Childhood Cancer

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Empowering specificity of AML immunotherapies by HSC engineering

Aflac Cancer Center and Blood Disorders Service of Children’s Healthcare of Atlanta, Boston Children’s Hospital
Pietro Genovese
Grant Type: 
Catalyst Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

Acute myeloid leukemia (AML) is the second most common childhood leukemia but is reaching acute lymphoblastic leukemia (ALL) as the leading cause of childhood leukemic mortality, primarily because of ineffective prognostic schemas and the absence of targeted therapies. While there have been significant advancements in supportive care and targeted treatments, AML shows a worse long-term prognosis across all groups when compared to other acute leukemias. While bone marrow transplantation provides potent immunotherapy for high-risk or recurring AML, nearly 30% of pediatric patients relapse after HSCT and face an abysmal prognosis due to the combination of increasingly refractory disease, reduced fitness, and limited treatment options. Innovations in gene engineering have made it possible to reprogram immune cells to attack specific targets on cancer cells, allowing the first adoptive cellular immunotherapies, known as CAR T cells, to be approved by the FDA for treating B lymphoblastic leukemia. A similar approach is currently under development for AML. Still, in contrast to B-ALL, no leukemia-specific target would be amenable to being attacked by immune cells without incurring severe adverse effects. This is due to the remarkable similarity between leukemia cells and normal bone marrow stem cells, which would be killed along with the targeted tumor cells, leading to anemia, low white blood cells, low platelets, and susceptibility to infections and hemorrhage.

To create a new treatment strategy for high-risk AML patients, we aim to modify normal bone marrow stem cells used for allogeneic transplantation to make them resistant to targeted therapies such as CAR-T cells. By combining different screening methods, we identified a single point mutation on two genes, expressed on the surface of both normal bone marrow stem cells and leukemic stem cells, which make the proteins invisible to antibodies directed against these targets. We will exploit advanced genetic engineering tools, such as CRSPR-mediated base editing enzymes, to introduce these single DNA changes in the genome of healthy bone marrow stem cells used in conventional allogeneic transplantation to enable specific antibody recognition only in the leukemic cells. This would allow the administration of highly effective immune therapies concomitantly targeting two proteins that are essential for tumor survival without the risk of severe toxicity on the healthy tissue counterpart.