1. Precision off-the-shelf natural killer cell therapies for oncology with logic-gated gene circuits.
- Author
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Frankel NW, Deng H, Yucel G, Gainer M, Leemans N, Lam A, Li Y, Hung M, Lee D, Lee CT, Banicki A, Tian M, Almudhfar N, Naitmazi L, Roguev A, Lee S, Wong W, Gordley R, Lu TK, and Garrison BS
- Subjects
- Humans, Animals, Mice, Receptors, Chimeric Antigen metabolism, Receptors, Chimeric Antigen immunology, Gene Regulatory Networks, Hematopoietic Stem Cells metabolism, Cell Line, Tumor, Precision Medicine methods, Cell- and Tissue-Based Therapy methods, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute immunology
- Abstract
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 is challenging because no single tumor-associated antigen (TAA) is highly expressed on all cancer subpopulations. Furthermore, TAAs are also expressed on healthy cells, leading to toxicity risk. To address these targeting challenges, we engineer natural killer (NK) cells with a multi-input gene circuit consisting of chimeric antigen receptors (CARs) controlled by OR and NOT logic gates. The OR gate kills a range of AML cells from leukemic stem cells to blasts using a bivalent CAR targeting FLT3 and/or CD33. The NOT gate protects healthy hematopoietic stem cells (HSCs) using an inhibitory CAR targeting endomucin, a protective antigen unique to healthy HSCs. NK cells with the combined OR-NOT gene circuit kill multiple AML subtypes and protect primary HSCs, and the circuit also works in vivo., Competing Interests: Declaration of interests N.W.F., H.D., G.Y., M.G., N.L., A.L., Y.L., M.H., D.L., C.-T.L., A.B., M.T., N.A., L.N., A.R., R.G., B.G., and T.K.L. are either current or former employees of Senti Biosciences, Inc., of which T.K.L. is also CEO and co-founder., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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