We have developed a novel approach to the treatment of primary GBM by combining simultaneous intracranial administration of gene-modified γδ T cells and standard temozolomide (TMZ) maintenance chemotherapy. Overall, we were able to generate dCLTX-CAR T cells with resistance to TMZ and showed improved activation and cytotoxicity against GBM cells under TMZ exposure. Our approach of combining the dCLTX-CAR and TMZ resistance will be further validated in animal model experiments and could be a potential candidate for clinical development for GBM.