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 genes for chimeric receptors that combine antigen recognition and signal-transducing elements. We have engineered and evaluated a new class of chimeric receptors that use the natural ligands of receptors found to be frequently overexpressed by cancer cells. The heregulin molecule, a ligand for Her3 and Her4 receptors when fused with the CD3 zeta-chain, was capable of redirecting T lymphocytes to recognize and respond to cancer cell lines that overexpress these receptors. Thus, CD8+ T lymphocytes were isolated from a healthy individual and transduced to express the chimeric heregulin-zeta receptor. 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 cells with the potential to recognize and eliminate tumor targets, are likely to increase the effectiveness of adoptive immunotherapy for the treatment of cancer.
Muniappan
A
A
RPR Gencell, Santa Clara, California 95054, USA.
Banapour
B
B
Lebkowski
J
J
Talib
S
S
D019264:Adoptive Transfer; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D020893:Receptor, ErbB-3 / Q000276:immunology; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D008024:Ligands; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011993:Recombinant Fusion Proteins