Specific T cells limited by immune tolerance to self-antigens. We use gene therapy to overcome tolerance to tumor-associated antigens (TAA) by redirecting T-cell specificity. This is achieved using non- viral gene transfer to express a chimeric antigen receptor (CAR) that recognizes a cell-surface TAA independent of MHC. The first aim builds upon MDACC’s clinical trial in which autologous T cells are electroporated with the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR for treatment of B-lymphoid malignancies after autologous hematopoietic stem-cell transplantation (HSCT). We will test the hypothesis whether mRNA coding for the SB transposase can be electro- transferred into T cells along with SB DNA plasmid coding for the transposon CD19-specfic CAR. This will avoid integration of the transposase thereby improving the safety of SB transposition. We will further adapt the electro-transfer of mRNA specifies to transiently express designer zinc finger nuclease (ZFN) targeting endogenous αβ T-cell receptor.