Contributions
Abstract: PB1542
Type: Publication Only
Session title: Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research
Background
Chimeric antigen receptors (CARs) are synthetic transmembrane receptors designed to target tumor-associated antigen to treat human malignancies. CARs have been used to redirect the specificity of T cells and NK cells against several hematologic cancers with notable clinical responses. Despite their antitumor activity, autologous CAR-modified T cells have many limitations including clinical safety and manufacturing difficulties. NK cells that have been engineered to express a CAR are candidate effectors for cancer treatment. Unlike T cells, allogeneic NK cells do not cause GvHD and can be safely administered without the need of full HLA matching based on previous clinical trials. This eliminates the need to produce a unique, patient-specific CAR product for each patient. A major advantage of NK cells is that they are naturally “off-the-shelf” and can be manufactured centrally so that product is available on-demand and ready-to-use.
Aims
iPSCs, with their ease to be genetically engineered, indefinite expansion capacity in vitro and feasibility to be differentiated into NK cells, are attractive starting cell resources to produce therapeutic NK products.
Methods
Extensive genetic modifications on iPSCs can be achieved by engineering a population of iPSCs, followed by single-cell-derived clone expansion and screening. The resulting iPSC clones carrying homogeneous genetic composition can be used as the MCB for downstream manufacturing.
Results
Here we report some characteristics of NK019 cells, a genetically engineered iPSC-derived NK cell therapy candidate. NK019 cells were differentiated from a modified human iPSC single-cell clone carrying 3 transgenes, including a Chimeric Antigen Receptor (CAR) targeting CD19, a modified CD16 and an IL15 molecule. The 3 transgenes maintain stable expression before and after differentiation from iPSC into NK cells. In addition, NK019 cells display typical NK cell characteristics, with CD19 target-specific cytotoxicity, enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and constitutively activated IL15 signaling. Furthermore, NK019 cells also show promising in vivo antitumor activity in a Raji NCG mouse model.
Here we report some characteristics of NK019 cells, a genetically engineered iPSC-derived NK cell therapy candidate. NK019 cells were differentiated from a modified human iPSC single-cell clone carrying 3 transgenes, including a Chimeric Antigen Receptor (CAR) targeting CD19, a modified CD16 and an IL15 molecule. The 3 transgenes maintain stable expression before and after differentiation from iPSC into NK cells. In addition, NK019 cells display typical NK cell characteristics, with CD19 target-specific cytotoxicity, enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and constitutively activated IL15 signaling. Furthermore, NK019 cells also show promising in vivo anti-tumor activity in a Raji NCG mouse model. In summary, we have engineered iPSC-derived NK cells as a promising clinical drug candidate for the treatment of B cell malignant lymphoma.
Conclusion
In summary, we have engineered iPSC-derived NK cells as a promising clinical drug candidate for the treatment of B cell malignant lymphoma.
Keyword(s): CD19, IL-15, NK cell, Stem cell
Abstract: PB1542
Type: Publication Only
Session title: Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research
Background
Chimeric antigen receptors (CARs) are synthetic transmembrane receptors designed to target tumor-associated antigen to treat human malignancies. CARs have been used to redirect the specificity of T cells and NK cells against several hematologic cancers with notable clinical responses. Despite their antitumor activity, autologous CAR-modified T cells have many limitations including clinical safety and manufacturing difficulties. NK cells that have been engineered to express a CAR are candidate effectors for cancer treatment. Unlike T cells, allogeneic NK cells do not cause GvHD and can be safely administered without the need of full HLA matching based on previous clinical trials. This eliminates the need to produce a unique, patient-specific CAR product for each patient. A major advantage of NK cells is that they are naturally “off-the-shelf” and can be manufactured centrally so that product is available on-demand and ready-to-use.
Aims
iPSCs, with their ease to be genetically engineered, indefinite expansion capacity in vitro and feasibility to be differentiated into NK cells, are attractive starting cell resources to produce therapeutic NK products.
Methods
Extensive genetic modifications on iPSCs can be achieved by engineering a population of iPSCs, followed by single-cell-derived clone expansion and screening. The resulting iPSC clones carrying homogeneous genetic composition can be used as the MCB for downstream manufacturing.
Results
Here we report some characteristics of NK019 cells, a genetically engineered iPSC-derived NK cell therapy candidate. NK019 cells were differentiated from a modified human iPSC single-cell clone carrying 3 transgenes, including a Chimeric Antigen Receptor (CAR) targeting CD19, a modified CD16 and an IL15 molecule. The 3 transgenes maintain stable expression before and after differentiation from iPSC into NK cells. In addition, NK019 cells display typical NK cell characteristics, with CD19 target-specific cytotoxicity, enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and constitutively activated IL15 signaling. Furthermore, NK019 cells also show promising in vivo antitumor activity in a Raji NCG mouse model.
Here we report some characteristics of NK019 cells, a genetically engineered iPSC-derived NK cell therapy candidate. NK019 cells were differentiated from a modified human iPSC single-cell clone carrying 3 transgenes, including a Chimeric Antigen Receptor (CAR) targeting CD19, a modified CD16 and an IL15 molecule. The 3 transgenes maintain stable expression before and after differentiation from iPSC into NK cells. In addition, NK019 cells display typical NK cell characteristics, with CD19 target-specific cytotoxicity, enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and constitutively activated IL15 signaling. Furthermore, NK019 cells also show promising in vivo anti-tumor activity in a Raji NCG mouse model. In summary, we have engineered iPSC-derived NK cells as a promising clinical drug candidate for the treatment of B cell malignant lymphoma.
Conclusion
In summary, we have engineered iPSC-derived NK cells as a promising clinical drug candidate for the treatment of B cell malignant lymphoma.
Keyword(s): CD19, IL-15, NK cell, Stem cell