Utilizing TIGIT-CAR natural killer cells to target acute myeloid leukemia
Mentor Name: Amanda Campbell
Natural killer (NK) cell therapy has emerged as a promising targeted strategy to combat standard therapy-resistant cancers, such as acute myeloid leukemia (AML). NK cell activity is regulated by a balance of activating and inhibitory signals, and cancer cells have developed strategies to engage inhibitory receptors to evade the immune response. NK cells express the activating receptor DNAM-1 and an inhibitory checkpoint receptor, TIGIT. These receptors compete for ligands upregulated by various cancers including AML. In our ex vivo NK cell expansion system, expression of TIGIT, but not DNAM-1, is upregulated on expanded NK cells. This identifies TIGIT as an important target for CRISPR/Cas9-directed modification. The hypothesis for this proposal is that by using CRISPR/Cas9 and chimeric antigen receptor (CAR) technology, co-opting the TIGIT signaling pathway to propagate activating signals upon ligand binding will enhance NK cell anti-tumor activity against AML. The aim of this work is to examine the therapeutic efficacy of a modified TIGIT-CAR on immune activation and cytotoxicity against AML. CRISPR/Cas9 gene editing technology will be employed to alter the TIGIT checkpoint on immune cell activation in expanded NK cells. NK cell cytotoxicity against primary AML cell lines and AML samples from The Ohio State University and HEME Biorepository will be examined to determine the effectiveness of the modified TIGIT-CAR. This work is significant because it provides a unique approach to treating AML with CAR NK cells and will develop a framework that may be applied to treat other forms of pediatric cancer in the years to come.
