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https://www.readbyqxmd.com/read/29775689/biomarkers-for-checkpoint-inhibition-in-hematologic-malignancies
#1
REVIEW
Djordje Atanackovic, Tim Luetkens
In the past few years we have seen remarkable paradigm shifts in the treatment of many solid tumors due to the introduction of inhibitors targeting immune checkpoints such as PD-1/PD-L1 and CTLA-4. Recent results indicate that checkpoint inhibition also represents a very promising approach for certain types of hematologic malignancies. Unfortunately, treatment with checkpoint inhibitors is also associated with substantial toxicities and high costs and only a subset of patients appears to derive clinical benefit from these treatments...
May 15, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29766234/the-severe-cytokine-release-syndrome-in-phase-i-trials-of-cd19-car-t-cell-therapy-a-systematic-review
#2
REVIEW
Zhen Jin, Rufang Xiang, Kai Qing, Xiaoyang Li, Yunxiang Zhang, Lining Wang, Hongming Zhu, Yuanfei Mao, Zizhen Xu, Junmin Li
CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive results in treating acute lymphoblastic leukemia (B-ALL), chronic lymphoblastic leukemia (B-CLL), and B-cell non-Hodgkin lymphoma (B-NHL) over the past few years. Meanwhile, the cytokine release syndrome (CRS), which could be moderate or even life-threatening, has emerged as the most significant adverse effect in the clinical course of this novel targeting immunotherapy. In this systematic review, we analyzed the incidence of severe CRS in 19 clinical trials selected from studies published between 2010 and 2017...
May 15, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29764250/immunological-changes-with-kinase-inhibitor-therapy-for-chronic-lymphocytic-leukemia
#3
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/29756258/a-prospective-analysis-of-circulating-saturated-and-monounsaturated-fatty-acids-and-risk-of-non-hodgkin-lymphoma
#4
Yu-Han Chiu, Kimberly A Bertrand, Shumin Zhang, Francine Laden, Mara M Epstein, Bernard A Rosner, Stephanie Chiuve, Hannia Campos, Edward L Giovannucci, Jorge E Chavarro, Brenda M Birmann
Circulating saturated (SFA) and monounsaturated fatty acids (MUFA), which are predominantly derived from endogenous metabolism, may influence non-Hodgkin lymphoma (NHL) risk by modulating inflammation or lymphocyte membrane stability. However, few biomarker studies have evaluated NHL risk associated with these fats. We conducted a prospective study of 583 incident NHL cases and 583 individually matched controls with archived pre-diagnosis red blood cell (RBC) specimens in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS)...
May 14, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29743179/a-cd19-cd3-bispecific-antibody-for-effective-immunotherapy-of-chronic-lymphocytic-leukemia-in-the-ibrutinib-era
#5
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's 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® format, is FDA approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Due to its short half-life of 2.1 hours, blinatumomab requires continuous intravenous dosing for efficacy...
May 9, 2018: Blood
https://www.readbyqxmd.com/read/29735552/hla-class-i-and-ii-diversity-contributes-to-the-etiologic-heterogeneity-of-non-hodgkin-lymphoma-subtypes
#6
Sophia S Wang, Mary Carrington, Sonja I Berndt, Susan L Slager, Paige M Bracci, Jenna Voutsinas, James R Cerhan, Karin Ekström Smedby, Henrik Hjalgrim, Joseph Vijai, Lindsay M Morton, Roel Vermeulen, Ora Paltiel, Claire M Vajdic, Martha S Linet, Alexandra Nieters, Silvia de Sanjosé, Wendy Cozen, Elizabeth E Brown, Jennifer Turner, John J Spinelli, Tongzhang Zheng, Brenda M Birmann, Christopher R Flowers, Nikolaus Becker, Elizabeth A Holly, Eleanor Kane, Dennis Weisenburger, Marc Maynadie, Pierluigi Cocco, Demetrius Albanes, Stephanie J Weinstein, Lauren R Teras, W Ryan Diver, Stephanie J Lax, Ruth C Travis, Rudolf Kaaks, Elio Riboli, Yolanda Benavente, Paul Brennan, James D McKay, Marie Helene Delfau-Larue, Brian K Link, Corrado Magnani, Maria G Ennas, Giancarlo Latte, Andrew L Feldman, Nicole Wong Doo, Graham G Giles, Melissa C Southey, Roger L Milne, Kenneth Offit, Jacob Muskinsky, Alan A Arslan, Mark P Purdue, Hans-Olov Adami, Mads Melbye, Bengt Glimelius, Lucia Conde, Nicola J Camp, Martha Glenn, Karen Curtin, Jacqueline Clavel, Alain Monnereau, David G Cox, Hervé Ghesquières, Gilles Salles, Paolo Boffetta, Lenka Foretova, Anthony Staines, Scott Davis, Richard K Severson, Qing Lan, Angela Brooks-Wilson, Martyn T Smith, Eve Roman, Anne Kricker, Yawei Zhang, Peter Kraft, Stephen J Chanock, Nathaniel Rothman, Patricia Hartge, Christine F Skibola
A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for: 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent...
