Interleukin-15 (IL-15) and IL-21 have been reported to support the function of anti-tumor T cells. However, their use in the clinic has been constrained, in part, by dose-limiting toxicity and the need for repeated administration. To overcome these limitations, researchers in the National Cancer Institute (NCI) Experimental Transplantation and Immunology Branch (ETIB) have developed synthetic IL-15 and IL-21 molecules for autocrine expression by the engineered therapeutic T cells. These molecules were designed with flexible linkers that connect to cell membrane anchors. This, in turn, reduces systemic toxicity caused by free cytokine molecules. The inventors have shown that co-expression of the novel IL-15 and IL-21 tethered molecules improves the anti-tumor efficacy of the therapeutic engineered T cells in vivo.