Cichocki et al. generated human iPSC-derived NK cells expressing a CD19-CAR containing the NKG2D, 2B4, and CD3ζ signaling domains, a high-affinity, non-cleavable CD16 shown to enhance therapeutic Ab-directed ADCC, and a membrane-bound IL-15/IL-15R fusion protein shown to boost general and CAR-directed NK cytolysis and in vivo persistence. These CAR NK cells had a propensity to kill malignant over healthy CD19+ cells and, unlike CD19-CAR T cells, in settings mimicking antigen escape, killed CD19+ and CD19- human B cell tumors. Their activity was enhanced by rituximab. In xenogeneic adoptive transfer models, these CAR NK cells eliminated CD19+ and CD19- lymphoma cells.
Contributed by Paula Hochman
ABSTRACT: Substantial numbers of B cell leukemia and lymphoma patients relapse due to antigen loss or heterogeneity after anti-CD19 chimeric antigen receptor (CAR) T cell therapy. To overcome antigen escape and address antigen heterogeneity, we engineered induced pluripotent stem cell (iPSC)-derived NK cells to express both an NK cell-optimized anti-CD19 CAR for direct targeting and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity (ADCC). In addition, we introduced a membrane-bound IL-15/IL-15R fusion (IL-15RF) protein to promote in vivo persistence. These engineered cells, termed iDuo NK cells, displayed robust CAR-mediated cytotoxic activity that could be further enhanced with therapeutic antibodies targeting B cell malignancies. In multiple in vitro and xenogeneic adoptive transfer models, iDuo NK cells exhibited robust anti-lymphoma activity. Furthermore, iDuo NK cells effectively eliminated both CD19+ and CD19- lymphoma cells and displayed a unique propensity for targeting malignant cells over healthy cells that expressed CD19, features not achievable with anti-CAR19 T cells. iDuo NK cells combined with therapeutic antibodies represents a promising approach to prevent relapse due to antigen loss and tumor heterogeneity in patients with B cell malignancies.