May 7, 2018: Cancer Research
https://www.readbyqxmd.com/read/29715621/elevated-mir-20b-5p-expression-in-peripheral-blood-mononuclear-cells-a-novel-independent-molecular-biomarker-of-favorable-prognosis-in-chronic-lymphocytic-leukemia
#7
Sotirios G Papageorgiou, Christos K Kontos, Panagiotis Tsiakanikas, Georgia Stavroulaki, Anthi Bouchla, Diamantina Vasilatou, Efthymia Bazani, Afroditi Lazarakou, Andreas Scorilas, Vasiliki Pappa
MicroRNA-20b-5p (miR-20b-5p) is part of the miR-106a/363 cluster and a member of the cancer-related miR-17 family. miR-20b-5p regulates important transcription factors, including hypoxia-inducible factor 1 (HIF1) and signal transducer and activator of transcription 3 (STAT3). Recently, the dysregulation of miR-20b-5p expression has been observed in many B-cell lymphomas and T-cell leukemias. In this research study, we examined the putative prognostic value of miR-20b-5p in CLL. Therefore, total RNA was isolated from peripheral blood mononuclear cells (PBMCs) collected from 88 CLL patients; next, total RNA was polyadenylated and first-strand cDNA was synthesized, using an oligo-dT-adapter primer...
April 26, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29713085/determinants-of-response-and-resistance-to-cd19-chimeric-antigen-receptor-car-t-cell-therapy-of-chronic-lymphocytic-leukemia
#8
Joseph A Fraietta, Simon F Lacey, Elena J Orlando, Iulian Pruteanu-Malinici, Mercy Gohil, Stefan Lundh, Alina C Boesteanu, Yan Wang, Roddy S O'Connor, Wei-Ting Hwang, Edward Pequignot, David E Ambrose, Changfeng Zhang, Nicholas Wilcox, Felipe Bedoya, Corin Dorfmeier, Fang Chen, Lifeng Tian, Harit Parakandi, Minnal Gupta, Regina M Young, F Brad Johnson, Irina Kulikovskaya, Li Liu, Jun Xu, Sadik H Kassim, Megan M Davis, Bruce L Levine, Noelle V Frey, Donald L Siegel, Alexander C Huang, E John Wherry, Hans Bitter, Jennifer L Brogdon, David L Porter, Carl H June, J Joseph Melenhorst
Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2 . We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response...
April 30, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29712773/chronic-lymphocytic-leukemia-derived-il-10-suppresses-antitumor-immunity
#9
Sara S Alhakeem, Mary K McKenna, Karine Z Oben, Sunil K Noothi, Jacqueline R Rivas, Gerhard C Hildebrandt, Roger A Fleischman, Vivek M Rangnekar, Natarajan Muthusamy, Subbarao Bondada
Chronic lymphocytic leukemia (CLL) patients progressively develop an immunosuppressive state. CLL patients have more plasma IL-10, an anti-inflammatory cytokine, than healthy controls. In vitro human CLL cells produce IL-10 in response to BCR cross-linking. We used the transgenic Eμ-T cell leukemia oncogene-1 ( TCL1 ) mouse CLL model to study the role of IL-10 in CLL associated immunosuppression. Eμ-TCL mice spontaneously develop CLL because of a B cell-specific expression of the oncogene, TCL1. Eμ- TCL1 mouse CLL cells constitutively produce IL-10, which is further enhanced by BCR cross-linking, CLL-derived IL-10 did not directly affect survival of murine or human CLL cells in vitro...
April 30, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29702521/dna-damage-pathways-and-b-cell-lymphomagenesis
#10
Gero Knittel, Tim Rehkämper, Pascal Nieper, Anna Schmitt, Ruth Flümann, H Christian Reinhardt
PURPOSE OF REVIEW: Recent lymphoma genome sequencing projects have shed light on the genomic landscape of indolent and aggressive lymphomas, as well as some of the molecular mechanisms underlying recurrent mutations and translocations in these entities. Here, we review these recent genomic discoveries, focusing on acquired DNA repair defects in lymphoma. In addition, we highlight recently identified actionable molecular vulnerabilities associated with recurrent mutations in chronic lymphocytic leukemia (CLL), which serves as a model entity...
