Reworking Negative Receptor Signals for Improved Anti-Glioma T-cell Therapy
Meenakshi G. Hegde, MD
Glioblastoma cells have been found to induce high levels of co-inhibitory receptors (PD-1, CTLA-4, BTLA, TIM3, and LAG3) on patient CAR T-cells in long-term co-cultures — reducing T-cell proliferation potential and effector functions. SHP2, a non-transmembrane phosphatase encoded by PTPN11, plays a central role in T-cell inhibitory receptor signaling, including PD-1, CTLA-4, BTLA and to some extent, LAG3. Dr. Hegde is determining if SHP2 disruption strategies could improve the functional ability of CAR T cells by reprogramming the co-inhibitory receptor signaling to act synergistically, and ameliorate their exhaustion. She anticipates that combining her research group’s CAR T-cell PD-L1/PD-1 axis modulation platform with SHP2 silencing strategies can positively impact the survival and functional properties of tumor-directed CAR T cells, and potentially minimize the risk of adoptive resistance that has been observed with PD-1 blockade alone.
Dr. Hegde completed her clinical fellowship in hematology-oncology at the Texas Children’s Cancer Center, Baylor College of Medicine, focusing on chimeric antigen receptor (CAR) T-cell therapy against brain tumors/solid tumors. She is a board-certified pediatric oncologist engaged in translational research on immunotherapy and tumor microenvironment to improve patient outcomes in high-risk cancer.