Precision off-the-shelf natural killer cell therapies for oncology with logic-gated gene circuits

• DOI: 10.1016/j.celrep.2024.114145
• Publication Date: 2024-04-25T17:56:10Z
• Authors: Nicholas W. Frankel; Han Deng; Gozde Yucel; Marcus Gainer; Nelia Leemans; Alice Lam; Yongshuai Li; Michelle Hung; Derrick Lee; Chen-Ting Lee; Andrew Banicki; Mengxi Tian; Niran Almudhfar; Lawrence Naitmazi; Assen Roguev; Seunghee Lee; Wilson Wong; Russell Gordley; Timothy K. Lu; Brian S. Garrison
• Keywords: 0301 basic medicine; Receptors, Chimeric Antigen; QH301-705.5; Cell- and Tissue-Based Therapy; CP: Immunology; Hematopoietic Stem Cells; Killer Cells, Natural; Leukemia, Myeloid, Acute; Mice; 03 medical and health sciences; Cell Line, Tumor; Humans; Animals; Gene Regulatory Networks; Biology (General); Precision Medicine; CP: Cancer

Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis (5-year survival rate of 30.5% in the United States). Designing cell therapies to target AML challenging because no single tumor-associated antigen (TAA) highly expressed on all cancer subpopulations. Furthermore, TAAs are also healthy cells, leading toxicity risk. To address these targeting challenges, we engineer natural killer (NK) cells multi-input gene circuit consisting chimeric receptors (CARs) controlled by OR and NOT logic gates. The gate kills range from leukemic stem blasts using bivalent CAR FLT3 and/or CD33. protects hematopoietic (HSCs) inhibitory endomucin, protective unique HSCs. NK combined OR-NOT kill multiple subtypes protect primary HSCs, works vivo.