Investigating a Dual-Targeting CD123 & CLL1 CAR-NK Cell Therapy for Acute Myeloid Leukemia
Mentor Name: Challice Bonifant
CAR-T and CAR-Natural Killer (CAR-NK) cell therapies are promising new cancer treatments. Chimeric antigen receptors, or CARs, are synthetic receptors that are genetically engineered to be expressed on the surface of immune T and NK cells to enable the cells to identify and attack cancer. Infusions of NK cells have been tested as Acute Myeloid Leukemia (AML) treatment because of their innate anti-AML activity and their history of safe infusion to patients. The side effect profile of NK cell treatment is favorable as compared to T cells, with a much lower risk of inflammatory side effects, such as “Cytokine Release Syndrome” and neurotoxicity. Donor T cells also have the risk of stimulating severe Graft versus Host Disease (GVHD), a toxicity not caused by NK cells. Addition of a CAR to the NK cell surface can improve cancer recognition and NK cell binding to target. CD123 is an AML-associated marker broadly expressed on AML cells and our lab has used CD123 for CAR-NK cell direction. However, CD123 is found on both leukemia cells and healthy cells, so targeting it poses the risk of damaging these. Exploring other antigen targets is therefore necessary to improve AML therapeutic specificity. CLL1 is another AML-associated target protein with no expression on healthy, immature hematopoietic stem cells (HSC). CLL1 is expressed on mature myeloid cells, but CD123 and CLL1 are rarely expressed together on the same healthy cell. CLL1 and CD123 are both highly expressed on leukemic stem cells (LSC), which are thought to be a main cause of AML relapse. Though CLL1 is not as broadly expressed across the different subtypes of AML as CD123, the two targets are often expressed together. Thus, this project aims to couple CD123 targeting and CLL1 targeting through the generation of dual-targeting CAR-NK cells, with the goal of generating a more powerful CAR-NK treatment for AML.
