-old man who presented with fatigue, pallor and lower limb pain and weakness. Initial laboratory studies showed Hb 7.7 g/dl, WBC 279.6 × 10(9)/1, PLT 143× 10(9)/1...
2016: BMC Cancer
https://www.readbyqxmd.com/read/27630324/malakoplakia-of-the-urinary-bladder-in-a-patient-with-chronic-lymphocytic-leukemia-under-ibrutinib-therapy-a-case-report
#8
Sotirios Sachanas, Gerassimos A Pangalis, Petros Karouzakis, Efstathios Koulieris, Maria Moschogiannis, Christina Kalpadakis, Xanthi Yiakoumis, Dimitra Rontogianni
Malakoplakia, a rare granulomatous disease of infectious etiology, is commonly observed in immunocompromised patients. Chronic lymphocytic leukemia (CLL) is characterized by profound immune dysregulation resulting in significant infection-related morbidity and mortality, and several drugs used in CLL treatment have a severe immunosuppressive effect. Ibrutinib, has become a new standard-of-care in patients with CLL, especially for those harboring unfavorable genetic characteristics such as 17 p deletion, with however, unknown long-term immunological consequences...
2016: Anticancer Research
https://www.readbyqxmd.com/read/27531597/histopathologic-spectrum-of-hypersensitivity-reactions-associated-with-anti-cd52-therapy-alemtuzumab
#9
Stacie L Clark, Julie Y Tse, David C Fisher, Nicole R LeBeouf, George F Murphy, Thomas S Kupper, Rachael A Clark, Christine G Lian
BACKGROUND: Alemtuzumab is a humanized monoclonal antibody directed against CD52, a cell surface antigen on B and T lymphocytes, and used to treat B-cell chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Skin rash is a common adverse reaction following treatment with alemtuzumab. However, the clinicopathologic features and immunologic basis for the reaction have not been previously reported. METHODS: Our hospital's electronic pathology database was searched for cases with documentation of 'alemtuzumab' or 'anti-CD52' in the clinical history provided by either the ordering physician or the pathologist...
November 2016: Journal of Cutaneous Pathology
https://www.readbyqxmd.com/read/27499044/cd5-expression-promotes-il-10-production-through-activation-of-the-mapk-erk-pathway-and-upregulation-of-trpc1-channels-in-b-lymphocytes
#10
Soizic Garaud, Taher E Taher, Marjolaine Debant, Miguel Burgos, Sarra Melayah, Christian Berthou, Kaushal Parikh, Jacques-Olivier Pers, Damien Luque-Paz, Gilles Chiocchia, Maikel Peppelenbosch, David A Isenberg, Pierre Youinou, Olivier Mignen, Yves Renaudineau, Rizgar A Mageed
CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukemia (CLL). Important functional properties are associated with CD5 expression in B cells, including signal transducer and activator of transcription 3 activation, IL-10 production and the promotion of B-lymphocyte survival and transformation. However, the pathway(s) by which CD5 influences the biology of B cells and its dependence on B-cell receptor (BCR) co-signaling remain unknown...
August 8, 2016: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/27402426/secondary-immunodeficiency-in-lymphoproliferative-malignancies
#11
REVIEW
Vanda Friman, Ola Winqvist, Cecilie Blimark, Petra Langerbeins, Helen Chapel, Fatima Dhalla
Secondary immunodeficiencies occur as a consequence of various diseases, including hematological malignancies, and the use of pharmacological therapies, such as immunosuppressive, anti-inflammatory, and biological drugs. Infections are the main cause of morbidity and mortality in multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients. Recent advances in treatment have prolonged the duration of remission and the time between relapse phases in MM and CLL patients. However, managing multiple relapses and the use of salvage therapies can lead to cumulative immunosuppression and a higher risk of infections...
