Abstract: The potential of cancer immunotherapy has been demonstrated recently using the chimeric antigen receptors-engineered (CAR) T cells, in which B cell haematological malignancies was successfully treated in clinical trials. However, challenges remain in the translation of the potential benefits into therapy of other types of cancer with similar efficacy and safety. Excessive activation of genetically-modified T cells may cause severe toxicities, such as cytokine storm, on-target toxicities, and tumor lysis syndrome. Genomic integration of viral vectors may cause genetic toxicities due to insertional mutagenesis of important genes. Strategies to overcome these toxicities are proposed and discussed, including the use of suicide genes, combinatorial antigen recognition, on-switch, non-viral vector and other innovative gene therapy strategies, to enhance safety of this promising immunotherapy.