Expanded NK cells from umbilical cord blood and adult peripheral blood combined with daratumumab are effective against tumor cells from multiple myeloma patients

Reina-Ortiz, Chantal; Constantinides, Michael G.; Fayd-Herbe-de-Maudave, Alexis; Présumey, Jessy; Hernandez, Javier; Cartron, Guillaume; Giraldos, David; Díez, Rosana; Izquierdo, Isabel; Azaceta, Gemma; Palomera, Luis; Marzo, Isabel; Naval, Javier; Anel, Alberto; Martín, Vicente

doi:10.1080/2162402x.2020.1853314

Cited by 30 publications

(45 citation statements)

References 53 publications

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“…This could increase cytotoxic lymphocyte-mediated tumor cell death. The PD-1/PD-L1 immune checkpoint is less relevant in NK-mediated killing and, additionally, we have observed that our eNK cells express low levels of PD-1 26 . Moreover, in MM samples pembrolizumab does not increase tumor killing by our eNK 26 .…”

Section: Discussionmentioning

confidence: 56%

“…We have developed a protocol to activate and expand umbilical cord blood (UCB)-derived NK cells in vitro 24 . These expanded NK (eNK) have high cytolytic activity against hematological cancer cells, even those resistant to chemotherapy 24 – 26 . We have investigated here if metformin sensitizes hematopoietic cells to CL and the possible mechanism(s) of action.…”

Section: Introductionmentioning

confidence: 99%

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Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1)

Allende-Vega

Marco-Brualla

Falvo

et al. 2022

Sci Rep

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Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The anti-diabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of anti-apoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1)

Allende-Vega

Marco-Brualla

Falvo

et al. 2022

Sci Rep

Self Cite

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“…However, we do not know if our results apply to naïve NK cells. eNK have a relatively high basal cytotoxicity compared to naïve NK cells and show a mature phenotype [24][25][26]. The more mature NK subsets, which possess higher cytotoxic potential, show the highest activation by LFA-1 [28].…”

Section: Discussionmentioning

confidence: 99%

“…We have developed a protocol to activate and expand umbilical cord blood (UCB)-derived NK cells in vitro [24]. These expanded NK (eNK) have high cytolytic activity against hematological cancer cells, even those resistant to chemotherapy [24][25][26]. We have investigated here if metformin sensitizes hematopoietic cells to CL and the possible mechanism(s) of action.…”

Section: Introductionmentioning

confidence: 99%

Metformin Sensitizes Leukemic Cells to Cytotoxic Lymphocytes by Increasing Expression of Intercellular Adhesion Molecule-1 (ICAM-1)

Allende-Vega¹,

Marco-Brualla²,

Falvo³

et al. 2021

Preprint

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Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The antidiabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of antiapoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.

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“…The presence of CD16a, the low-affinity receptor for IgG1 and IgG3, on the surface of NK-cells is crucial for ADCC-dependent cell killing by tumor-targeting mAbs [ 32 ]. Depending on the expansion and culture conditions, this CD16a expression can decrease, but the combined use of expanded NK-cells (from umbilical cord blood or peripheral blood) with daratumumab shows encouraging results in preclinical studies [ 33 , 34 ]. To avoid daratumumab-mediated fratricide, the CD38-gene can be deleted in expanded primary NK cells without affecting their in vivo persistence or the ADCC activity against MM cell lines and primary MM cells [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma

Lejeune

Duray

Peipp

et al. 2021

Cancers

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Multiple myeloma (MM) is an incurable cancer characterized by the proliferation and accumulation of monoclonal plasma cells in the bone marrow. The monoclonal anti-CD38 daratumumab has taken a central place in the different treatment regimens for newly diagnosed and relapsed, refractory myeloma. In this study, we correlated the NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and potential fratricide induced by daratumumab with CD38-expression levels on both effector and target cells. We show that CD38 expression can be modulated by adding all-trans retinoic acid (ATRA) or interferon-α to MM cells to further fine-tune these effects. In addition, we observed that ADCC becomes inefficient when fratricide occurs and both ADCC and fratricide depend on the balance between CD38 expression on effector and target cells. However, the addition of adjuvants (retinoic acid or interferon-α) to myeloma cells or the inhibition of fratricide using a CD38-blocking nanobody on NK-cells can reverse this balance towards ADCC and thus promote lysis of target cells by ADCC. ATRA and interferon-α increased the CD38 expression at the surface of MM cells about three-fold and two-fold, respectively. This increase was of interest for MM cells with low CD38 expression, that became susceptible to daratumumab-mediated ADCC after preincubation. A CD38-blocking nanobody prevented the binding of daratumumab to these NK-cells and blunted the fratricidal effect on effector NK cells. In conclusion, our study highlights the importance of a balanced CD38 expression on target and effector cells and attempts to alter this balance will affect the susceptibility of MM cells towards daratumumab-mediated ADCC.

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Expanded NK cells from umbilical cord blood and adult peripheral blood combined with daratumumab are effective against tumor cells from multiple myeloma patients

Cited by 30 publications

References 53 publications

Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1)

Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1)

Metformin Sensitizes Leukemic Cells to Cytotoxic Lymphocytes by Increasing Expression of Intercellular Adhesion Molecule-1 (ICAM-1)

Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma

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