September 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27252234/phenotype-and-immune-function-of-lymph-node-and-peripheral-blood-cll-cells-are-linked-to-transendothelial-migration
#12
Marta Pasikowska, Elisabeth Walsby, Benedetta Apollonio, Kirsty Cuthill, Elizabeth Phillips, Eve Coulter, Maria Serena Longhi, Yun Ma, Deborah Yallop, Linda D Barber, Piers Patten, Chris Fegan, Alan G Ramsay, Chris Pepper, Stephen Devereux, Andrea G S Buggins
Several lines of evidence suggest that homing of tumor cells to lymphoid tissue contributes to disease progression in chronic lymphocytic leukemia (CLL). Here, we demonstrate that lymph node (LN)-derived CLL cells possess a distinct phenotype, and exhibit enhanced capacity for T-cell activation and superior immune synapse formation when compared with paired peripheral blood (PB) samples. LN-derived CLL cells manifest a proliferative, CXCR4(dim)CD5(bright) phenotype compared with those in the PB and higher expression of T-cell activation molecules including CD80, CD86, and HLA-D-related (DR)...
July 28, 2016: Blood
https://www.readbyqxmd.com/read/27154182/addition-of-rice-bran-arabinoxylan-to-curcumin-therapy-may-be-of-benefit-to-patients-with-early-stage-b-cell-lymphoid-malignancies-monoclonal-gammopathy-of-undetermined-significance-smoldering-multiple-myeloma-or-stage-0-1-chronic-lymphocytic-leukemia-a-preliminary
#13
Terry Golombick, Terrence H Diamond, Arumugam Manoharan, Rajeev Ramakrishna
Hypothesis Prior studies on patients with early B-cell lymphoid malignancies suggest that early intervention with curcumin may lead to delay in progressive disease and prolonged survival. These patients are characterized by increased susceptibility to infections. Rice bran arabinoxylan (Ribraxx) has been shown to have immunostimulatory, anti-inflammatory, and proapoptotic effects. We postulated that addition of Ribraxx to curcumin therapy may be of benefit. Study design Monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) or stage 0/1 chronic lymphocytic leukemia (CLL) patients who had been on oral curcumin therapy for a period of 6 months or more were administered both curcumin (as Curcuforte) and Ribraxx...
June 2016: Integrative Cancer Therapies
https://www.readbyqxmd.com/read/27118451/extracellular-vesicles-released-by-cd40-il-4-stimulated-cll-cells-confer-altered-functional-properties-to-cd4-t-cells
#14
Dawn T Smallwood, Benedetta Apollonio, Shaun Willimott, Larissa Lezina, Afaf Alharthi, Ashley R Ambrose, Giulia De Rossi, Alan G Ramsay, Simon D Wagner
The complex interplay between cancer cells, stromal cells, and immune cells in the tumor microenvironment (TME) regulates tumorigenesis and provides emerging targets for immunotherapies. Crosstalk between CD4(+) T cells and proliferating chronic lymphocytic leukemia (CLL) tumor B cells occurs within lymphoid tissue pseudofollicles, and investigating these interactions is essential to understand both disease pathogenesis and the effects of immunotherapy. Tumor-derived extracellular vesicle (EV) shedding is emerging as an important mode of intercellular communication in the TME...
July 28, 2016: Blood
https://www.readbyqxmd.com/read/26153226/emerging-immunological-drugs-for-chronic-lymphocytic-leukemia
#15
REVIEW
Pawel Robak, Piotr Smolewski, Tadeusz Robak
INTRODUCTION: Over the last few years, several new immunological drugs, particularly monoclonal antibodies (mAbs), immunomodulatory drugs and B-cell receptor (BCR) pathway inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). This article summarizes recent discoveries regarding their mechanism of action, pharmacological properties, clinical activity and toxicity, as well as the emerging role of these agents in CLL. AREAS COVERED: A literature review of mAbs, BCR pathway inhibitors and immunomodulating drugs was conducted of the MEDLINE database via PubMed for articles in English...
