Abstract
Recurrent Glioblastoma (GBM) tumors often arise from glioma-initiating cells or glioma stem cells (GSCs). GSCs are usually resistant to the standard therapeutic regiment of radiation and chemotherapy and hence have been an attractive target for the development of immunotherapeutic strategies to treating recurrent GBMs. Chimeric antigen receptor expressing engineered T (CAR-T) cells are redirected to detect and destroy rare tumor cells that express specific tumor antigens. CAR-T cells have been successful in treating hematological cancers, and moderately effective in remission of primary GBM tumors, but not yet been successful in the immunotherapeutic targeting of GSCs or recurrent GBMs. In this study, we have treated two patient-derived GSCs and tumor cell line derived neurospheres, as well as GSC/neurosphere-derived secondary tumor cells with CAR-T cells that specifically target IL13Rα2 tumor antigens on GBMs. These GSCs and neurospheres were resistant to radiation and adjuvant chemotherapy but were successful in activating antigen-specific CAR-T cells- as observed by increased proliferation as well as secretion of cytokines. In vitro co-culture of CAR-T cells with GSCs, neurospheres, and secondary tumors resulted in the effective cytotoxic killing of tumor cells. In experimental animals bearing xenograft implantation of GSCs or redefined secondary tumor cells, tumors went into remission when treated with CAR-T cells, in comparison to treatment with T cells that did not express specific CAR molecule. Together, we conclude that CAR-T cell immunotherapy can be an effective approach to targeting GSCs and treating secondary or recurrent GBM tumors.