Abstract LB-182: Differential modulation of the PD-1 pathway impacts the anti-tumor activity of CAR T cells

Abstract

Abstract Adoptive T cell therapy using ex vivo expanded tumor-infiltrating lymphocytes (TILs) or T cells engineered with chimeric antigen receptors (CAR T) has shown tremendous success in many hematological diseases, however treatments of solid tumors have been less successful so far. It is presumed that adoptive cell therapy is limited by the presence of immune-suppressive mechanisms within the solid tumor microenvironment. To enhance T cell activity against solid tumors, we seek to overcome these immune barriers and one approach is to do this by blocking checkpoints such as the PD-1 receptor. Using CAR T cells targeting the glioblastoma (GBM) tumor-specific antigen EGFRvIII, we investigated 3 approaches of inhibiting PD-1: (i) shRNA-mediated knockdown, (ii) TALEN®-mediated knockout, and (iii) antibody-mediated blockade. In contrast to the PD-1 antibody that augmented CAR T cell activity in vivo, the PD-1 shRNA impaired the anti-tumor activity of CAR T cells in vitro and in vivo. Detrimental effects of the PD-1 shRNA were associated with impaired survival of CAR T cells in vitro and in vivo. Interestingly, TALEN®-mediated PD-1 knockout generated CAR T cells with superior cytotoxic potency and prolonged functional persistence in vitro. Further characterization of PD-1 TALEN® CAR T cells, and how they compare in activity against the CAR T/anti-PD-1 combination in both subcutaneous and intracranial GBM models, is underway. These studies will not only elucidate the role of PD-1 in CAR T cell biology, but also inform CAR T cell combination therapy approaches for solid tumor indications. Citation Format: Regina J. Lin, Anne-Sophie Gautron, Laurent Poirot, Oi Kwan Wong, Barbra Sasu, Bijan Boldajipour. Differential modulation of the PD-1 pathway impacts the anti-tumor activity of CAR T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-182. doi:10.1158/1538-7445.AM2017-LB-182