Development of Hematopoietic Stem Cell-Engineered Invariant Natural Killer T Cell Therapy for Cancer

Yanni Zhu; Drake J Smith; Yang Zhou; Yan-Ruide Li; Jiaji Yu; Derek Lee; Yu-Chen Wang; Stefano Di Biase; Xi Wang; Christian Hardoy; Josh Ku; Tasha Tsao; Levina J Lin; Alexander T Pham; Heesung Moon; Jami McLaughlin; Donghui Cheng; Roger P Hollis; Beatriz Campo-Fernandez; Fabrizia Urbinati; Liu Wei; Larry Pang; Valerie Rezek; Beata Berent-Maoz; Mignonette H Macabali; David Gjertson; Xiaoyan Wang; Zoran Galic; Scott G Kitchen; Dong Sung An; Siwen Hu-Lieskovan; Paula J Kaplan-Lefko; Satiro N De Oliveira; Christopher S Seet; Sarah M Larson; Stephen J Forman; James R Heath; Jerome A Zack; Gay M Crooks; Caius G Radu; Antoni Ribas; Donald B Kohn; Owen N Witte; Lili Yang

doi:10.1016/j.stem.2019.08.004

Development of Hematopoietic Stem Cell-Engineered Invariant Natural Killer T Cell Therapy for Cancer

Cell Stem Cell. 2019 Oct 3;25(4):542-557.e9. doi: 10.1016/j.stem.2019.08.004. Epub 2019 Sep 5.

Authors

Yanni Zhu¹, Drake J Smith¹, Yang Zhou¹, Yan-Ruide Li¹, Jiaji Yu¹, Derek Lee¹, Yu-Chen Wang¹, Stefano Di Biase¹, Xi Wang¹, Christian Hardoy¹, Josh Ku¹, Tasha Tsao¹, Levina J Lin¹, Alexander T Pham¹, Heesung Moon¹, Jami McLaughlin¹, Donghui Cheng¹, Roger P Hollis¹, Beatriz Campo-Fernandez¹, Fabrizia Urbinati¹, Liu Wei², Larry Pang², Valerie Rezek³, Beata Berent-Maoz⁴, Mignonette H Macabali⁴, David Gjertson⁵, Xiaoyan Wang⁴, Zoran Galic³, Scott G Kitchen³, Dong Sung An⁶, Siwen Hu-Lieskovan⁴, Paula J Kaplan-Lefko⁷, Satiro N De Oliveira⁸, Christopher S Seet³, Sarah M Larson⁹, Stephen J Forman¹⁰, James R Heath¹¹, Jerome A Zack¹², Gay M Crooks¹³, Caius G Radu¹⁴, Antoni Ribas¹⁵, Donald B Kohn¹⁶, Owen N Witte¹⁷, Lili Yang¹⁸

Affiliations

¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Medicine, 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; Department of Biostatistics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA; AIDS Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; 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 Hematological Malignancies and Hematopoietic Stem Cell Transplantation Institute, City of Hope, Duarte, CA 91010, USA.
¹¹ Institute for Systems Biology, Seattle, WA 98109, USA.
¹² Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹³ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁴ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁵ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁶ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁷ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁸ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: liliyang@ucla.edu.

Abstract

Invariant natural killer T (iNKT) cells are potent immune cells for targeting cancer; however, their clinical application has been hindered by their low numbers in cancer patients. Here, we developed a proof-of-concept for hematopoietic stem cell-engineered iNKT (HSC-iNKT) cell therapy with the potential to provide therapeutic levels of iNKT cells for a patient's lifetime. Using a human HSC engrafted mouse model and a human iNKT TCR gene engineering approach, we demonstrated the efficient and long-term generation of HSC-iNKT cells in vivo. These HSC-iNKT cells closely resembled endogenous human iNKT cells, could deploy multiple mechanisms to attack tumor cells, and effectively suppressed tumor growth in vivo in multiple human tumor xenograft mouse models. Preclinical safety studies showed no toxicity or tumorigenicity of the HSC-iNKT cell therapy. Collectively, these results demonstrated the feasibility, safety, and cancer therapy potential of the proposed HSC-iNKT cell therapy and laid a foundation for future clinical development.

Keywords: HSC; HSC transfer; HSCT; T cell receptor; TCR; cancer immunotherapy; cell therapy; gene therapy; hematopoietic stem cell; iNKT; invariant natural killer T cell; preclinical development; sr39TK suicide gene; stem cell therapy.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cells, Cultured
Genetic Engineering
Hematopoietic Stem Cells / physiology*
Humans
Immunotherapy, Adoptive / methods*
Mice
Mice, SCID
Natural Killer T-Cells / physiology*
Natural Killer T-Cells / transplantation
Neoplasms / immunology
Neoplasms / therapy*
Receptors, Antigen, T-Cell / genetics
Xenograft Model Antitumor Assays

Substances

Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding