Dismal long-term progression-free survival of glioblastoma (GBM) patients, who are concurrently treated with radiation and chemotherapy, demands development of alternative strategies for management of this disease. Recent clinical success of chimeric antigen receptors expressing T cells (CAR-T) in GBM patients, interest in tumor-directed immunotherapy has been reinvigorated. However as per standard care, immunotherapy must be concurrent with or following the standard care protocol for glioma therapy, which includes Temozolomide (TMZ) chemotherapy. Concurrent chemotherapy with TMZ reduces the efficacy of adoptive T cell immunotherapy by inducing severe lymphopenia, while post-chemotherapy treatment minimizes the window of opportunity for effective immunotherapy, because of inherent tumor heterogeneity resulting in an altered antigenic profile in recurrent GBMs. To address this, we have created a TMZ-resistant CAR-T cell directed against IL13Rα2+ GBM tumors by introducing a mutated O6-methylguanine-DNA methyltransferase (MGMT) moiety in the existing IL13CAR backbone. This specific mutation in MGMT (P140KMGMT) blocks the interaction of TMZ to MGMT and therefore protects the rapidly proliferating anti-GBM CAR-T cells from TMZ-induced lymphopenia. Activated P140KMGMT-IL13CAR-T cells were protected from TMZ-induced cytotoxicity in vitro without any loss of anti-tumor effects of these modified CAR-T cells. Experimental xenograft animals treated with P140KMGMT-IL13CAR-T cells and concurrent TMZ therapy showed 2-fold increase in median survival over groups that were treated with TMZ alone, and 2.8-fold increase in overall survival over groups that were treated with TMZ-sensitive second generation IL13CAR-T cells and concurrent TMZ. These encouraging results point us strongly in the direction of developing this CAR-T technology towards a promising future of concurrent chemotherapy and immunotherapy of GBM.

Citation Format: Sadhak Sengupta, Mansour Gergi, Prajna Guha, Sudarshana Sengupta, Richard P. Junghans, Prakash Sampath. Concurrent chemotherapy and temozolomide-resistant CAR-T immunotherapy enhances glioblastoma clearance in experimental animals [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 2543.