Towards clinical testing of epitope editing to enable novel adoptive immunotherapies
Pietro Genovese
PhDBoston Children's Hospital
Project Term: July 1, 2023 - June 30, 2026
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 the treatment B lymphoblastic leukemia. A similar approach is currently under development for AML, but in contrast to B-ALL, there is no leukemia-specific target which would be amenable to targeting by immune cells without incurring severe adverse effects. Here, we aim to modify normal bone marrow stem cells used for allogeneic transplantation to make them resistant to CAR-T cells, thus enabling targeting proteins essential for tumor survival without the risk of severe toxicity on the healthy tissue counterpart.
Acute myeloid leukemia (AML) is the most common leukemia in adults and the second in childhood. Yet, despite recent advances and diffuse use of therapeutic bone marrow transplantation, AML is still associated with a dismal outcome for over 50% of affected patients. 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 the treatment B lymphoblastic leukemia. A similar approach is currently under development for AML, but in contrast to B-ALL, there is no leukemia-specific target which would be amenable to be attacked by immune cells without incurring in severe adverse effects. This is due to the great 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 in order to make them resistant to targeted therapies such as CAR-T cells. By combining different screening methods, we identified a single point mutation on three 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 of the leukemic cells. This would allow the administration of highly effective immunotherapies targeting proteins that are essential for tumor survival without the risk of severe toxicity on the healthy tissue counterpart.