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https://www.readbyqxmd.com/read/27430580/targeting-kir-blockade-in-multiple-myeloma-trouble-in-checkpoint-paradise
#1
Martin Felices, Jeffrey S Miller
Findings within the current issue indicate that treatment with IPH2101 when used as a monotherapy in smoldering multiple myeloma, meant to enhance natural killer (NK) cell function through inhibitory KIR blockade, results in a surprising reduction of NK-cell function mediated through monocyte trogocytosis. The significance of these findings is discussed. Clin Cancer Res; 22(21); 5161-3. ©2016 AACRSee related article by Carlsten et al., p. 5211.
November 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27307594/checkpoint-inhibition-of-kir2d-with-the-monoclonal-antibody-iph2101-induces-contraction-and-hyporesponsiveness-of-nk-cells-in-patients-with-myeloma
#2
Mattias Carlsten, Neha Korde, Ritesh Kotecha, Robert Reger, Simona Bor, Dickran Kazandjian, Ola Landgren, Richard W Childs
PURPOSE: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. Based on data showing KIR-ligand mismatched NK-cells reduce the risk of leukemia and multiple myeloma (MM) relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK-cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK-cells, our single-arm phase II clinical trial in patients with smoldering MM was prematurely terminated due to lack of clinical efficacy...
June 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27141379/overexpression-of-kir-inhibitory-ligands-hla-i-determines-that-immunosurveillance-of-myeloma-depends-on-diverse-and-strong-nk-cell-licensing
#3
María V Martínez-Sánchez, Adela Periago, Isabel Legaz, Lourdes Gimeno, Anna Mrowiec, Natividad R Montes-Barqueros, José A Campillo, José M Bolarin, María V Bernardo, María R López-Álvarez, Consuelo González, María C García-Garay, Manuel Muro, Valentin Cabañas-Perianes, Jose L Fuster, Ana M García-Alonso, José M Moraleda, María R Álvarez-Lopez, Alfredo Minguela
Missing self recognition makes cancer sensitive to natural killer cell (NKc) reactivity. However, this model disregards the NKc licensing effect, which highly increases NKc reactivity through interactions of inhibitory killer cell immunoglobulin-like receptors (iKIR) with their cognate HLA-I ligands. The influence of iKIR/HLA-ligand (HLA-C1/C2) licensing interactions on the susceptibility to and progression of plasma cell (PC) dyscrasias was evaluated in 164 Caucasian patients and 286 controls. Compared to controls, myeloma accumulates KIR2DL1(-)L2(+)L3(-) genotypes (2...
April 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27083212/decreased-cd161-activating-and-increased-cd158a-inhibitory-receptor-expression-on-nk-cells-underlies-impaired-nk-cell-cytotoxicity-in-patients-with-multiple-myeloma
#4
Gordana Konjević, Ana Vuletić, Katarina Mirjačić Martinović, Nataša Colović, Milica Čolović, Vladimir Jurišić
AIM: As innate immune cells natural killer (NK), NK-like T and CTLγδ are important in antitumour response in multiple myeloma (MM), the aim of this study was to investigate some functional and phenotypical characteristics of these cells in MM. METHODS: 29 patients with MM prior to therapy, in clinical stage I-III and 15 healthy controls (HCs) were investigated. Percent of immune cells in peripheral blood, NK cell activity, expression of activating (CD161) and inhibitory (CD158a, CD158b) NK cell receptors on CD3(-)CD16(+) NK cells were evaluated using 51-chromium-release assay and by flow cytometry...
April 15, 2016: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/26961084/immune-checkpoint-inhibitors-enhance-cytotoxicity-of-cytokine-induced-killer-cells-against-human-myeloid-leukaemic-blasts
#5
Su Li Poh, Yeh Ching Linn
We studied whether blockade of inhibitory receptors on cytokine-induced killer (CIK) cells by immune checkpoint inhibitors could increase its anti-tumour potency against haematological malignancies. CIK cultures were generated from seven normal donors and nine patients with acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) or multiple myeloma (MM). The inhibitory receptors B and T lymphocyte attenuator, CD200 receptor, lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3) were present at variable percentages in most CIK cultures, while cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death-1 (PD-1) and killer cell immunoglobulin-like receptors (KIR2DL1/2/3) were expressed at low level in most cultures...
May 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/26635797/nk-cell-subgroups-phenotype-and-functions-after-autologous-stem-cell-transplantation
#6
Benedikt Jacobs, Sara Tognarelli, Kerstin Poller, Peter Bader, Andreas Mackensen, Evelyn Ullrich
High-dose chemotherapy with consecutive autologous stem cell transplantation (autoSCT) is a well-established treatment option for patients suffering from malignant lymphoma or multiple myeloma. Natural killer (NK) cells are an important part of the immune surveillance, and their cell number after autoSCT is predictive for progression-free and overall survival. To improve knowledge about the role of NK cells after autoSCT, we investigated different NK cell subgroups, their phenotype, and their functions in patients treated with autoSCT...
2015: Frontiers in Immunology
https://www.readbyqxmd.com/read/25999435/a-phase-i-trial-of-the-anti-kir-antibody-iph2101-and-lenalidomide-in-patients-with-relapsed-refractory-multiple-myeloma
#7
MULTICENTER STUDY
Don M Benson, Adam D Cohen, Sundar Jagannath, Nikhil C Munshi, Gary Spitzer, Craig C Hofmeister, Yvonne A Efebera, Pascale Andre, Robert Zerbib, Michael A Caligiuri
PURPOSE: Natural killer (NK) cells may play an important role in the immune response to multiple myeloma; however, multiple myeloma cells express killer immunoglobulin-like receptor (KIR) ligands to prevent NK cell cytotoxicity. Lenalidomide can expand and activate NK cells in parallel with its direct effects against multiple myeloma; however, dexamethasone may impair these favorable immunomodulatory properties. IPH2101, a first-in-class antiinhibitory KIR antibody, has acceptable safety and tolerability in multiple myeloma as a single agent...
September 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/25920521/optimal-selection-of-natural-killer-cells-to-kill-myeloma-the-role-of-hla-e-and-nkg2a
#8
Subhashis Sarkar, Michel van Gelder, Willy Noort, Yunping Xu, Kasper M A Rouschop, Richard Groen, Harry C Schouten, Marcel G J Tilanus, Wilfred T V Germeraad, Anton C M Martens, Gerard M J Bos, Lotte Wieten
Immunotherapy with allogeneic natural killer (NK) cells offers therapeutic perspectives for multiple myeloma patients. Here, we aimed to refine NK cell therapy by evaluation of the relevance of HLA-class I and HLA-E for NK anti-myeloma reactivity. We show that HLA-class I was strongly expressed on the surface of patient-derived myeloma cells and on myeloma cell lines. HLA-E was highly expressed by primary myeloma cells but only marginally by cell lines. HLA-E(low) expression on U266 cells observed in vitro was strongly upregulated after in vivo (bone marrow) growth in RAG-2(-/-) γc(-/-) mice, suggesting that in vitro HLA-E levels poorly predict the in vivo situation...
August 2015: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/25664323/immunomodulatory-effects-of-the-agaricus-blazei-murrill-based-mushroom-extract-andosan-in-patients-with-multiple-myeloma-undergoing-high-dose-chemotherapy-and-autologous-stem-cell-transplantation-a-randomized-double-blinded-clinical-study
#9
RANDOMIZED CONTROLLED TRIAL
Jon-Magnus Tangen, Anne Tierens, Jo Caers, Marilene Binsfeld, Ole Kristoffer Olstad, Anne-Marie Siebke Trøseid, Junbai Wang, Geir Erland Tjønnfjord, Geir Hetland
Forty patients with multiple myeloma scheduled to undergo high dose chemotherapy with autologous stem cell support were randomized in a double blinded fashion to receive adjuvant treatment with the mushroom extract AndoSan, containing 82% of Agaricus blazei Murrill (19 patients) or placebo (21 patients). Intake of the study product started on the day of stem cell mobilizing chemotherapy and continued until the end of aplasia after high dose chemotherapy, a period of about seven weeks. Thirty-three patients were evaluable for all study endpoints, while all 40 included patients were evaluable for survival endpoints...
