Engineering T cells with a chimeric antigen receptor (CAR) recognizing proteins specifically expressed on tumor cells is a new cancer therapy. While CAR T cells can successfully treat hematopoietic malignancies, CAR T cells have not shown success in treating solid tumors. In addition, one side effect observed after CAR T cell infusion is Cytokine Release Syndrome (CRS) which causes damaging inflammation. There are many factors that may enhance CAR T cell efficacy and safety for solid tumor treatment, including costimulatory domains to increase T cell functions and switching T cell type from alpha beta to gamma delta T cells. We developed a novel CAR (chimeric PD-1, chPD1) that targets the programmed death 1 receptor (PD-1) ligands expressed on many types of solid tumors. The aim of this study was to compare anti-tumor efficacy and CRS induction between chPD1-expressing gamma delta and alpha beta T cells in murine breast cancer models. Inclusion of different costimulatory domains, CD28, 4-1BB, and Dap-10, in the chPD1 receptor was also compared. There were no differences in T cell viability and proliferation when comparing costimulatory domains or T cell type. Additionally, there were no significant differences in killing of murine 4T-1 and E077 breast cancer cells. ChPD1-CD28 T cells had increased secretion of proinflammatory and CRS-inducing cytokines and chemokines, including IFN-gamma, IL-2, and nitric oxide, compared to chPD1-41BB and chPD1-Dap10 receptors. Overall, alpha beta chPD1 T cells also had increased cytokine secretion compared to chPD1 gamma delta T cells. Therefore, inclusion of 4-1BB or Dap10 domains in gamma delta T cells may be a safer and more efficacious option for CAR T cell therapy of solid tumors.
Willis, Stephanie, "Costimulatory Domains Alter the Efficacy and Safety of Chimeric Antigen Receptor-expression Gamma Delta T cells" (2022). Longwood Senior Theses. 13.