scholarly journals NK cells and multiple myeloma-associated endothelial cells: molecular interactions and influence of IL-27

Oncotarget ◽  
2017 ◽  
Vol 8 (21) ◽  
pp. 35088-35102 ◽  
Author(s):  
Alessandra Dondero ◽  
Beatrice Casu ◽  
Francesca Bellora ◽  
Angelo Vacca ◽  
Annunziata De Luisi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Endothelial Cells ◽  
Nk Cells ◽  
Molecular Interactions

scholarly journals Role and Modulation of NK Cells in Multiple Myeloma

Hemato ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 167-181
Author(s):  
Marie Thérèse Rubio ◽  
Adèle Dhuyser ◽  
Stéphanie Nguyen
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Proteasome Inhibitors ◽  
Disease Evolution ◽  
Cell Functions

Myeloma tumor cells are particularly dependent on their microenvironment and sensitive to cellular antitumor immune response, including natural killer (NK) cells. These later are essential innate lymphocytes implicated in the control of viral infections and cancers. Their cytotoxic activity is regulated by a balance between activating and inhibitory signals resulting from the complex interaction of surface receptors and their respective ligands. Myeloma disease evolution is associated with a progressive alteration of NK cell number, phenotype and cytotoxic functions. We review here the different therapeutic approaches that could restore or enhance NK cell functions in multiple myeloma. First, conventional treatments (immunomodulatory drugs-IMids and proteasome inhibitors) can enhance NK killing of tumor cells by modulating the expression of NK receptors and their corresponding ligands on NK and myeloma cells, respectively. Because of their ability to kill by antibody-dependent cell cytotoxicity, NK cells are important effectors involved in the efficacy of anti-myeloma monoclonal antibodies targeting the tumor antigens CD38, CS1 or BCMA. These complementary mechanisms support the more recent therapeutic combination of IMids or proteasome inhibitors to monoclonal antibodies. We finally discuss the ongoing development of new NK cell-based immunotherapies, such as ex vivo expanded killer cell immunoglobulin-like receptors (KIR)-mismatched NK cells, chimeric antigen receptors (CAR)-NK cells, check point and KIR inhibitors.

Phenotypic Analyses of NK Cells in Patients with Multiple Myeloma

2017 ◽  
Vol 17 (1) ◽  
pp. e101-e102
Author(s):  
Mika Kijima ◽  
Kaori Tanaka-Furuyama ◽  
Ryu Yakabe ◽  
Noriko Toyama-Sorimachi ◽  
Shotaro Hagiwara
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells

scholarly journals Hypoxia Induced Impairment of NK Cell Cytotoxicity against Multiple Myeloma Can Be Overcome by IL-2 Activation of the NK Cells

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e64835 ◽  
Author(s):  
Subhashis Sarkar ◽  
Wilfred T. V. Germeraad ◽  
Kasper M. A. Rouschop ◽  
Elisabeth M. P. Steeghs ◽  
Michel van Gelder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Cytotoxicity ◽  
Nk Cell Cytotoxicity

scholarly journals HB-EGF–EGFR Signaling in Bone Marrow Endothelial Cells Mediates Angiogenesis Associated with Multiple Myeloma

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 173 ◽  
Author(s):  
Luigia Rao ◽  
Donato Giannico ◽  
Patrizia Leone ◽  
Antonio Giovanni Solimando ◽  
Eugenio Maiorano ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Clinical Investigation ◽  
Endothelial Cell Proliferation ◽  
Heparin Binding ◽  
Egfr Signaling ◽  
Potent Inducer ◽  
Egfr Expression

Epidermal growth factor receptor (EGFR) and its ligand heparin-binding EGF-like growth factor (HB-EGF) sustain endothelial cell proliferation and angiogenesis in solid tumors, but little is known about the role of HB-EGF–EGFR signaling in bone marrow angiogenesis and multiple myeloma (MM) progression. We found that bone marrow endothelial cells from patients with MM express high levels of EGFR and HB-EGF, compared with cells from patients with monoclonal gammopathy of undetermined significance, and that overexpressed HB-EGF stimulates EGFR expression in an autocrine loop. We also found that levels of EGFR and HB-EGF parallel MM plasma cell number, and that HB-EGF is a potent inducer of angiogenesis in vitro and in vivo. Moreover, blockade of HB-EGF–EGFR signaling, by an anti-HB-EGF neutralizing antibody or the EGFR inhibitor erlotinib, limited the angiogenic potential of bone marrow endothelial cells and hampered tumor growth in an MM xenograft mouse model. These results identify HB-EGF–EGFR signaling as a potential target of anti-angiogenic therapy, and encourage the clinical investigation of EGFR inhibitors in combination with conventional cytotoxic drugs as a new therapeutic strategy for MM.

