Redirecting mouse T hybridoma against human breast and ovarian carcinomas: in vivo activity against HER-2/neu expressing cancer cells.

Abstract

Chimeric receptors comprising of the T-cell receptor-zeta cytoplasmic signalling chain fused to an extracellular ligand-binding domain of a single-chain antibody (scFv) have served as effective tools for redirecting cytotoxic T lymphocytes (CTL) against tumour cells. In this report, we constructed a chimeric scFv/zeta gene composed of the variable regions of an HER-2/neu-specific monoclonal antibody (MAb) joined to the TCR-zeta chain. The scFv(anti-HER-2/neu)/zeta chimeric gene was successfully expressed as a functional surface receptor in the MD.45 CTL hybridoma (MD.45-HER/zeta). More importantly, the scFv(anti-HER-2/neu)/zeta receptor was functionally active, since it triggered cytokine secretion by the MD.45-HER/zeta cells upon recognition of HER-2/neu-positive (+) tumour cell lines, or primary tumour cells from patients with HER-2/neu(+) cancers. The MD.45-HER/zeta-transduced cells also lysed HER-2/neu(+) target cells in vitro with high specificity. We tested the antitumour efficacy of scFv(anti-HER-2/neu)/zeta expressing MD.45 cells in severe combined immunodeficiency disease mice/human and murine tumour models. The adoptively transferred MD.45-HER/zeta cells both slowed significantly the growth of human FM3 melanoma or murine ALC leukaemic cells both transfected to express HER-2/neu. Our data demonstrate the feasibility of redirecting MD.45 CTL with the scFv(anti-HER-2/neu)/zeta chimeric receptor to respond specifically against HER-2/neu expressing tumour cells in vitro and in vivo. Moreover, they make it likely that T cells transduced with the same chimeric gene might be utilised in the treatment of patients with HER-2/neu(+) tumours.

• Authors: A D Gritzapis, A Mamalaki, A Kretsovali, J Papamatheakis, M Belimezi, S A Perez, C N Baxevanis, M Papamichail
• Journal: British journal of cancer (Br J Cancer) Vol. 88 Issue 8 Pg. 1292-300 (Apr 22 2003) ISSN: 0007-0920 [Print] England
• PMID: 12698199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon-gamma
• Receptor, ErbB-2

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• Breast Neoplasms (immunology)
• Cell Line, Tumor
• Cytotoxicity, Immunologic
• Female
• Flow Cytometry
• Humans
• Hybridomas (immunology)
• Interferon-gamma (biosynthesis)
• Mice
• Mice, SCID
• Molecular Sequence Data
• Ovarian Neoplasms (immunology)
• Receptor, ErbB-2 (genetics)
• T-Lymphocytes (immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Transfection