April 26, 2018: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29695515/novel-role-of-prostate-apoptosis-response-4-tumor-suppressor-in-b-cell-chronic-lymphocytic-leukemia
#11
Mary K McKenna, Sunil K Noothi, Sara S Alhakeem, Karine Z Oben, Joseph T Greene, Rajeswaran Mani, Kathryn L Perry, James P Collard, Jacqueline R Rivas, Gerhard Hildebrandt, Roger Fleischman, Eric B Durbin, John C Byrd, Chi Wang, Natarajan Muthusamy, Vivek M Rangnekar, Subbarao Bondada
Prostate apoptosis response-4 (Par-4), a pro-apoptotic tumor suppressor protein, is down regulated in many cancers including renal cell carcinoma, glioblastoma, endometrial and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from the Eµ-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1 to S cell cycle transition...
April 25, 2018: Blood
https://www.readbyqxmd.com/read/29672642/runx1-pdcd6-fusion-resulting-from-a-novel-t-5-21-p15-q22-chromosome-translocation-in-myelodysplastic-syndrome-secondary-to-chronic-lymphocytic-leukemia
#12
Ioannis Panagopoulos, Ludmila Gorunova, Eva-Marie Jacobsen, Kristin Andersen, Francesca Micci, Sverre Heim
Leukemic cells often carry chromosome aberrations which generate chimeric genes of pathogenetic, diagnostic, and prognostic importance. New rearrangements giving rise to novel fusion genes define hitherto unrecognized genetic leukemia subgroups. G-banding, fluorescence in situ hybridization (FISH), and molecular genetic analyses were done on bone marrow cells from a patient with chronic lymphocytic leukemia (CLL) and secondary myelodysplasia. The G-banding analysis revealed the karyotype 46,XX,del(21)(q22)[9]/46,XX[2]...
2018: PloS One
https://www.readbyqxmd.com/read/29666622/chemotactic-cues-for-notch1-dependent-leukemia
#13
REVIEW
Erich Piovan, Valeria Tosello, Alberto Amadori, Paola Zanovello
The NOTCH signaling pathway is a conserved signaling cascade that regulates many aspects of development and homeostasis in multiple organ systems. Aberrant activity of this signaling pathway is linked to the initiation and progression of several hematological malignancies, exemplified by T-cell acute lymphoblastic leukemia (T-ALL). Interestingly, frequent non-mutational activation of NOTCH1 signaling has recently been demonstrated in B-cell chronic lymphocytic leukemia (B-CLL), significantly extending the pathogenic significance of this pathway in B-CLL...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29650518/secretory-igm-exacerbates-tumor-progression-by-inducing-accumulations-of-mdscs-in-mice
#14
Chih-Hang Anthony Tang, Shiun Chang, Ayumi Hashimoto, Yi-Ju Chen, Chang Won Kang, Anthony R Mato, Juan R Del Valle, Dmitry Gabrilovich, Chih-Chi Andrew Hu
Chronic lymphocytic leukemia cells can secrete immunoglobulin M. However, it is not clear whether secretory IgM (sIgM) plays a role in disease progression. We crossed the Eμ-TCL1 mouse model of CLL, in which the expression of human TCL1 oncogene was driven by the V(H) promoter-Ig(H)-Eμ enhancer, with MD4 mice whose B cells produced B cell receptor (membrane-bound IgM) and sIgM with specificity for hen egg lysozyme (HEL). CLL cells developed in these MD4/Eμ-TCL1 mice reactivated a parental Ig gene allele and secreted IgM, and did not recognize HEL...
April 12, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29569742/lenalidomide-as-immune-adjuvant-to-a-dendritic-cell-vaccine-in-chronic-lymphocytic-leukemia-patients
#15
Marzia Palma, Lotta Hansson, Tom A Mulder, Lars Adamson, Barbro Näsman-Glaser, Ingrid Eriksson, Kia Heimersson, Fariba Mozaffari, Ann Svensson, Giusy Gentilcore, Anders Österborg, Håkan Mellstedt
OBJECTIVES: We previously showed that immunization with ex-vivo generated autologous dendritic cells loaded with apoptotic tumor cells (Apo-DC) potentiated tumor-specific immunity in chronic lymphocytic leukemia (CLL) patients. Here, we evaluated safety and immunogenicity of Apo-DC in combination with lenalidomide, granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose cyclophosphamide (CTX). METHODS: Ten previously untreated patients with slowly progressing CLL received 5 Apo-DC vaccinations and lenalidomide orally for 24 weeks either alone (cohort I, n=5) or together with subcutaneous GM-CSF and intravenous CTX (cohort II, n=5)...
