Anti-TIM3 chimeric antigen receptor-natural killer cells from engineered induced pluripotent stem cells effectively target acute myeloid leukemia cells

被引:6
|
作者
Klaihmon, Phatchanat [1 ]
Luanpitpong, Sudjit [1 ,2 ]
Kang, Xing [1 ]
Issaragrisil, Surapol [1 ,3 ,4 ]
机构
[1] Mahidol Univ, Siriraj Hosp, Fac Med, Siriraj Ctr Excellence Stem Cell Res, Bangkok, Thailand
[2] Mahidol Univ, Fac Med, Blood Prod & Cellular Immunotherapy Res Grp, Siriraj Hosp, Bangkok, Thailand
[3] Mahidol Univ, Fac Med, Siriraj Hosp 2, Dept Med,Siriraj Hosp,Div Hematol, Bangkok 10700, Thailand
[4] Wattanosoth Canc Hosp, BDMS Ctr Excellence Hematol, Bangkok, Thailand
关键词
Induced pluripotent stem cells; Natural killer cells; Chimeric antigen receptor; CAR; TIM3; Acute myelogenous leukemia; Immunotherapy; T-CELLS; TRANSPLANTATION; CANCER; TIM-3; EXPRESSION; HIERARCHY; EXPANSION;
D O I
10.1186/s12935-023-03153-9
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BackgroundAcute myeloid leukemia (AML) is a clonal malignant disorder which originates from a small number of leukemia-initiating cells or leukemic stem cells (LSCs)-the subpopulation that is also the root cause of relapsed/refractory AML. Chimeric antigen receptor (CAR)-T cell therapy has proved successful at combating certain hematologic malignancies, but has several hurdles that limit its widespread applications. CAR-natural killer (NK) cells do not carry the risk of inducing graft-versus-host disease (GvHD) frequently associated with allogeneic T cells, thereby overcoming time-consuming, autologous cell manufacturing, and have relatively safer clinical profiles than CAR-T cells. The present study aimed to generate anti-TIM3 CAR-NK cells targeting LSCs from a clonal master induced pluripotent stem cells engineered with the third-generation anti-TIM3 CAR.MethodsA clonal master umbilical cord blood NK-derived induced pluripotent stem cell (iPSC) line, MUSIi013-A, was used as a starting cells for engineering of an anti-TIM3 CAR harboring TIM3 scFv fragment (clone TSR-022), CD28, 4-1BB, and CD3 zeta signaling (CAR-TIM3). The established CAR-TIM3 iPSCs were further differentiated under serum- and feeder-free conditions into functional CAR-TIM3 NK cells and tested for its anti-tumor activity against various TIM3-positive AML cells.ResultsWe successfully established a single-cell clone of CAR-TIM3 iPSCs, as validated by genomic DNA sequencing as well as antibody and antigen-specific detection. We performed thorough iPSC characterization to confirm its retained pluripotency and differentiation capacity. The established CAR-TIM3 iPSCs can be differentiated into CAR-TIM3 NK-like cells, which were further proven to have enhanced anti-tumor activity against TIM3-positive AML cells with minimal effect on TIM3-negative cells when compared with wild-type (WT) NK-like cells from parental iPSCs.ConclusionsiPSCs engineered with CARs, including the established single-cell clone CAR-TIM3 iPSCs herein, are potential alternative cell source for generating off-the-shelf CAR-NK cells as well as other CAR-immune cells. The feasibility of differentiation of functional CAR-TIM3 NK cells under serum- and feeder-free conditions support that Good Manufacturing Practice (GMP)-compliant protocols can be further established for future clinical applications.
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页数:16
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