Abstract 1535: T Cells engineered to express the IL-13Rα2 specific CAR and a PD-L1 specific switch receptor show increased anti-tumor activity in the Glioblastoma tumor microenvironment

Abstract

Abstract Glioblastoma multiforme (GBM) is an aggressive brain cancer with poor prognosis with traditional treatments such as chemotherapy and radiotherapy, which often leave lasting and pervasive damage to the individual. GBM cells upregulate the surface protein interleukin 13 receptor subunit alpha-2 (IL13Rα2), which can be targeted as a novel immunotherapeutic marker for the immune response to be initiated. In this study, IL13Rα2 is targeted using a first generation chimeric antigen receptor (CAR) that contains an intracellular zeta chain domain. However, a limitation to this approach is that the tumor microenvironment exhausts the T cells that interact with the tumor through a receptor-mediated response. Programmed Death Ligand 1 (PD-L1) is a molecule that is expressed on cancerous cells that binds to Programmed Death 1 (PD-1) on T cells. When the ligand binds to PD-1 on T cells, there is decreased T cell proliferation, cytokine production, and anti-tumor activity. This problem can be avoided via creation of a switch receptor with a PD-1 extracellular domain fused to transmembrane and intracellular costimulatory CD28, which converts tumor mediated inhibition into stimulation upon ligation of PD-L1. It is hypothesized that the incorporation of additional costimulatory domains will enhance the stimulatory effects of the switch receptor. Engineered T cells expressing varied switch receptors in conjunction with the IL13Rα2-specific CAR have been created and have been assessed in vitro as a basis for glioblastoma treatment. Tests performed include cytokine secretion and T-cell proliferation assays. Results of these preliminary studies suggest that the the inclusion of additional costimulatory domains in the switch receptor design may be advantageous in enhancing anti-tumor responses in the GBM microenvironment. Citation Format: Abel De Castro, Megan E. Keys, Jonathan Arroyo, Megan E. Prosser. T Cells engineered to express the IL-13Rα2 specific CAR and a PD-L1 specific switch receptor show increased anti-tumor activity in the Glioblastoma tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1535.