2015: BioMed Research International
https://www.readbyqxmd.com/read/25606456/kir-genotype-distribution-among-patients-with-multiple-myeloma-higher-prevalence-of-kir-2ds4-and-kir-2ds5-genes
#10
R Hoteit, A Bazarbachi, A Antar, Z Salem, D Shammaa, R Mahfouz
INTRODUCTION: Natural killer (NK) cells possess an antitumor activity against multiple myeloma cells proven by the susceptibility of plasmocytes to NK lysis. In the early stage of MM, the killing of MM cells is mediated by natural cytotoxicity receptors (NRC) and NKG2D-dependent pathway, while in the late stage, NK cells lose their killing potential against MM cells due to the high expression of HLA class I molecules on MM cells. AIM: The aim of this paper is to study KIR expression of NK cells in MM patients and in healthy controls, to check for any association between KIR genotypes and MM...
December 2014: Meta Gene
https://www.readbyqxmd.com/read/25578514/acute-exercise-preferentially-redeploys-nk-cells-with-a-highly-differentiated-phenotype-and-augments-cytotoxicity-against-lymphoma-and-multiple-myeloma-target-cells-part-ii-impact-of-latent-cytomegalovirus-infection-and-catecholamine-sensitivity
#11
Austin B Bigley, Katayoun Rezvani, Mira Pistillo, Justin Reed, Nadia Agha, Hawley Kunz, Daniel P O'Connor, Takuya Sekine, Catherine M Bollard, Richard J Simpson
We showed previously that acute exercise is associated with a preferential redeployment of highly-differentiated NK-cells and increased cytotoxicity against HLA-expressing tumor cell lines during exercise recovery. In this part II study, we retrospectively analyzed these findings in the context of latent cytomegalovirus (CMV) infection and performed additional experiments to explore potential mechanisms underpinning the marked reduction in NK-cell redeployment with exercise in CMV-seropositive individuals. We show here that latent CMV infection impairs NK-cell mobilization with exercise, only when the intensity of the exercise bout exceeds the individual blood lactate threshold (BLT)...
October 2015: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/25510242/daratumumab-mediated-lysis-of-primary-multiple-myeloma-cells-is-enhanced-in-combination-with-the-human-anti-kir-antibody-iph2102-and-lenalidomide
#12
Inger S Nijhof, Jeroen J Lammerts van Bueren, Berris van Kessel, Pascale Andre, Yannis Morel, Henk M Lokhorst, Niels W C J van de Donk, Paul W H I Parren, Tuna Mutis
Despite recent treatment improvements, multiple myeloma remains an incurable disease. Since antibody-dependent cell-mediated cytotoxicity is an important effector mechanism of daratumumab, we explored the possibility of improving daratumumab-mediated cell-mediated cytotoxicity by blocking natural killer cell inhibitory receptors with the human monoclonal anti-KIR antibody IPH2102, next to activation of natural killer cells with the immune modulatory drug lenalidomide. In 4-hour antibody-dependent cell-mediated cytotoxicity assays, IPH2102 did not induce lysis of multiple myeloma cell lines, but it did significantly augment daratumumab-induced myeloma cell lysis...
