1. 3D-organoid culture supports differentiation of human CAR+ iPSCs into highly functional CAR T cells
- Author
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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, and Brown, Christine E
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Stem Cell Research - Induced Pluripotent Stem Cell ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Biotechnology ,Regenerative Medicine ,Stem Cell Research ,Vaccine Related ,Immunization ,Underpinning research ,Development of treatments and therapeutic interventions ,1.1 Normal biological development and functioning ,5.2 Cellular and gene therapies ,Animals ,Cell Differentiation ,Humans ,Immunotherapy ,Immunotherapy ,Adoptive ,Induced Pluripotent Stem Cells ,Mice ,Organoids ,Receptors ,Chimeric Antigen ,3D-organoid culture ,CAR ,PSC-ATO ,chimeric antigen receptor T cells ,human iPSC ,immunotherapy ,off-the-shelf ,pluripotent stem cell-artificial thymic organoid culture ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - 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.
- Published
- 2022