Ligand-mediated cytolysis of tumor cells: Use of heregulin-zeta chimeras to redirect cytotoxic T lymphocytes

New specificities may be engrafted onto lymphocytes by the transfer of gene s for chimeric receptors that combine antigen recognition and signal-transd ucing elements. We have engineered and evaluated a new class of chimeric re ceptors that use the natural ligands of receptors found to be frequently ov erexpressed by cancer cells. The heregulin molecule, a ligand for Her3 and Her4 receptors when fused with the CD3 zeta-chain, was capable of redirecti ng T lymphocytes to recognize and respond to cancer cell lines that overexp ress these receptors. Thus, CD8(+) T lymphocytes were isolated from a healt hy individual and transduced to express the chimeric heregulin-zeta recepto r. These modified effector cells acquired the ability to specifically lyse a breast cancer cell line that overexpresses Her3 and Her4. A new class of chimeric receptors, such as heregulin-zeta endowing anti-cancer effector ce lls with the potential to recognize and eliminate tumor targets, are likely to increase the effectiveness of adoptive immunotherapy for the treatment of cancer.