Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy
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Chimeric antigen receptor‑engineered natural killer cells for cancer immunotherapy Ahmet Yilmaz1†, Hanwei Cui1†, Michael A. Caligiuri2,3,4,5† and Jianhua Yu2,3,4,5*†
Abstract Natural killer (NK) cells are a critical component of the innate immune system. Chimeric antigen receptors (CARs) redirect NK cells toward tumor cells carrying corresponding antigens, creating major opportunities in the fight against cancer. CAR NK cells have the potential for use as universal CAR cells without the need for human leukocyte antigen matching or prior exposure to tumor-associated antigens. Exciting data from recent clinical trials have renewed interest in the field of cancer immunotherapy due to the potential of CAR NK cells in the production of “off-the-shelf” anti-cancer immunotherapeutic products. Here, we provide an up-to-date comprehensive overview of the recent advancements in key areas of CAR NK cell research and identify under-investigated research areas. We summarize improvements in CAR design and structure, advantages and disadvantages of using CAR NK cells as an alternative to CAR T cell therapy, and list sources to obtain NK cells. In addition, we provide a list of tumor-associated antigens targeted by CAR NK cells and detail challenges in expanding and transducing NK cells for CAR production. We additionally discuss barriers to effective treatment and suggest solutions to improve CAR NK cell function, proliferation, persistence, therapeutic effectiveness, and safety in solid and liquid tumors. Keywords: Chimeric antigen receptor, Natural killer cells, T cells, Cancer immunotherapy Background Natural killer (NK) cells are large granular lymphocytes with surface markers CD3−CD56+NKp46+ in humans. They have been recognized as a subset of innate lymphoid cells (ILCs) that lack antigen receptors with recombination activating gene (RAG)-dependent rearrangement [1, 2]. There are three groups of ILCs (Groups 1–3), each with distinct functions and expression profiles of key transcription factors. NK cells are included in Group 1 ILCs, which also include innate lymphoid cell 1 (ILC1). Both NK cells and ILC1 depend on the transcription factor T-bet for their proper function and development, and secrete interferon-γ (IFN-γ) rather than type 2 cytokines (IL-5 and IL-13), IL-17, or IL-22 [3]. The development *Correspondence: [email protected] † All authors contributed equally to this work 2 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 1500 E. Duarte Road, KCRB, Bldg. 158, 3rd Floor, Room 3017, Los Angeles, CA 91010, USA Full list of author information is available at the end of the article
of NK cells involves bone marrow and extra-medullary sites such as tonsils, uterus, and liver [4–6]. The NK cell developmental process is initiated in the bone marrow microenvironment where hematopoietic stem cells differentiate into common lymphoid progenitors (CLPs) which can give rise to all subtypes of lymphoid cells. CLPs first develop into NK progenitor cells, an
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