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• W4386317087 abstract "In the absence of cell surface cancer-specific antigens, immunotherapies such as chimeric antigen receptor (CAR) T cells, monoclonal antibodies, or bispecific T cell engagers typically target lineage antigens. Currently, such immunotherapies are individually designed and tested for each disease. This approach is inefficient and limited to a few lineage antigens for which the on-target/off-tumor toxicities are clinically tolerated. Here, we sought to develop a universal CAR T cell therapy for blood cancers directed against the pan-leukocyte marker CD45. To protect healthy hematopoietic cells, including CAR T cells, from CD45-directed on-target/off-tumor toxicity while preserving the essential functions of CD45, we mapped the epitope on CD45 that is targeted by the CAR and used CRISPR adenine base editing to install a function-preserving mutation sufficient to evade CAR T cell recognition. Epitope-edited CD45 CAR T cells were fratricide resistant and effective against patient-derived acute myeloid leukemia, B cell lymphoma, and acute T cell leukemia. Epitope-edited hematopoietic stem cells (HSCs) were protected from CAR T cells and, unlike CD45 knockout cells, could engraft, persist, and differentiate in vivo. Ex vivo epitope editing in HSCs and T cells enables the safe and effective use of CD45-directed CAR T cells and bispecific T cell engagers for the universal treatment of hematologic malignancies and might be exploited for other diseases requiring intensive hematopoietic ablation." @default.
• W4386317087 created "2023-09-01" @default.
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• W4386317087 date "2023-09-20" @default.
• W4386317087 modified "2023-10-14" @default.
• W4386317087 title "Epitope base editing CD45 in hematopoietic cells enables universal blood cancer immune therapy" @default.
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• W4386317087 doi "https://doi.org/10.1126/scitranslmed.adi1145" @default.
• W4386317087 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37651540" @default.
• W4386317087 hasPublicationYear "2023" @default.
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