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

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Publication Year:
2019
Authors:
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
PubMed ID:
31495780
Funding Grants:
Public Summary:
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.
Scientific 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.