Journal
ISCIENCE
Volume 25, Issue 9, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2022.104859
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Categories
Funding
- NIH
- Partnering Opportunity for Translational Research Projects Award
- California Institute for Regenerative Medicine [DP2 CA196335]
- Concern Foundation
- STOP CANCER Foundation [CIRM TRAN1-08 533, DISC2-11157]
- Rose Hills Research Foundation
- Ablon Scholars Award
- UCLA Whitcome Predoctoral Fellowship in Molecular Biology
- UCLA Medical Scientist Training Program Grant
- UCLA Tumor Immunology Training Grant
- UCLA Broad Stem Cell Research Center (BSCRC) [T32-GM008042]
- [T32-CA009120]
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Third-party HSC-engineered human iNKT cells, generated using a combination of HSC gene engineering and in vitro HSC differentiation, closely resemble endogenous human iNKT cells in phenotype and functionality. These cells display potent anti-GvHD functions without negatively impacting tumor eradication by allogeneic T cells, making them a promising off-the-shelf cell therapy candidate for GvHD prophylaxis.
Allo-HSCT is a curative therapy for hematologic malignancies owing to GvL effect mediated by alloreactive T cells; however, the same T cells also mediate GvHD, a severe side effect limiting the widespread application of allo-HSCT in clinics. Invariant natural killer T (iNKT) cells can ameliorate GvHD while preserving GvL effect, but the clinical application of these cells is restricted by their scarcity. Here, we report the successful generation of third-party HSC-engineered human iNKT ((HSC)-H-3rd-iNKT) cells using a method combining HSC gene engineering and in vitro HSC differentiation. The (HSC)-H-3rd-iNKT cells closely resembled the CD4(-)CD8(-/+) subsets of endogenous human iNKT cells in phenotype and functionality. These cells displayed potent anti-GvHD functions by eliminating antigen-presenting myeloid cells in vitro and in xenograft models without negatively impacting tumor eradication by allogeneic T cells in preclinical models of lymphoma and leukemia, supporting (HSC)-H-3rd-iNKT cells as a promising off-the-shelf cell therapy candidate for GvHD prophylaxis.
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