This project is tightly aligned with the CPRIT mission to find a cure for cancer in order to save lives and prevent cancer. The goal of the proposed work is to engineer smart therapeutic T cells to advance precision medicine by delivering durable and controllable cell-based immunotherapy against cancer. Over the past five years, chimeric antigen receptor (CAR) T-cell based immunotherapy, also regarded as “living drugs” in the body, has achieved miraculous outcomes in certain patients with lymphoma and leukemia. Nonetheless, CAR T-cell therapy still faces challenges, partially because of severe side effects and its inability to last long-term therapeutic effects in some cancer patients. B...

Read More

This project is tightly aligned with the CPRIT mission to find a cure for cancer in order to save lives and prevent cancer. The goal of the proposed work is to engineer smart therapeutic T cells to advance precision medicine by delivering durable and controllable cell-based immunotherapy against cancer. Over the past five years, chimeric antigen receptor (CAR) T-cell based immunotherapy, also regarded as “living drugs” in the body, has achieved miraculous outcomes in certain patients with lymphoma and leukemia. Nonetheless, CAR T-cell therapy still faces challenges, partially because of severe side effects and its inability to last long-term therapeutic effects in some cancer patients. Bearing these challenges in mind, we propose to combine state-of-the-art chemical biology and protein engineering technologies to design improved chimeric antigen receptor (CAR) T-cells with higher efficacy and safety, which will be achieved through precise control over the epigenetic and metabolic regulatory pathways in therapeutic T cells. We aim to remodel epigenetic landscapes and metabolism in CAR T-cells to maximally promote immune responses against cancer cells. Specifically, the team will focus on manipulating the Ten-elven Translocation 2 (TET2) protein (Aim 1) and its metabolic inhibitor L-2-hydroxyglutarate (Aim 2), and testing the therapeutic outcomes in animal models of lymphoma and melanoma. Our innovative approaches and novel findings may advance the design and application of intelligent therapeutic cells to fight against cancer, thereby making CAR T-cells as a living drug that can be applied to more cancer patients. Collectively, our study will open new avenues to engineer safer and more potent therapeutic immune cells to benefit both basic and translational studies on immunotherapy.

Read Less