Year: 2017
Type: conference-abstract
Abstract: The goal of this project is to develop T-cells expressing IL13Rα2-specific chimeric antigen receptor (CAR) as an effective immunotherapy for diffuse intrinsic pontine glioma (DIPG) and glioblastoma (GBM), the most aggressive, highly lethal, primary human brain tumors in children. We recently demonstrated that IL13Rα2-CARs with a CD28.ζ endodomain had potent anti-GBM activity in preclinical models. However, IL13Rα2-CAR T-cell persistence was limited, resulting in recurrence of IL13Rα2-positive GBMs. Next we wanted to evaluate if transgenic expression of IL15 enhances persistence and anti-tumor activity of IL13Rα2-CAR.CD28.ζ T-cells. We generated IL13Rα2-CAR.CD28.ζ T-cells expressing IL-15 (IL13Rα2-CAR.IL15 T cells) and determined the effector function of IL13Rα2-CAR.IL15 T cells in vitro and in vivo. Double transduction of CD3/CD28-activated T cells resulted in T-cell lines that expressed both transgenes in 45–50% of T cells. At base line IL13Rα2-CAR.IL15 T cells produced on average 69.5 pg/ml of IL15. Production was significantly increased after CD3 or antigen-specific T-cell stimulation (176.7 pg/ml; n=6; p<0.001). IL13Rα2-CAR.IL15 T-cells were as efficient as IL13Rα2-CAR T-cells in killing IL13Rα2-positive GBMs in vitro. After intratumoral injection into U373 glioma-bearing mice IL13Rα2-CAR.IL15 T cells persisted significantly longer than IL13Rα2-CAR T cells (p<0.05). This resulted in a significant increase in progression free (84 vs 49 days; p=0.008) and overall survival (p=0.02) of treated mice. 3/5 examined, recurring U373 gliomas post IL13Rα2-CAR.IL15 T-cell therapy had down regulated IL13Rα2 expression, indicating immune escape. While all recurring GBMs expressed the glioma-associated antigen EphA2, 1/5 GBMs had also down regulated the expression of the glioma-associated antigen HER2. In conclusion, transgenic expression of IL15 enhances the in vivo persistence of IL13Rα2-CAR T cells resulting in improved anti-glioma activity. However, enhanced in vivo T-cell persistence resulted in the development of antigen-specific and -unspecific loss variants highlighting the need to target multiple glioma-associated antigens in tumors with heterogeneous antigen expression such as GBM.
Source: Neuro-Oncology
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2617070649