| Autor: |
Wellhausen, Nils, O'Connell, Ryan P., Lesch, Stefanie, Engel, Nils W., Rennels, Austin K., Gonzales, Donna, Herbst, Friederike, Young, Regina M., Garcia, K. Christopher, Weiner, David, June, Carl H., Gill, Saar I. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 9/20/2023, Vol. 15 Issue 714, p1-15, 15p |
| Abstrakt: |
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. Editor's summary: The use of immunotherapies such as chimeric antigen receptor (CAR) T cells to treat blood cancers is limited by on-target/off-tumor toxicities and the need to be individually designed and tested. Here, Wellhausen and colleagues developed a CAR T cell targeting the pan-leukocyte marker CD45. To avoid on-target/off-tumor toxicities, they used epitope editing to insert a mutation in CD45 that resulted in avoidance of CAR T cell recognition but preserved CD45 function. Edited CD45-targeting CAR T cells were effective against patient-derived myeloid and lymphoid cancers. Insertion of the same mutation into hematopoietic stem cells (HSCs) ex vivo resulted in engraftment and survival in mice, allowing successful killing of hematologic malignancies with reconstitution of the hematopoietic system. This approach paves way for the treatment of most blood cancers. —Melissa Norton [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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