Improving CAR T-Cell Therapy for Pediatric Osteosarcoma by Manipulating Arginine Metabolism
Background: Osteosarcoma is the most common bone tumor in children and young adults. A combination of chemotherapy and surgery are the current standard of care. With this therapy, the outcome of patients, who have local disease is good. However, about one in five patients have tumors that have spread to other organs. The outcome for these patients, and those in which the disease has come back, remains poor. Immunotherapy may be an ideal treatment option for these patients. We have previously developed a form of immunotherapy, which consists of immune cells, called T cells, that are engineered to express a chimeric antigen receptor (CAR). CAR T cells seek out and kill tumor cells. We have tested our approach already in the clinic and while it was safe, not all patients benefited from our approach. In order to improve the anti-tumor activity of our CAR T cells, we propose here to enhance the ability to our T cells to function within tumors. Nutrients are critical for the function of immune cells like T cells. Within tumors, T cells normally do not get all the nutrients they need to function properly since tumor cells take them up much faster.
Project Goal: We now propose to engineer CAR T cells to be much better in taking up amino acids, which are critical building blocks for all cells that want to grow and divide. Specifically, we will focus on an amino acid called arginine, which is critical for
T cell function. We will test our approach in models that closely mimic human osteosarcoma. If our approach is successful, it could be readily incorporated into ongoing CAR T cell therapy studies not only for osteosarcoma but also other cancers.
Project Update 2022: So far, I developed a high capacity arginine transporter – CAT-2a – expressed by CAR T-cells. However, I unexpectedly found CAR T cells expressing CAT-2a did not have improved anti-tumor activity. Based on this finding, we have developed an alternative approach by creating a chimeric cytokine receptor GM-CSFR/IL18R (GM18) that signals through MyD88. We found GM18 significantly enhances the antitumor function of CAR T cells several in vitro and in vivo models, leading to a high-impact publication in Cancer Discovery. In addition, we have developed alternative receptors that activate MyD88 and are currently performing studies with the goal of selecting an optimal MyD88-activating receptor for clinical testing in CAR T cells for pediatric patients with recurrent/refractory pediatric solid tumors.
