Open AccessThe CD38low natural killer cell line KHYG1 transiently expressing CD16F158V in combination with daratumumab targets multiple myeloma cells with minimal effector NK cell fratricide
Author(s) -
Subhashis Sarkar,
Sachin Kumar Singh Chauhan,
J.M. Daly,
Alessandro Natoni,
Heather Fairfield,
Robert B. Henderson,
Emma Nolan,
Dawn Swan,
Jinsong Hu,
Michaela R. Reagan,
Michael O’Dwyer
Publication year - 2020
Publication title -
cancer immunology, immunotherapy/cancer immunology and immunotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.389
H-Index - 115
eISSN - 1432-0851
pISSN - 0340-7004
DOI - 10.1007/s00262-019-02477-8
Subject(s) - daratumumab , antibody dependent cell mediated cytotoxicity , nk 92 , immunology , cd16 , cancer research , lymphokine activated killer cell , cytotoxic t cell , biology , interleukin 21 , cd38 , population , ex vivo , natural killer cell , monoclonal antibody , antibody , immune system , medicine , t cell , in vivo , cd8 , cd34 , microbiology and biotechnology , stem cell , in vitro , cd3 , environmental health , biochemistry
Multiple myeloma (MM) is a clonal plasma cell malignancy typically associated with the high and uniform expression of the CD38 transmembrane glycoprotein. Daratumumab is a humanized IgG1κ CD38 monoclonal antibody (MoAb) which has demonstrated impressive single agent activity even in relapsed refractory MM patients as well as strong synergy with other anti-MM drugs. Natural Killer (NK) cells are cytotoxic immune effector cells that mediate in vivo tumour immunosurveillance. NK cells also play an important role during MoAb therapy by inducing antibody dependent cellular cytotoxicity (ADCC) via their FcγRIII (CD16) receptor. Furthermore, 15% of the population express a naturally occurring variant of CD16 harbouring a single-point polymorphism (F158V). However, the contribution of NK cells to the efficacy of daratumumab remains debatable as clinical data clearly indicate the rapid depletion of CD38 high peripheral blood NK cells in patients upon daratumumab administration. In contrast, CD38 low peripheral blood NK cells have been shown to survive daratumumab mediated fratricide in vivo, while still retaining their potent anti-MM cytolytic effector functions ex vivo. Therefore, we hypothesize that transiently expressing the CD16 F158V receptor using a "safe" mRNA electroporation-based approach on CD38 low NK cells in combination with daratumumab could represent a novel therapeutic option for treatment of MM. In the present study, we investigate a NK cell line (KHYG-1), derived from a patient with aggressive NK cell leukemia, as a platform for generating CD38 low NK cells expressing CD16 F158V which can be administered as an "off-the-shelf" therapy to target both CD38 high and CD38 low tumour clones in patients receiving daratumumab.