Theranostics 2018; 8(14):3856-3869. doi:10.7150/thno.25149

Research Paper

Expansion of allogeneic NK cells with efficient antibody-dependent cell cytotoxicity against multiple tumors

Diego Sanchez-Martinez1,#, Nerea Allende-Vega1,2,#, Stefania Orecchioni3, Giovanna Talarico3, Amelie Cornillon1, Dang-Nghiem Vo1, Celine Rene1, Zhao-Yang Lu1, Ewelina Krzywinska1, Alberto Anel4, Eva M. Galvez5, Julian Pardo4, Bruno Robert6, Pierre Martineau6, Yosr Hicheri7, Francesco Bertolini3, Guillaume Cartron7, Martin Villalba1,2,✉

1. IRMB, Univ Montpellier, INSERM, CHU Montpellier, Montpellier, France.
2. IRMB, CHU Montpellier, France.
3. Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
4. University of Zaragoza/Institute of Health Research of Aragón (IIS-Aragón), Spain.
5. Instituto de Carboquimica, Consejo Superior de Investigaciones Científicas (CSIC).
6. IRCM, INSERM U1194, Univ Montpellier, France.
7. Département d'Hématologie Clinique, CHU Montpellier, Univ Montpellier, France.
# These two authors have equally contributed to this manuscript

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Sanchez-Martinez D, Allende-Vega N, Orecchioni S, Talarico G, Cornillon A, Vo DN, Rene C, Lu ZY, Krzywinska E, Anel A, Galvez EM, Pardo J, Robert B, Martineau P, Hicheri Y, Bertolini F, Cartron G, Villalba M. Expansion of allogeneic NK cells with efficient antibody-dependent cell cytotoxicity against multiple tumors. Theranostics 2018; 8(14):3856-3869. doi:10.7150/thno.25149. Available from

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Monoclonal antibodies (mAbs) have significantly improved the treatment of certain cancers. However, in general mAbs alone have limited therapeutic activity. One of their main mechanisms of action is to induce antibody-dependent cell-mediated cytotoxicity (ADCC), which is mediated by natural killer (NK) cells. Unfortunately, most cancer patients have severe immune dysfunctions affecting NK activity. This can be circumvented by the injection of allogeneic, expanded NK cells, which is safe. Nevertheless, despite their strong cytolytic potential against different tumors, clinical results have been poor.

Methods: We combined allogeneic NK cells and mAbs to improve cancer treatment. We generated expanded NK cells (e-NK) with strong in vitro and in vivo ADCC responses against different tumors and using different therapeutic mAbs, namely rituximab, obinutuzumab, daratumumab, cetuximab and trastuzumab.

Results: Remarkably, e-NK cells can be stored frozen and, after thawing, armed with mAbs. They mediate ADCC through degranulation-dependent and -independent mechanisms. Furthermore, they overcome certain anti-apoptotic mechanisms found in leukemic cells.

Conclusion: We have established a new protocol for activation/expansion of NK cells with high ADCC activity. The use of mAbs in combination with e-NK cells could potentially improve cancer treatment.

Keywords: NK cells, monoclonal antibodies (mAbs), antibody-dependent cell cytotoxicity (ADCC), cancer