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

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

doi:10.1016/j.xcrm.2021.100449

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

Cell Rep Med. 2021 Nov 16;2(11):100449. doi: 10.1016/j.xcrm.2021.100449.

Authors

Yan-Ruide Li¹, Yang Zhou¹, Yu Jeong Kim¹, Yanni Zhu¹, Feiyang Ma², Jiaji Yu¹, Yu-Chen Wang¹, Xianhui Chen³, Zhe Li¹, Samuel Zeng¹, Xi Wang¹, Derek Lee¹, Josh Ku¹, Tasha Tsao¹, Christian Hardoy¹, Jie Huang¹, Donghui Cheng⁴, Amélie Montel-Hagen⁵, Christopher S Seet^{4

6

7}, Gay M Crooks^{4

5

7

8}, Sarah M Larson⁹, Joshua P Sasine^{4

7

10}, Xiaoyan Wang⁶, Matteo Pellegrini^{2

4}, Antoni Ribas^{4

7

11

12}, Donald B Kohn^{1

4

10}, Owen Witte^{1

4

7

12

13}, Pin Wang³, Lili Yang^{1

4

7

13}

Affiliations

¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Internal Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹² Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹³ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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.

Keywords: CAR-engineered conventional αβ T cells; HLA-ablated universal HSC-iNKT cells; allogeneic HSC-engineered iNKT cells; allogeneic off-the-shelf cell therapy; allorejection; cancer immunotherapy; chimeric antigen receptor; graft-versus-host disease; hematopoietic stem cell; invariant natural killer T cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

HLA Antigens
Receptors, Chimeric Antigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding