Blood advancesJul 22, 2026

Modifying Stem Cells to Protect Them from Immune Attacks After Transplant

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 23, 2026

Abstract

Epitope engineering of hematopoietic stem cells may expand the therapeutic window of precision immunotherapies.

Targeted immunotherapies face limitations due to on-target, off-tumor toxicity from shared antigens in healthy tissues.
Knockout of target antigens in donor hematopoietic stem cells is limited to markers that do not affect normal hematopoietic function.
Epitope engineering modifies target antigens on healthy cells while maintaining their biological activity.
Recent advances in base and prime editing approaches are being explored for epitope editing.
Challenges include editing efficiency, off-target effects, delivery methods, and long-term safety in hematopoietic stem cells.

Simplified

Targeted immunotherapies have transformed the treatment of hematologic malignancies, yet their clinical utility is often constrained by on-target, off-tumor toxicity arising from shared antigen expression between malignant cells and essential healthy tissues. An early approach to mitigate this limitation involved the knockout (KO) of the target antigen in donor hematopoietic stem and progenitor cells (HSPCs). However, this strategy is restricted to markers that are dispensable for normal hematopoietic function. Epitope engineering has emerged as an alternative paradigm to decouple therapeutic susceptibility from physiological function by modifying the target antigen on healthy cells while preserving biological activity. In this review, we discuss recent advances in base and prime editing approaches used for epitope editing. We examine recent preclinical and emerging translational studies of this strategy in both malignant and non-malignant contexts. Finally, we discuss challenges related to editing efficiency, off-target effects, delivery strategies, and long-term safety in hematopoietic stem cells. Collectively, epitope engineering of hematopoietic stem cells represents a versatile platform to expand the therapeutic window of precision immunotherapies and may enable safer, more effective combinatorial treatment strategies for both non-malignant and malignant hematologic conditions.

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Modifying Stem Cells to Protect Them from Immune Attacks After Transplant

Abstract

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