Enhancing TRAIL-mediated killing of ErbB2-CAR-NK-92 (NK-92/5.28.z) with bortezomib

Treatment resistance of metastatic rhabdomyosarcoma (RMS) making the urgent medical need for this entity to a key issue in pediatric oncology. Immune-editing and the immunesuppressive microenvironment of solid tumors hamper chimeric antigen receptor (CAR) immunotherapies. This escape mechanism of metastatic RMS may be reversed by combining CAR-NK-92 cells (NK-92/5.28.z) with additional anticancer therapies. In this first assessment of its kind, the proteasome inhibitor bortezomib induced apoptosis in RMS cells. Furthermore, the surface expression of tumor necrosis factor related apoptosis inducing ligand (TRAIL) receptor DR5 was enhanced on RMS cells upon bortezomib treatment in a dose dependent manner. Combinational administration of bortezomib and NK-92/5.28.z showed an increased antitumor activity compared to single treatment. Cytotoxic assessment with purified TRAIL, to exclude other cell-mediated effects revealed synergism between bortezomib and TRAIL-mediated cytotoxicity in RMS cells. Thus, the combination of NK-92/5.28.z cell immunotherapy with bortezomib might be a powerful immunotherapy approach, that can be harnessed for clinical translation.