Anti-tumor activity of human T cells expressing the CC49-zeta chimeric immune receptor

A chimeric immune receptor consisting of an extracellular antigen-binding d omain derived from the CC49 humanized single-chain antibody, linked to the CD3 zeta signaling domain of the T cell receptor, was generated (CC49-zeta) , This receptor binds to TAG-72, a mucin antigen expressed by most human ad enocarcinomas. CC49-zeta was expressed in CD4(+) and CD8(+) T cells and ind uced cytokine production on stimulation. Human T cells expressing CC49-zeta recognized and killed tumor cell lines and primary tumor cells expressing TAG-72, CC49-zeta T cells did not mediate bystander killing of TAG-72-negat ive cells. In addition, CC49-zeta T cells not only killed Fast-positive tum or cells in vitro and in vivo, but also survived in their presence, and wer e immunoprotective in intraperitoneal and subcutaneous murine tumor xenogra ft models with TAG-72-positive human tumor cells. Finally, receptor-positiv e T cells were still effective in killing TAG-72-positive targets in the pr esence of physiological levels of soluble TAG-72, and did not induce killin g of TAG-72-negative cells under the same conditions, This approach is bein g currently being utilized in a phase I clinical trial for the treatment of colon cancer.