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Epitope-engineered human hematopoietic stem cells are shielded from CD123-targeted immunotherapy
Romina Marone1,2, Emmanuelle Landmann1,2, Anna Devaux1,2
1Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland.
The Journal of Experimental Medicine
|September 29, 2023
Summary
Researchers developed a method to protect healthy stem cells from targeted immunotherapy, enabling effective treatment for myeloid malignancies like acute myeloid leukemia (AML) while preserving normal blood cell function.
Area of Science:
- Immunology
- Hematology
- Gene Editing
Background:
- Targeted immunotherapies like monoclonal antibodies (mAb) and chimeric antigen receptor (CAR) cells are effective for B cell malignancies.
- Myeloid malignancies, including acute myeloid leukemia (AML), lack suitable targets due to shared antigen expression on healthy cells.
- CD123 is a promising target for AML but is also present on healthy hematopoietic stem and progenitor cells (HSPCs), risking myelotoxicity.
Purpose of the Study:
- To develop a strategy for selective targeting of CD123-expressing myeloid malignancies.
- To protect healthy HSPCs from potential damage during CD123-targeted immunotherapy.
- To enable effective immunotherapy for AML while maintaining a functional hematopoietic system.
Main Methods:
- Utilized epitope engineering to shield CD123 on HSPCs from targeted immunotherapy.
- Employed genome editing techniques to modify HSPCs.
- Performed transplantation studies with engineered HSPCs.
Main Results:
- Epitope-engineered HSPCs remained functional and were protected from CD123-targeted immunotherapy.
- CD123-deficient HSPCs showed a competitive disadvantage.
- Genome-edited HSPCs facilitated tumor-selective immunotherapy and reconstitution of a functional hematopoietic system.
Conclusions:
- HSPC modification can enable targeted immunotherapy for myeloid malignancies with reduced toxicity.
- This approach allows for continued post-transplant therapies, such as for minimal residual disease (MRD).
- The strategy holds broad applicability for other targets and cell types, potentially making previously undruggable targets accessible for immunotherapy.
