Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method

Author:

Li Yan-Ruide,Zhou Yang,Yu Jiaji,Kim Yu Jeong,Li Miao,Lee Derek,Zhou Kuangyi,Chen YuningORCID,Zhu Yichen,Wang Yu-Chen,Li Zhe,Yu Yanqi,Dunn Zachary Spencer,Guo WenbinORCID,Cen Xinjian,Husman TiffanyORCID,Bajpai Aarushi,Kramer AdamORCID,Wilson Matthew,Fang Ying,Huang Jie,Li Shuo,Zhou Yonggang,Zhang Yuchong,Hahn Zoe,Zhu EnboORCID,Ma FeiyangORCID,Pan CalvinORCID,Lusis Aldons J.ORCID,Zhou Jin J.,Seet Christopher S.ORCID,Kohn Donald B.ORCID,Wang PinORCID,Zhou Xianghong Jasmine,Pellegrini MatteoORCID,Puliafito Benjamin R.,Larson Sarah M.,Yang LiliORCID

Abstract

AbstractCancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using ‘off-the-shelf’ products, such as allogeneic CAR natural killer T (AlloCAR-NKT) cells. Previously, we reported a system for differentiating human hematopoietic stem and progenitor cells into AlloCAR-NKT cells, but the use of three-dimensional culture and xenogeneic feeders precluded its clinical application. Here we describe a clinically guided method to differentiate and expand IL-15-enhanced AlloCAR-NKT cells with high yield and purity. We generated AlloCAR-NKT cells targeting seven cancers and, in a multiple myeloma model, demonstrated their antitumor efficacy, expansion and persistence. The cells also selectively depleted immunosuppressive cells in the tumor microenviroment and antagonized tumor immune evasion via triple targeting of CAR, TCR and NK receptors. They exhibited a stable hypoimmunogenic phenotype associated with epigenetic and signaling regulation and did not induce detectable graft versus host disease or cytokine release syndrome. These properties of AlloCAR-NKT cells support their potential for clinical translation.

Funder

California Institute for Regenerative Medicine

UC | University of California, Los Angeles

Department of Defense CDMRP PRCRP Impact Award

Publisher

Springer Science and Business Media LLC

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