scholarly journals Ex Vivo Activity of Immunotherapeutic Approaches Targeting CD38 Against Daratumumab-Resistant Multiple Myeloma Patient Samples

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1848-1848
Author(s):  
Maria Karvouni ◽  
Heyue Zhou ◽  
Arnika Kathleen Wagner ◽  
Qiangzhong Ma ◽  
Alamdar H. Baloch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Phase 1 ◽  
Employment Equity ◽  
Multiple Myeloma Patient ◽  
Myeloma Cells ◽  
Car T ◽  
Equity Ownership

Background: Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The identification of CD38, a transmembrane glycoprotein overexpressed on MM cells, led to the development of target-specific therapeutics such as the FDA approved monoclonal antibody (mAb) Daratumumab (DARA). Although a valuable treatment option for refractory/relapsed (R/R) MM patients, DARA has a limited response rate of below 50%, which highlights the clinical need for novel therapeutics. Aims: Aiming to further exploit the therapeutic potential of CD38 in the MM setting, immunotherapies based on the novel anti-CD38 mAb CD38A2 were tested. Methods: For the first approach, the CD38A2 mAb -that binds to a unique, distinct from DARA's, CD38 epitope- was conjugated with either the alkylating agent Duomycin (ADC-136) or the microtubulin binder Duostatin (ADC-129). The ADCs were compared to DARA, in cultures of primary MM cells from patients refractory to DARA treatment. In a second approach, a chimeric antigen receptor (CAR) consisting of the CD38A2 scFv and the intracellular domains of CD28 and CD3ζ was used to transduce primary T and NK cells from R/R MM patients. The functionality of the CAR-T and CAR-NK cells was assessed in cytotoxicity assays against autologous myeloma cells. Results: ADC-136 demonstrated the most potent cytotoxicity against the MM cells with an IC50 of 6pM at day 6 following a single dose treatment. ADC-129 showed cell killing with an IC50 of 30pM, while DARA did not exhibit appreciable cytotoxicity. Regarding the cell therapy approach, patients' T and NK cells were effectively transduced, showing a CD38A2-CAR expression ranging between 11-68%. In functional assays, CAR-T and CAR-NK cells were assayed against autologous myeloma cells, where they exhibited an increase in target cell cytotoxicity, compared to the untransduced cells. Summary/Conclusion: Altogether, our preliminary findings demonstrate that CD38 targeting using CD38A2-based immunotherapies could be a viable therapeutic approach in R/R MM patients previously exposed to DARA. Currently, an anti-CD38 CAR-T therapy based on CD38A2 is being evaluated in Phase 1 studies in R/R MM patients by Sorrento Therapeutics, Inc. Disclosures Zhou: Sorrento Therapeutics Inc: Employment, Equity Ownership. Ma:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhu:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhang:Sorrento Therapeutics Inc: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

scholarly journals Natural Killer Cells in the Malignant Niche of Multiple Myeloma

2022 ◽  
Vol 12 ◽  
Author(s):  
Ondrej Venglar ◽  
Julio Rodriguez Bago ◽  
Benjamin Motais ◽  
Roman Hajek ◽  
Tomas Jelinek
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Natural Killer ◽  
Defense Mechanisms ◽  
Hematological Malignancies ◽  
Cell Function ◽  
Nk Cell ◽  
Current Knowledge ◽  
Suppressor Activity ◽  
Infected Cells

Natural killer (NK) cells represent a subset of CD3- CD7+ CD56+/dim lymphocytes with cytotoxic and suppressor activity against virus-infected cells and cancer cells. The overall potential of NK cells has brought them to the spotlight of targeted immunotherapy in solid and hematological malignancies, including multiple myeloma (MM). Nonetheless, NK cells are subjected to a variety of cancer defense mechanisms, leading to impaired maturation, chemotaxis, target recognition, and killing. This review aims to summarize the available and most current knowledge about cancer-related impairment of NK cell function occurring in MM.

scholarly journals Human NK Cells Lyse Organ-Specific Endothelial Cells: Analysis of Adhesion and Cytotoxic Mechanisms

2005 ◽  
Vol 174 (9) ◽  
pp. 5573-5582 ◽  
Author(s):  
Aleksandra Bielawska-Pohl ◽  
Claire Crola ◽  
Anne Caignard ◽  
Catherine Gaudin ◽  
Danuta Dus ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Nk Cells ◽  
Organ Specific
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