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.
Author Info: (1) University of Minnesota, Minneapolis, Minnesota, United States. (2) Fate Therapeutics, United States. (3) Fate Therapeutics, Inc, San Diego, California, United States. (4) Fate
Author Info: (1) University of Minnesota, Minneapolis, Minnesota, United States. (2) Fate Therapeutics, United States. (3) Fate Therapeutics, Inc, San Diego, California, United States. (4) Fate Therapeutics, San Diego, California, United States. (5) University of Minnesota, Minneapolis, Minnesota, United States. (6) Fate Therapeutics, San Diego, California, United States. (7) Fate Therapeutics, Inc, San Diego, California, United States. (8) Fate Therapeutics, Inc, San Diego, California, United States. (9) Fate Therapeutics, Inc, San Diego, California, United States. (10) University of Minnesota, Minneapolis, Minnesota, United States. (11) University of Minnesota, Minneapolis, Minnesota, United States. (12) University of Minnesota. (13) University of Minnesota, Minneapolis, Minnesota, United States. (14) Fate Therapeutics, San Diego, California, United States. (15) Fate Therapeutics, Inc, San Diego, California, United States. (16) Fate Therapeutics, Inc, San Diego, California, United States. (17) Fate Therapeutics, San Diego, California, United States. (18) University of Minnesota, St. Paul, Minnesota, United States. (19) Fate Therapeutics, San Diego, California, United States. (20) U of MN, Minneapolis, Minnesota, United States.