March 23, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29562857/obinutuzumab-induces-depletion-of-nk-cells-in-patients-with-chronic-lymphocytic-leukemia
#16
Ricardo García-Muñoz, Lorea Aguinaga, Jesus Feliu, Judit Anton-Remirez, Lorena Jorge-Del-Val, Andrea Casajús-Navasal, María José Nebot-Villacampa, Isabel Daroca-Fernandez, Elena Domínguez-Garrido, Pilar Rabasa, Carlos Panizo
AIM: Obinutuzumab induces NK cell antibody-dependent cell-mediated cytotoxicity. OBJECTIVE: Investigate the effects on the human immune system after obinutuzumab monotherapy treatment in patients with chronic lymphocytic leukemia (CLL). METHOD: To evaluate these effects, we analyzed the distribution of CD4+ and CD8+ T cells, B cells and NK cells in the peripheral blood of eight CLL patients who were treated with obinutuzumab in monotherapy...
March 1, 2018: Immunotherapy
https://www.readbyqxmd.com/read/29532605/hepatitis-b-virus-and-risk-of-non-hodgkin-lymphoma-an-updated-meta-analysis-of-58-studies
#17
M Li, Y Gan, C Fan, H Yuan, X Zhang, Y Shen, Q Wang, Z Meng, D Xu, H Tu
Previous studies have focused on the relationship between hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). However, the results remain inconsistent and somehow conflicting in different subgroups. The aim of this study was to combine the findings of independent studies to comprehensively assess the association between HBV and NHL using a meta-analysis. Relevant studies were identified through structured keyword searches in PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database, and 58 studies with a total of 53 714 NHL cases and 1 778 591 controls were finally included...
March 13, 2018: Journal of Viral Hepatitis
https://www.readbyqxmd.com/read/29526569/elevated-levels-of-follicular-t-helper-cells-and-their-association-with-therapeutic-effects-in-patients-with-chronic-lymphocytic-leukaemia
#18
Liannv Qiu, Yonglie Zhou, Qinhua Yu, Sujie Zheng, Zhenni Wang, Qiang Huang
Chronic lymphocytic leukaemia (CLL) is characterized by an abnormal expansion of mature B cells with variable progression. Follicular T helper (Tfh) cells help B cells differentiate into plasma cells or long-lived memory B cells in germinal centres (GCs). However, the role of Tfh cells in CLL is poorly understand, and whether it plays a critical role in disease progression in vivo is lacking. In this study, we investigate the dynamic change of circulating Tfh cells in peripheral blood from patients with CLL during the treatment periods to evaluate their utility to predict disease progression...
May 2018: Immunology Letters
https://www.readbyqxmd.com/read/29504446/the-clinical-significance-of-b-cell-maturation-antigen-as-a-therapeutic-target-and-biomarker
#19
Eric Sanchez, Edward J Tanenbaum, Saurabh Patil, Mingjie Li, Camilia M Soof, Aleksandra Vidisheva, Gabriel N Waterman, Tara Hekmati, George Tang, Cathy S Wang, Haiming Chen, James Berenson
B-cell maturation antigen (BCMA) is a cell membrane bound tumor necrosis factor receptor family member that is expressed exclusively on late stage normal and malignant B-cells and plasma cells. Addition of two of its ligands, B-cell activating factor and a proliferation inducting ligand, to normal B-cells cause B-cell proliferation and antibody production. Serum BCMA is elevated among patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), and is a prognostic and monitoring tool for these patients...
April 2018: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/29479062/distinct-roles-for-phosphoinositide-3-kinases-%C3%AE-and-%C3%AE-in-malignant-b-cell-migration
#20
Ahmed Y Ali, Xun Wu, Nour Eissa, Sen Hou, Jean-Eric Ghia, Thomas T Murooka, Versha Banerji, James B Johnston, Francis Lin, Spencer B Gibson, Aaron J Marshall
The PI 3-kinases (PI3K) are essential mediators of chemokine receptor signaling necessary for migration of chronic lymphocytic leukemia (CLL) cells and their interaction with tissue-resident stromal cells. While the PI3Kδ-specific inhibitor idelalisib shows efficacy in treatment of CLL and other B cell malignancies, the function of PI3Kγ has not been extensively studied in B cells. Here, we assess whether PI3Kγ has non-redundant functions in CLL migration and adhesion to stromal cells. We observed that pharmaceutical PI3Kγ inhibition with CZC24832 significantly impaired CLL cell migration, while dual PI3Kδ/γ inhibitor duvelisib had a greater impact than single isoform-selective inhibitors...
January 31, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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