Enhancing the therapeutic efficacy of chimeric antigen receptor T cells for acute myeloid leukemia
T cells can be genetically engineered to target a specific cell surface marker that is present on cancer cells, and this form of therapy, termed chimeric antigen receptor (CAR) T cells, has been highly successful in the treatment of pediatric acute lymphoblastic leukemia (ALL). We propose to adapt CAR T cell therapy to meet the unmet needs of children with acute myeloid leukemia (AML), a disease with suboptimal clinical outcomes.
We have generated CAR T cells against myeloid antigens such as CD33 and CLL-1. To maximize therapeutic efficacy, we propose to develop dual-targeting CAR T cells with activity against both CD33 and CLL-1 expressing tumor cells, and evaluate their anti-tumor efficacy and also their ability to prevent antigen-negative escape using in vivo mouse xenograft models. We will also use a novel long-acting IL-7 hybrid fusion cytokine (NT-I7) to enhance the expansion and persistence of CAR T cell activity in vivo, and evaluate whether this combination can generate long-term immunologic memory against tumor cells. By performing these studies, we hope to generate a potent CAR construct that in the future can be used clinically to mediate long-term disease-free survival in children with AML.