Chimeric cytokine receptors to improve CAR T-cell therapy for osteosarcoma
The clinical outcome for many patients with solid tumors including bone tumors, called osteosarcoma, remains poor. This is particularly true for patients in whom the cancer has recurred or spread to the lungs. Immunotherapy has the potential to improve outcomes for these patients. We are interested in a form of immunotherapy called chimeric antigen receptor (CAR) T-cell therapy, which takes the patient’s own immune cells, modifies them in the laboratory to recognize and kill cancer cells, and puts them back into the patients. CAR T-cell therapies have been very successful in curing blood cancers, but they have not worked as well for solid tumors. One of the primary challenges is the inability of CAR T cells to persist long enough inside the tumor mass to destroy the cancer completely. Thus, investigators are interested in expressing genes in CAR T cells to increase their killing function within the tumor to make them more effective against solid tumors. Many groups, including us, focus on a specific class of genes that encode cytokine signals, which play essential roles in regulating T-cell function and survival. However, T cells can be impacted by many different cytokine signals, and it is not yet understood which signals will have the most profound impact on CAR T-cell therapy because they have not been directly compared.
Project Goals
The overarching goal of this project is to improve CAR T-cell function against osteosarcoma (OS). This goal will be accomplished by expressing genes responsible for conducting cytokine signals in T cells. I will focus on the two most promising candidate genes, where each of them activates a different cytokine signaling pathway, and make a head-to-head comparison of their functions in murine CAR T cells. I will compare these genetically modified CAR T cells both outside and inside of our animal models using a range of assays. This project focuses on evaluating CAR T cells in mouse models that closely mimic human OS. I will use murine OS cancer cell lines derived from a genetically identical mouse and graft cells into mice with fully intact natural immune systems, which provide better predictions of how CAR T cells behave in humans. This approach is novel as it is standard in the field to test human CAR-T cells in mouse models where mice lack full immune systems to enable the establishment of human-derived tumor cells. Our approach not only allows me to evaluate the efficacy of these modified CAR T cells but also offers unique opportunities to gain insights into safety and how they interact with other immune cell populations present within the tumors. If successful, we are planning to develop a clinical study to evaluate our approach in children, adolescents, and young adults, who have osteosarcoma, in the future.
