Family haploidentical donor-derived cytokine-induced killer cell biotherapy combined with bortezomib in two patients with relapsed multiple myeloma in a non-allogeneic transplant setting

2012 ◽  
Vol 54 (1) ◽  
pp. 209-211 ◽  
Author(s):  
Xin Zhou ◽  
Jianping Zhu ◽  
Hongli Sun ◽  
Lizheng Shao ◽  
Ming Xu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Killer Cell ◽  
Allogeneic Transplant

scholarly journals Plasma cells in multiple myeloma express a natural killer cell- associated antigen: CD56 (NKH-1; Leu-19)

Blood ◽  
1990 ◽  
Vol 76 (2) ◽  
pp. 377-382 ◽  
Author(s):  
B Van Camp ◽  
BG Durie ◽  
C Spier ◽  
M De Waele ◽  
I Van Riet ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Natural Killer Cell ◽  
Natural Killer ◽  
Plasma Cells ◽  
Killer Cell ◽  
Neoplastic Tissue ◽  
Aggressive Disease ◽  
Reactive Plasma ◽  
Gut Mucosa ◽  
Cd56 Expression

Abstract Bone marrow samples from 55 patients with multiple myeloma (MM) and 23 patients with monoclonal gammopathy of undertermined significance (MGUS) were evaluated with a broad panel of monoclonal antibodies. Plasma cells from 78% (43/55) of patients with MM strongly expressed the natural killer cell antigen CD56 (NKH-1, Leu-19). Of the 23 patients with MGUS, none showed strong CD56 reactivity, although three had weak reactivity in less than 20% of plasma cells. Myeloma cells expressing CD56 did not coexpress the CD57 or CD16 antigens. Patients with CD56-positive plasma cells had both indolent and aggressive disease. However, the 12 CD56-negative patients had predominantly aggressive disease with an unexpected preponderance of kappa Bence Jones only myeloma (5/10[50%] evaluable patients). Polyclonal plasma cells from non-neoplastic tissue sites (normal bone marrows, lymph nodes, tonsillar biopsies, and gut-mucosa biopsies) showed a near absence of CD56. We conclude that isolated, strong CD56 expression is common in MM, but not in MGUS or reactive plasma cells. The potential biologic importance of CD56 positivity in myeloma is reviewed.

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.

scholarly journals The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti–PD-1 antibody

Blood ◽  
2010 ◽  
Vol 116 (13) ◽  
pp. 2286-2294 ◽  
Author(s):  
Don M. Benson ◽  
Courtney E. Bakan ◽  
Anjali Mishra ◽  
Craig C. Hofmeister ◽  
Yvonne Efebera ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune Response ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Immune Response ◽  
Cell Versus

Abstract T-cell expression of programmed death receptor-1 (PD-1) down-regulates the immune response against malignancy by interacting with cognate ligands (eg, PD-L1) on tumor cells; however, little is known regarding PD-1 and natural killer (NK) cells. NK cells exert cytotoxicity against multiple myeloma (MM), an effect enhanced through novel therapies. We show that NK cells from MM patients express PD-1 whereas normal NK cells do not and confirm PD-L1 on primary MM cells. Engagement of PD-1 with PD-L1 should down-modulate the NK-cell versus MM effect. We demonstrate that CT-011, a novel anti–PD-1 antibody, enhances human NK-cell function against autologous, primary MM cells, seemingly through effects on NK-cell trafficking, immune complex formation with MM cells, and cytotoxicity specifically toward PD-L1+ MM tumor cells but not normal cells. We show that lenalidomide down-regulates PD-L1 on primary MM cells and may augment CT-011's enhancement of NK-cell function against MM. We demonstrate a role for the PD-1/PD-L1 signaling axis in the NK-cell immune response against MM and a role for CT-011 in enhancing the NK-cell versus MM effect. A phase 2 clinical trial of CT-011 in combination with lenalidomide for patients with MM should be considered.

scholarly journals Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells

2013 ◽  
Vol 8 (2) ◽  
pp. 297-310 ◽  
Author(s):  
Hua Jiang ◽  
Wenhao Zhang ◽  
Peipei Shang ◽  
Hui Zhang ◽  
Weijun Fu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Natural Killer Cell ◽  
Natural Killer ◽  
Cell Activation ◽  
Killer Cell ◽  
Myeloma Cells ◽  
Natural Killer Cell Activation

Lenalidomide can induce long-term responses in patients with multiple myeloma relapsing after multiple chemotherapy lines, in particular after allogeneic transplant

2011 ◽  
Vol 52 (7) ◽  
pp. 1262-1270 ◽  
Author(s):  
Francesco Spina ◽  
Vittorio Montefusco ◽  
Claudia Crippa ◽  
Annalisa Citro ◽  
Simona Sammassimo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Allogeneic Transplant

scholarly journals IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect

Blood ◽  
2011 ◽  
Vol 118 (24) ◽  
pp. 6387-6391 ◽  
Author(s):  
Don M. Benson ◽  
Courtney E. Bakan ◽  
Shuhong Zhang ◽  
Shauna M. Collins ◽  
Jing Liang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Allogeneic Transplantation ◽  
Cell Receptor ◽  
Phase 2 Trial ◽  
Cell Versus

Abstract 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. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.

scholarly journals Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Sara Petillo ◽  
Cristina Capuano ◽  
Rosa Molfetta ◽  
Cinzia Fionda ◽  
Abdelilah Mekhloufi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Membrane ◽  
Natural Killer ◽  
Nk Cell ◽  
Hematologic Malignancy ◽  
Mrna Level ◽  
Killer Cell ◽  
Mrna Levels ◽  
Cell Recognition ◽  
Nkg2d Ligands

AbstractMultiple Myeloma (MM) is an incurable hematologic malignancy of terminally differentiated plasma cells (PCs), where immune interactions play a key role in the control of cancer cell growth and survival. In particular, MM is characterized by a highly immunosuppressive bone marrow microenvironment where the anticancer/cytotoxic activity of Natural Killer (NK) cells is impaired. This study is focused on understanding whether modulation of neddylation can regulate NK cell-activating ligands expression and sensitize MM to NK cell killing. Neddylation is a post-translational modification that adds a ubiquitin-like protein, NEDD8, to selected substrate proteins, affecting their stability, conformation, subcellular localization, and function. We found that pharmacologic inhibition of neddylation using a small-molecule inhibitor, MLN4924/Pevonedistat, increases the expression of the NK cell-activating receptor NKG2D ligands MICA and MICB on the plasma membrane of different MM cell lines and patient-derived PCs, leading to enhanced NK cell degranulation. Mechanistically, MICA expression is upregulated at mRNA level, and this is the result of an increased promoter activity after the inhibition of IRF4 and IKZF3, two transcriptional repressors of this gene. Differently, MLN4924/Pevonedistat induced accumulation of MICB on the plasma membrane with no change of its mRNA levels, indicating a post-translational regulatory mechanism. Moreover, inhibition of neddylation can cooperate with immunomodulatory drugs (IMiDs) in upregulating MICA surface levels in MM cells due to increased expression of CRBN, the cellular target of these drugs. In summary, MLN4924/Pevonedistat sensitizes MM to NK cell recognition, adding novel information on the anticancer activity of neddylation inhibition.

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