February 2015: Haematologica
https://www.readbyqxmd.com/read/24200514/acute-exercise-preferentially-redeploys-nk-cells-with-a-highly-differentiated-phenotype-and-augments-cytotoxicity-against-lymphoma-and-multiple-myeloma-target-cells
#13
Austin B Bigley, Katayoun Rezvani, Claude Chew, Takuya Sekine, Mira Pistillo, Brian Crucian, Catherine M Bollard, Richard J Simpson
NK-cells undergo a "licensing" process as they develop into fully-functional cells capable of efficiently killing targets. NK-cell differentiation is accompanied by an increased surface expression of inhibitory killer immunoglobulin-like receptor (KIR) molecules, which is positively associated with cytotoxicity against the HLA-deficient K562 cell line. NK-cells are rapidly redeployed between the blood and tissues in response to acute exercise, but it is not known if exercise evokes a preferential trafficking of differentiated NK-cells or impacts NK-cell cytotoxic activity (NKCA) against HLA-expressing target cells...
July 2014: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/23724099/hypoxia-induced-impairment-of-nk-cell-cytotoxicity-against-multiple-myeloma-can-be-overcome-by-il-2-activation-of-the-nk-cells
#14
Subhashis Sarkar, Wilfred T V Germeraad, Kasper M A Rouschop, Elisabeth M P Steeghs, Michel van Gelder, Gerard M J Bos, Lotte Wieten
BACKGROUND: Multiple Myeloma (MM) is an incurable plasma cell malignancy residing within the bone marrow (BM). We aim to develop allogeneic Natural Killer (NK) cell immunotherapy for MM. As the BM contains hypoxic regions and the tumor environment can be immunosuppressive, we hypothesized that hypoxia inhibits NK cell anti-MM responses. METHODS: NK cells were isolated from healthy donors by negative selection and NK cell function and phenotype were examined at oxygen levels representative of hypoxic BM using flowcytometry...
2013: PloS One
https://www.readbyqxmd.com/read/23033266/a-phase-1-trial-of-the-anti-kir-antibody-iph2101-in-patients-with-relapsed-refractory-multiple-myeloma
#15
Don M Benson, Craig C Hofmeister, Swaminathan Padmanabhan, Attaya Suvannasankha, Sundar Jagannath, Rafat Abonour, Courtney Bakan, Pascale Andre, Yvonne Efebera, Jérôme Tiollier, Michael A Caligiuri, Sherif S Farag
Natural killer (NK) cells elicit cytotoxicity against multiple myeloma (MM); however, MM cells express HLA class I molecules as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIRs) as a means of immunoevasion. KIR-ligand mismatch may improve outcomes in allogeneic transplantation for MM. Extrapolating on this concept, we conducted a phase 1 trial of IPH2101, an anti-KIR antibody, in patients with relapsed/refractory MM. IPH2101 was administered intravenously every 28 days in 7 dose-escalated cohorts (0...
November 22, 2012: Blood
https://www.readbyqxmd.com/read/22491731/haploidentical-allogeneic-hematopoietic-cell-transplantation-in-adults-using-cd3-cd19-depletion-and-reduced-intensity-conditioning-a-phase-ii-study
#16
MULTICENTER STUDY
Birgit Federmann, Martin Bornhauser, Christoph Meisner, Lambros Kordelas, Dietrich W Beelen, Gernot Stuhler, Matthias Stelljes, Rainer Schwerdtfeger, Maximilian Christopeit, Gerhard Behre, Christoph Faul, Wichard Vogel, Michael Schumm, Rupert Handgretinger, Lothar Kanz, Wolfgang A Bethge
BACKGROUND: We report a prospective multicenter phase II study of haploidentical hematopoietic stem cell transplantation using CD3/CD19-depleted grafts after reduced intensity conditioning with fludarabine, thiotepa, melphalan and OKT-3. DESIGN AND METHODS: Sixty-one adults with a median age of 46 years (range 19-65 years) have been enrolled. Diagnoses were acute myeloid leukemia (n=38), acute lymphoblastic leukemia (n=8), non-Hodgkin's lymphoma (n=6), myeloma (n=4), chronic myeloid leukemia (n=3), chronic lymphatic leukemia (n=1) and myelodysplastic syndrome (n=1)...
