Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy.

Abstract

Cell-based immunotherapy has become the new-generation cancer medicine, and "off-the-shelf" cell products that can be manufactured at large scale and distributed readily to treat patients are necessary. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing allogeneic cell therapy because they are powerful immune cells targeting cancers without graft-versus-host disease (GvHD) risk. However, healthy donor blood contains extremely low numbers of endogenous iNKT cells. Here, by combining hematopoietic stem cell (HSC) gene engineering and in vitro differentiation, we generate human allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells at high yield and purity; these cells closely resemble endogenous iNKT cells, effectively target tumor cells using multiple mechanisms, and exhibit high safety and low immunogenicity. These cells can be further engineered with chimeric antigen receptor (CAR) to enhance tumor targeting or/and gene edited to ablate surface human leukocyte antigen (HLA) molecules and further reduce immunogenicity. Collectively, these preclinical studies demonstrate the feasibility and cancer therapy potential of AlloHSC-iNKT cell products and lay a foundation for their translational and clinical development.

• Authors: Yan-Ruide Li, Yang Zhou, Yu Jeong Kim, Yanni Zhu, Feiyang Ma, Jiaji Yu, Yu-Chen Wang, Xianhui Chen, Zhe Li, Samuel Zeng, Xi Wang, Derek Lee, Josh Ku, Tasha Tsao, Christian Hardoy, Jie Huang, Donghui Cheng, Amélie Montel-Hagen, Christopher S Seet, Gay M Crooks, Sarah M Larson, Joshua P Sasine, Xiaoyan Wang, Matteo Pellegrini, Antoni Ribas, Donald B Kohn, Owen Witte, Pin Wang, Lili Yang
• Journal: Cell reports. Medicine (Cell Rep Med) Vol. 2 Issue 11 Pg. 100449 (11 16 2021) ISSN: 2666-3791 [Electronic] United States
• PMID: 34841295 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors.

Chemical References

• HLA Antigens
• Receptors, Chimeric Antigen

Topics

• Allogeneic Cells (immunology, metabolism)
• Animals
• Cell Engineering
• Cell Line, Tumor
• Gene Expression Profiling
• HLA Antigens (metabolism)
• Hematopoietic Stem Cells (immunology, metabolism)
• Humans
• Immunotherapy
• Mice, Inbred NOD
• Mice, SCID
• Natural Killer T-Cells (immunology, metabolism)
• Neoplasms (immunology, therapy)
• Phenotype
• Receptors, Chimeric Antigen (metabolism)
• Transcriptome (genetics)