Cellular immunotherapy is becoming a new pillar in cancer treatment after recent striking results in different clinical trials with chimeric antigen receptor T cells. However, this innovative therapy is not exempt from challenges such as off-tumor toxicity, tumor recurrence in heterogeneous tumors, and affordability. To surpass these limitations, we exploit the unique anti-tumor characteristics of natural killer (NK) cells. In this study, we aimed to obtain a clinically relevant number of allogeneic NK cells derived from peripheral blood (median of 14,050 million cells from a single donor) to target a broad spectrum of solid and liquid tumor types. To boost their anti-tumor activity, we combined allogeneic NK cells with the approved anti-cluster of differentiation 38 (CD-38) monoclonal antibody Daratumumab to obtain a synergistic therapeutic effect against incurable multiple myeloma. The combination therapy was refined with CD16 polymorphism donor selection and uncomplicated novel in vitro pretreatment to avoid undesired fratricide, increasing the in vitro therapeutic effect against the CD-38 positive multiple myeloma cell line by more than 20%. Time-lapse imaging of mice with established human multiple myeloma xenografts revealed that combination therapy of selected and pretreated NK cells with Daratumumab presented tumor volumes 43-fold smaller than control ones. Combination therapy with an allogeneic source of fully functional NK cells could be beneficial in future clinical settings to circumvent monoclonal antibodies' low therapeutic efficiency due to NK cell dysfunctionality in MM patients.

Center for Translational Research and Molecular Biology of Cancer Maria Sklodowska Curie National Research Institute of Oncology Gliwice Branch 44 102 Gliwice Poland

Department of Bone Marrow Transplantation and Onco Hematology Maria Sklodowska Curie National Research Institute of Oncology Gliwice Branch 44 102 Gliwice Poland

Department of Haematooncology University Hospital Ostrava 708 00 Ostrava Czech Republic

Faculty of Medicine University of Ostrava 703 00 Ostrava Czech Republic

Faculty of Science University of Ostrava 701 00 Ostrava Czech Republic

PrimeCell Advanced Therapy Inc 708 52 Ostrava Czech Republic

Spadia LAB a s Frenštát pod Radhoštěm 700 30 Ostrava Czech Republic

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NK92 Expressing Anti-BCMA CAR and Secreted TRAIL for the Treatment of Multiple Myeloma: Preliminary In Vitro Assessment

Novel Local "Off-the-Shelf" Immunotherapy for the Treatment of Myeloma Bone Disease