Targeting the Checkpoint Receptor TIGIT via CRISPR/Cas9 Genome Editing to Enhance NK Cell Anti-Tumor Activity
Pediatric cancer remains the second leading cause of death in children. One type of cancer that is particularly difficult to treat is FLT3 mutant acute myeloid leukemia (AML). AML cells that have a FLT3 mutation grow at a rapid rate and develop strategies to escape monitoring by the immune system, including blocking natural killer (NK) cell anti-tumor activity. We also know that many cancer patients have low NK cell numbers and decreased NK cell activity as a result of chemotherapy. Our laboratory has created an effective strategy to generate large numbers of activated NK cells for cellular therapy for pediatric cancer. In this project, our goal is to enhance NK cell anti-tumor activity by targeting an inhibitory receptor on NK cells called TIGIT. When TIGIT binds to proteins expressed by tumor cells like FLT3 mutant AML cells, NK cell activity is blocked. We propose to genetically modify NK cells to knock-out TIGIT expression, and also will introduce a receptor that triggers an activating signal when NK cells interact with tumor cells (rather than triggering an inhibitory signal). We believe that this new cell therapy will provide an powerful treatment option for children with AML.
Project Goal:
The goal of this project is to engineer immune cells to target cancer, particularly a type of pediatric cancer called acute myeloid leukemia (AML). AML cells develop strategies to escape surveillance by the immune system. Despite current therapies, cancer cells are able to survive and progress. Natural killer (NK) cells play an important role in the immune response to cancer by recognizing and killing tumor cells. NK cell activity is regulated by activating and inhibitory receptors. Tumor cells express proteins that provide inhibitory signals to NK cells, blocking NK cell anti-tumor functions and allowing for tumor escape. We propose to tip the balance in favor of immune cell activation by knocking out a key NK cell inhibitory receptor, TIGIT. We hypothesize that eliminating NK cell TIGIT expression will remove inhibitory “brakes” on NK cell activation and enhance anti-tumor activity. The purpose of this study is to develop an effective cellular therapy for pediatric AML.
Project Update 2024:
In this project, we are working to create processes that favor immune cell activation by knocking out a key NK cell inhibitory receptor, TIGIT. We have hypothesized that eliminating NK cell inhibitory TIGIT signaling will promote and enhance anti-tumor activity. Over the last year, we have generated TIGIT knockout NK cells and have shown that these cells are able to effectively target and kill AML cancer cells. Taking this a step further, we have designed TIGIT chimeric antigen receptor (CAR) NK cells that are able to generate activating signals upon interactions with tumor cells. Overall, the purpose of this study is to develop an effective cellular therapy for AML to benefit pediatric cancer patients.
