The generation of chimeric antigen receptor (CAR) T cells, an immunotherapy for the treatment of cancers, has showed high efficacy in anti-CD19 CAR-T cells in B cell malignancies, with up to a 90% complete remission rate. However, the clinical efficacy of CAR T cells in hematological malignancies has not been achieved in solid tumors. CAR T-cell therapy for solid tumors faces multiple hurdles, including inefficient CAR-T trafficking and nonhomogeneous tumor antigen expression. In order to boost the trafficking of CAR-T cell and avoid antigen escape for solid tumors, we have designed CAR-T cells that target more than one tumor antigen. Our key focus is TAG-72 is a glycoprotein specifically found on the surface of many adenocarcinoma cells, including ovary, prostate, breast, colon, lung and pancreatic cancers. We are combining this with another transmembrane protein which is also highly expressed in many tumors. Accordingly we have generated a second generation anti-TAG72 CAR which co-stimulates CAR-T cells to become cytolytic but also induces T-cell expansion upon repeated exposure to the antigen. The synergistic combination of the two markedly enhances the binding affinity of the CAR-T cell to the cancer cells and results in more complete cytotoxicity of cancer cells in vitro, as demonstrated using the real-time xCelligence platform. We also found that the dual combination did not lead to destruction of normal cells in our in vitro cytotoxicity assay.