51. Mutant B2M‐HLA‐E and B2M‐HLA‐G fusion proteins protects universal chimeric antigen receptor‐modified T cells from allogeneic NK cell‐mediated lysis
- Author
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Haoyi Wang, Zhiqiang Wu, Jian Bo, Yelei Guo, Chuan Tong, Weidong Han, Jin Wang, Yao Wang, Deyun Chen, and Beilei Xu
- Subjects
Cytotoxicity, Immunologic ,T-Lymphocytes ,Antigens, CD19 ,Immunology ,Receptors, Antigen, T-Cell ,Human leukocyte antigen ,Biology ,Lymphocyte Activation ,Jurkat cells ,Immunophenotyping ,Gene Knockout Techniques ,HLA-E ,Antigen ,HLA-G ,Humans ,Immunology and Allergy ,HLA-G Antigens ,Receptors, Chimeric Antigen ,Histocompatibility Antigens Class I ,T-cell receptor ,Fusion protein ,Molecular biology ,Chimeric antigen receptor ,Killer Cells, Natural ,Mutation ,beta 2-Microglobulin - Abstract
Recent studies have indicated the antitumor activity and reduced allogeneic response of universal chimeric antigen receptor-modified T (UCAR T) cells lacking endogenous T cell receptors and beta-2 microglobulin (B2M) generated using gene-editing technologies. However, these cells are vulnerable to lysis by allogeneic natural killer (NK) cells due to their lack of human leukocyte antigen (HLA) class I molecule expression. Here, constitutive expression of mutant B2M-HLA-E (mBE) and B2M-HLA-G (mBG) fusion proteins in anti-CD19 UCAR T (UCAR T-19) cells was conducted to protect against allogeneic NK cell-mediated lysis. The ability of cells expressing mBE or mBG to resist NK cell-mediated lysis was observed in gene-edited Jurkat CAR19 cells. UCAR T-19 cells constitutively expressing the mBE and mBG fusion proteins were manufactured and showed effective and specific anti-tumor activity. Constitutive expression of the mBE and mBG fusion proteins in UCAR T-19 cells prevented allogeneic NK cell-mediated lysis. In addition, these cells were not recognizable by allogeneic T cells. Additional experiments, including those in animal models and clinical trials, are required to evaluate the safety and efficacy of UCAR T-19 cells that constitutively express mBE and mBG.
- Published
- 2021
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