Dual antigen–targeted off-the-shelf NK cells show durable response and prevent antigen escape in lymphoma and leukemia
Frank Cichocki, Jodie P. Goodridge, Ryan Bjordahl, Sajid Mahmood, Zachary Davis, Svetlana Gaidarova, Ramzey Abujarour, Brian Groff, Alec Witty, Hongbo Wang, Katie Tuininga, Behiye Kodal, Martin Felices, Greg Bonello, Janel Huffman, Thomas Dailey, Tom T. Lee, Bruce Walcheck, Bahram Valamehr, Jeffrey S. Miller
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-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. In addition, we introduced a membrane-bound IL-15/IL-15R fusion 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 represent a promising approach to prevent relapse due to antigen loss and tumor heterogeneity in patients with B cell malignancies.