October 2012: Haematologica
https://www.readbyqxmd.com/read/22033416/proteasome-inhibitor-lactacystin-augments-natural-killer-cell-cytotoxicity-of-myeloma-via-downregulation-of-hla-class-i
#17
Xiaosong Wu, Yang Shao, Yi Tao, Gongwen Ai, Rong Wei, Xiuqin Meng, Jun Hou, Ying Han, Fenghuang Zhan, Junhua Zheng, Jumei Shi
Modulation of inhibitory and activating natural killer (NK) receptor ligands on tumor cells represents a promising therapeutic approach against cancer, including multiple myeloma (MM). Human leukocyte antigen (HLA) class I molecules, the NK cell inhibitory killer cell immunoglobulin-like receptor (KIR) ligands, are critical determinants of NK cell activity. Proteasome inhibitors have demonstrated significant anti-myeloma activity in MM patients. In this study, we evaluated the effect of proteasome inhibitors on the surface expression of class I in human MM cells...
November 11, 2011: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/22031859/iph2101-a-novel-anti-inhibitory-kir-antibody-and-lenalidomide-combine-to-enhance-the-natural-killer-cell-versus-multiple-myeloma-effect
#18
Don M Benson, Courtney E Bakan, Shuhong Zhang, Shauna M Collins, Jing Liang, Shivani Srivastava, Craig C Hofmeister, Yvonne Efebera, Pascale Andre, Francois Romagne, Mathieu Bléry, Cécile Bonnafous, Jianying Zhang, David Clever, Michael A Caligiuri, Sherif S Farag
Multiple myeloma (MM) patients who receive killer cell Ig-like receptor (KIR) ligand-mismatched, T cell-depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand-matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells...
December 8, 2011: Blood
https://www.readbyqxmd.com/read/21154164/iph-2101-a-fully-human-anti-nk-cell-inhibitory-receptor-mab-for-the-potential-treatment-of-hematological-cancers
#19
Evren Alici
NK-cell activity against tumor cells is regulated by a complex balance of inhibitory and activating signals, which are mediated by the binding of NK-cell receptors to activating and inhibitory ligands expressed on tumor cells. Thus, the disruption of the inhibitory cascade would shift the balance to activation. IPH-2101 (1-7F9), being developed by Innate Pharma, is a fully human IgG4 anti-killer immunoglobulin-like receptor (KIR) mAb for the treatment of hematological malignancies, such as acute myeloid leukemia (AML) and multiple myeloma (MM)...
December 2010: Current Opinion in Molecular Therapeutics
https://www.readbyqxmd.com/read/20562327/interaction-between-kir3ds1-and-hla-bw4-predicts-for-progression-free-survival-after-autologous-stem-cell-transplantation-in-patients-with-multiple-myeloma
#20
Ian H Gabriel, Ruhena Sergeant, Richard Szydlo, Jane F Apperley, Hugues DeLavallade, Abdullah Alsuliman, Ahmad Khoder, David Marin, Edward Kanfer, Nichola Cooper, John Davis, Donald MacDonald, Marco Bua, Letizia Foroni, Chrissy Giles, Dragana Milojkovic, Amin Rahemtulla, Katayoun Rezvani
Natural killer (NK) cells exert antimyeloma cytotoxicity. The balance between inhibition and activation of NK-cells played by the inherited repertoire of killer immunoglobulin-like receptor (KIR) genes therefore may influence prognosis. One hundred eighty-two patients with multiple myeloma (MM) were analyzed for KIR repertoire. Multivariate analysis showed that progression-free survival (PFS) after autologous stem cell transplantation (ASCT) was significantly shorter for patients who are KIR3DS1(+) (P = .01)...
September 23, 2010: Blood
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