Journal
FRONTIERS IN IMMUNOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.626098
Keywords
universal antigen presenting cell; cell engineering; K562 cells; adoptive cancer immunotherapy; NK cell expansion
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Funding
- Stand Up To Cancer [SU2C-AACR-DT29-19]
- CPRIT [RP160693]
- National Institute of Health, National Cancer Institute [1 R01 CA211044-01, 5 P01CA148600-03, P50CA100632-16]
- Cancer Center Support (CORE) grant - Flow Cytometry and Cellular Imaging Facility at MD Anderson Cancer Center [CA016672]
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Research has genetically engineered a universal antigen presenting cell (uAPC) to stimulate the expansion and enhance the effector function of NK cells, showing promising results for generating GMP-grade CAR NK cells for cancer immunotherapy.
Natural killer (NK) cells are innate lymphocytes recognized for their important role against tumor cells. NK cells expressing chimeric antigen receptors (CARs) have enhanced effector function against various type of cancer and are attractive contenders for the next generation of cancer immunotherapies. However, a number of factors have hindered the application of NK cells for cellular therapy, including their poor in vitro growth kinetics and relatively low starting percentages within the mononuclear cell fraction of peripheral blood or cord blood (CB). To overcome these limitations, we genetically-engineered human leukocyte antigen (HLA)-A(-) and HLA-B- K562 cells to enforce the expression of CD48, 4-1BBL, and membrane-bound IL-21 (mbIL21), creating a universal antigen presenting cell (uAPC) capable of stimulating their cognate receptors on NK cells. We have shown that uAPC can drive the expansion of both non-transduced (NT) and CAR-transduced CB derived NK cells by >900-fold in 2 weeks of co-culture with excellent purity (>99.9%) and without indications of senescence/exhaustion. We confirmed that uAPC-expanded research- and clinical-grade NT and CAR-transduced NK cells have higher metabolic fitness and display enhanced effector function against tumor targets compared to the corresponding cell fractions cultured without uAPCs. This novel approach allowed the expansion of highly pure GMP-grade CAR NK cells at optimal cell numbers to be used for adoptive CAR NK cell-based cancer immunotherapy.
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