TY - JOUR
T1 - GMP-Compliant Universal Antigen Presenting Cells (uAPC) Promote the Metabolic Fitness and Antitumor Activity of Armored Cord Blood CAR-NK Cells
AU - Liu, Enli
AU - Ang, Sonny O.T.
AU - Kerbauy, Lucila
AU - Basar, Rafet
AU - Kaur, Indreshpal
AU - Kaplan, Mecit
AU - Li, Li
AU - Tong, Yijiu
AU - Daher, May
AU - Ensley, Emily L.
AU - Uprety, Nadima
AU - Nunez Cortes, Ana Karen
AU - Yang, Ryan Z.
AU - Li, Ye
AU - Shaim, Hila
AU - Reyes Silva, Francia
AU - Lin, Paul
AU - Mohanty, Vakul
AU - Acharya, Sunil
AU - Shanley, Mayra
AU - Muniz-Feliciano, Luis
AU - Banerjee, Pinaki P.
AU - Chen, Ken
AU - Champlin, Richard E.
AU - Shpall, Elizabeth J.
AU - Rezvani, Katayoun
N1 - Publisher Copyright:
© Copyright © 2021 Liu, Ang, Kerbauy, Basar, Kaur, Kaplan, Li, Tong, Daher, Ensley, Uprety, Nunez Cortes, Yang, Li, Shaim, Reyes Silva, Lin, Mohanty, Acharya, Shanley, Muniz-Feliciano, Banerjee, Chen, Champlin, Shpall and Rezvani.
PY - 2021/2/26
Y1 - 2021/2/26
N2 - 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.
AB - 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.
KW - K562 cells
KW - NK cell expansion
KW - adoptive cancer immunotherapy
KW - cell engineering
KW - universal antigen presenting cell
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UR - http://www.scopus.com/inward/citedby.url?scp=85102437123&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.626098
DO - 10.3389/fimmu.2021.626098
M3 - Article
C2 - 33717142
AN - SCOPUS:85102437123
SN - 1664-3224
VL - 12
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 626098
ER -