Engineering CAR-expressing natural killer cells with cytokine signaling and synthetic switch for an off-the-shelf cell-b
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Synthetic Biology Research Letter
Engineering CAR-expressing natural killer cells with cytokine signaling and synthetic switch for an off-the-shelf cell-based cancer immunotherapy Yun Qu*, Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA Elizabeth Siegler*, Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA Chumeng Cheng, Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA Jiangyue Liu, Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA 90089, USA Gunce Cinay, and Neelesh Bagrodia, Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA Pin Wang , Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA Address all correspondence to Pin Wang at [email protected] (Received 29 November 2018; accepted 28 February 2019)
Abstract Immune cells can be genetically engineered with a synthetic chimeric antigen receptor (CAR) to eliminate cancer cells, but clinical efficacy in solid tumors has been disappointing due in part to the immunosuppressive tumor microenvironment (TME). Additionally, the cost and logistical issues of personalized medicine necessitate the creation of an off-the-shelf CAR therapy. Synthetic biology tools were implemented in addressing these problems: an anti-mesothelin CAR, membrane-bound IL-15/IL-15Rα complex, and inducible caspase 9 “kill switch” were expressed in natural killer cells for tumor-targeting capabilities, immunostimulatory effects, and safety in treating a preclinical model of ovarian cancer with a renewable, allogenic cell therapy.
Introduction Synthetic biology initially focused on the use of molecular biology tools to engineer bacterial hosts, but has also made considerable progress in the engineering of mammalian cells with potential therapeutic applications.[1,2] The strategies of synthetic biology have been used to engineer immune cells to treat cancer using chimeric antigen receptors (CARs). CARs are synthetic receptors that can improve the cancer-targeting capabilities of immune cells by equipping them to recognize tumor-associated antigens. CAR-engineered autologous T cells have shown remarkable success in treating hematologic malignancies, but have had disappointing clinical results in targeting solid tumor due to the immunosuppressive tumor microenvironment (TME). Additionally, CARs targeting tumor-associated antigens that are also expressed on normal tissue may result in “on-target, off-tumor” toxicity and have caused significant safety concerns.[3] These unresolved issues of CAR-related treatments necessitate better CAR design. A number of tools and approaches can program the therapeutic CAR-modified immu
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