Epitope base editing CD45 in hematopoietic cells enables universal blood cancer immune therapy

Author:

Wellhausen Nils1ORCID,O’Connell Ryan P.2ORCID,Lesch Stefanie1ORCID,Engel Nils W.1ORCID,Rennels Austin K.1ORCID,Gonzales Donna1ORCID,Herbst Friederike1ORCID,Young Regina M.1ORCID,Garcia K. Christopher34ORCID,Weiner David2ORCID,June Carl H.156ORCID,Gill Saar I.17ORCID

Affiliation:

1. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

2. Vaccine and Immunotherapy Center, Wistar Institute, Philadelphia, PA 19104, USA.

3. Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

4. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.

5. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

6. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.

7. Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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