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Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
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Pluripotent stem cell-derived NK cells with high-affinity noncleavable CD16a mediate improved antitumor activity
Huang Zhu1, Robert H Blum1, Ryan Bjordahl2
1Department of Medicine, University of California, San Diego, La Jolla, CA.
Blood
|December 20, 2019
Summary
Engineered natural killer (NK) cells with a modified CD16a receptor (hnCD16-iNK) show enhanced antibody-dependent cellular cytotoxicity (ADCC) against tumors. These cells offer a promising off-the-shelf therapy for refractory hematologic malignancies and solid tumors.
Area of Science:
- Immunology
- Cell Biology
- Cancer Therapy
Background:
- Antibody-dependent cellular cytotoxicity (ADCC) is a crucial NK cell mechanism mediated by therapeutic monoclonal antibodies (mAbs).
- The Fc receptor CD16a on NK cells facilitates ADCC but is susceptible to cleavage by metalloprotease ADAM17 upon stimulation.
- Previous work showed a point mutation in CD16a prevents this cleavage.
Purpose of the Study:
- To engineer a noncleavable, high-affinity CD16a variant (hnCD16) into human induced pluripotent stem cells (iPSCs).
- To generate a renewable source of engineered NK cells (hnCD16-iNK) with enhanced ADCC properties.
- To evaluate the efficacy of hnCD16-iNK cells in preclinical cancer models.
Main Methods:
- Engineered human iPSCs to express a noncleavable, high-affinity CD16a variant (hnCD16).
- Generated hnCD16-iNK cells from these engineered iPSCs.
- Assessed CD16a cleavage resistance, functional maturity, and ADCC activity of hnCD16-iNK cells compared to unmodified iNK and peripheral blood-derived NK (PB-NK) cells.
- Evaluated in vivo efficacy in human B-cell lymphoma and ovarian cancer xenograft models using anti-CD20 and anti-HER2 mAbs, respectively.
Main Results:
- hnCD16-iNK cells demonstrated high resistance to activation-induced CD16a cleavage.
- These engineered NK cells were functionally mature and exhibited enhanced ADCC against various tumor targets.
- In vivo studies showed significantly improved B-cell lymphoma regression and enhanced survival in ovarian cancer models when treated with hnCD16-iNK cells and mAbs.
Conclusions:
- hnCD16-iNK cells represent a standardized, off-the-shelf engineered NK cell therapy with superior ADCC capabilities.
- This approach is effective against hematologic malignancies and solid tumors resistant to conventional NK cell therapies.
- Engineered hnCD16-iNK cells hold significant potential for treating refractory cancers.
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