Grant: Project Grant

Acute myeloid leukemia (AML) is an aggressive blood cancer. Even when patients achieve remission after chemotherapy and stem cell transplantation, the disease often returns. One reason is that current targeted antibody therapies, including antibody-drug conjugates (ADCs), cannot be used at full strength. The surface markers they attack on leukemia cells are also found on healthy cells. As a result, treatment can severely damage normal blood production, limiting dose and combinations. Our research aims to solve this problem by genetically shielding healthy blood-forming cells while leaving leukemia cells exposed. We build on a clinically established Canadian innovation: UM171-expanded cord blood transplantation, which has already been used in more than 100 patients and improves stem cell engraftment. Within this platform, we recently developed a precise gene-editing strategy that modifies a small region (epitope) of CD33, a common AML target. This change prevents therapeutic antibodies from binding to healthy transplanted cells, while preserving normal stem cell function. In preclinical models, these edited cells successfully reconstituted blood formation and were protected from antibody-related toxicity. In this project, we extend this strategy beyond CD33. We have identified additional surface markers that are enriched in specific high-risk AML subtypes and developed corresponding antibody candidates. However, these markers are also present on normal cells, which currently makes combination therapy unsafe. We will engineer stem cell grafts with multiple protective edits such that combination antibody therapies can be given safely after transplantation. In laboratory and animal models, we will test whether this approach improves leukemia control while preserving healthy blood production. Our goal is to enable safer and more effective post-transplant immunotherapy for patients with high-risk AML, where durable treatment breakthroughs remain limited.