학술논문
3D-organoid culture supports differentiation of human CAR+ iPSCs into highly functional CAR T cells
Document Type
article
Author
Wang, Zhiqiang; McWilliams-Koeppen, Helen P; Reza, Hernan; Ostberg, Julie R; Chen, Wuyang; Wang, Xiuli; Huynh, Christian; Vyas, Vibhuti; Chang, Wen-Chung; Starr, Renate; Wagner, Jamie R; Aguilar, Brenda; Yang, Xin; Wu, Xiwei; Wang, Jinhui; Chen, Wei; Koelker-Wolfe, Ellery; Seet, Christopher S; Montel-Hagen, Amélie; Crooks, Gay M; Forman, Stephen J; Brown, Christine E
Source
Cell Stem Cell. 29(4)
Subject
Language
Abstract
Unlimited generation of chimeric antigen receptor (CAR) T cells from human-induced pluripotent stem cells (iPSCs) is an attractive approach for "off-the-shelf" CAR T cell immunotherapy. Approaches to efficiently differentiate iPSCs into canonical αβ T cell lineages, while maintaining CAR expression and functionality, however, have been challenging. We report that iPSCs reprogramed from CD62L+ naive and memory T cells followed by CD19-CAR engineering and 3D-organoid system differentiation confers products with conventional CD8αβ-positive CAR T cell characteristics. Expanded iPSC CD19-CAR T cells showed comparable antigen-specific activation, degranulation, cytotoxicity, and cytokine secretion compared with conventional CD19-CAR T cells and maintained homogeneous expression of the TCR derived from the initial clone. iPSC CD19-CAR T cells also mediated potent antitumor activity in vivo, prolonging survival of mice with CD19+ human tumor xenografts. Our study establishes feasible methodologies to generate highly functional CAR T cells from iPSCs to support the development of "off-the-shelf" manufacturing strategies.