September 2015: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/26095886/immunotherapy-in-acute-myeloid-leukemia
#16
REVIEW
Dolores A Grosso, Rosemary C Hess, Mark A Weiss
Despite the remarkable progress made in some leukemias such as CML and CLL, cytotoxic treatment for AML remains essentially unchanged over the last 4 decades. Several lines of evidence, including the graft versus leukemia effect associated with allogeneic hematopoietic stem cell transplantation (HSCT), suggest that immunotherapy is an active modality in AML. Given the lack of progress for chemotherapy in this disease, many novel immunologic treatment approaches have been explored. The goals of non-transplant-based immune approaches have largely consisted of the stimulation or restoration of endogenous immune responses or the targeting of specific tumor antigens by immune cells...
August 15, 2015: Cancer
https://www.readbyqxmd.com/read/26084672/perturbation-of-the-normal-immune-system-in-patients-with-cll
#17
REVIEW
Francesco Forconi, Paul Moss
Immune dysregulation is a cardinal feature of chronic lymphocytic leukemia (CLL) from its early stage and worsens during clinical observation, even in absence of disease progression. Although the mechanisms remain unclear, new insights are emerging into the complex relationship between the CLL clone and its immune environment. T cells are increased in early-stage disease and show progressive accumulation and exhaustion. The mechanisms that drive this expansion may include auto-antigens involved in the original clonal expansion...
July 30, 2015: Blood
https://www.readbyqxmd.com/read/25972916/aberrant-epstein-barr-virus-antibody-patterns-and-chronic-lymphocytic-leukemia-in-a-spanish-multicentric-case-control-study
#18
Delphine Casabonne, Yolanda Benavente, Claudia Robles, Laura Costas, Esther Alonso, Eva Gonzalez-Barca, Adonina Tardón, Trinidad Dierssen-Sotos, Eva Gimeno Vázquez, Marta Aymerich, Elias Campo, Gemma Castaño-Vinyals, Nuria Aragones, Marina Pollan, Manolis Kogevinas, Hedy Juwana, Jaap Middeldorp, Silvia de Sanjose
BACKGROUND: Epstein-Barr virus (EBV)-related malignancies harbour distinct serological responses to EBV antigens. We hypothesized that EBV serological patterns can be useful to identify different stages of chronic lymphocytic leukemia. METHODS: Information on 150 cases with chronic lymphocytic leukemia and 157 frequency-matched (by age, sex and region) population-based controls from a Spanish multicentre case-control study was obtained. EBV immunoglobulin G serostatus was evaluated through a peptide-based ELISA and further by immunoblot analysis to EBV early antigens (EA), nuclear antigen (EBNA1), VCA-p18, VCA-p40 and Zebra...
2015: Infectious Agents and Cancer
https://www.readbyqxmd.com/read/25956014/advances-in-basic-and-clinical-immunology-in-2014
#19
REVIEW
Javier Chinen, Luigi D Notarangelo, William T Shearer
Genetic identification of immunodeficiency syndromes has become more efficient with the availability of whole-exome sequencing, expediting the identification of relevant genes and complementing traditional linkage analysis and homozygosity mapping. New genes defects causing immunodeficiency include phophoglucomutase 3 (PGM3), cytidine 5' triphosphate synthase 1 (CTPS1), nuclear factor κB-inducing kinase (NIK), cytotoxic T lymphocyte-associated antigen 4 (CTLA4), B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10), phosphoinositide-3 kinase regulatory subunit 1 (PIK3R1), IL21, and Jagunal homolog 1 (JAGN1)...
May 2015: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/25917633/an-update-on-current-and-prospective-immunotherapies-for-chronic-lymphocytic-leukemia
#20
REVIEW
Josephine N Emole, Frederick L Locke, Javier Pinilla-Ibarz
Chronic lymphocytic leukemia (CLL) is the most common leukemia. Combined agent chemotherapy is the current standard front-line treatment for physically fit patients with CLL. Use of chemotherapy can be complicated by significant toxicity, especially in patients with advanced age or comorbid conditions. Moreover, patients may relapse and become refractory to further chemotherapy. Immunotherapy targets the aberrant immunological processes in CLL without the toxicity of chemotherapy. Immunotherapeutic strategies can also be combined with chemotherapy to improve response rates in this incurable disease...
2015: Immunotherapy
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