Genome Editing Enables Shielding of Cells Enabling New Therapies

The Jeker lab (University of Basel) and collaborators, including the Corn lab (ETH Zurich) describe a new approach to treat hematologic diseases. While breakthroughs were made for treating B cell malignancies by identifying suitable antigens on the target cells to be eliminated, this is not the case for myeloid malignancies. There are highly expressed antigens in cancer cells but these are also present on healthy hematopoietic stem and progenitor cells (HSPCs), which need to be protected from eliminiation. The researchers now show that they by genome engineering can epitope shield HSPCs and they escape adverse treatment effects, while unengineered HSPCs are susceptible to treatment.  including progenitor cells which should be spared. This approach should be broadly appicable and pave the way to new treatments. Their findings have been published in the article "Epitope-engineered human hematopoietic stem cells are shielded from CD123-targeted immunotherapy"  in the Journal of Experimental Medicine.

Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody-drug conjugates (ADC), T cell engagers (TCE), or chimeric antigen receptor (CAR) cells is very effective for hematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various hematological malignancies, including acute myeloid leukemia (AML). However, shared CD123 expression on healthy hematopoietic stem and progenitor cells (HSPCs) bears the risk for myelotoxicity. We demonstrate that epitope-engineered HSPCs were shielded from CD123-targeted immunotherapy but remained functional, while CD123-deficient HSPCs displayed a competitive disadvantage. Transplantation of genome-edited HSPCs could enable tumor-selective targeted immunotherapy while rebuilding a fully functional hematopoietic system. We envision that this approach is broadly applicable to other targets and cells, could render hitherto undruggable targets accessible to immunotherapy, and will allow continued posttransplant therapy, for instance, to treat minimal residual disease (MRD).

Read the Publication in the Journal of Experimental Medicine (Open Access)

Website Jeker Lab

Website Corn Lab

Abstract, figure and title from Marone, Landmann, Devaux, Lepore et al (2023) J Exp Med published under a CC BY 4.0 license.