A new successful pre-transplant strategy without chemo or radiotherapy

A study recently published on Nature showed a new strategy to maximize haematopoietic niche clearance without chemo-radiotherapy or monoclonal antibody wash-out in hemopoietic stem/progenitor cells (HSPCs) transplantation. The paper was co-authored by one of the recipients of 2025 Gianni Bonadonna Fellowship, Francesco Romano, now working with lead author Pietro Genovese at Dana-Farber Cancer Institute in Boston.

Researchers aimed to find an alternative way to genotoxic pre-transplant chemotherapy or radiotherapy in HSPCs transplantation and gene therapies, because chemo and radiotherapy carry substantial early and late treatment-related morbidity and mortality. They focused on monoclonal antibodies targeting KIT, investigated as an alternative but with a pharmacokinetic leading to the risk of depleting transplanted cells; researchers identified amino acid changes in the extracellular domain of KIT that disrupt the binding of two therapeutic monoclonal antibodies, which impair stem cell factor-mediated signaling without affecting KIT expression or functionality. They introduced these mutations in HSPCs in combination with the disruption of the BCL11A erythroid enhancer: this strategy of in vivo-co-selection of gene-engineered cells allowed an extended treatment with anti-KIT regimens that led to superior in vivo enrichment while avoiding clonal selection. As authors conclude, these findings «support the paradigm-shifting potential of epitope editing to design next-generation hemopoietic stem cells transplantation. By decoupling stem cell conditioning from toxicity, this approach overcomes key obstacles to the broader deployment of gene and cell therapies. Moreover, in vivo co-delivery of therapeutic and epitope edits could leverage immune-mediated selection to enrich genome-modified cells within the host. We envision a future where patients receive life-saving stem cell therapies without risks of prolonged aplasia, infertility or secondary malignancies, and with minimal or no hospitalization».