CYTOTOXIC T-LYMPHOCYTES WITH A GRAFTED RECOGNITION SPECIFICITY FOR ERBB2-EXPRESSING TUMOR-CELLS

Experimental approaches which exploit the targeted cytolytic activity of lymphocytes are being developed for cancer therapy. We generated cy totoxic T lymphocytes (CTLs) with specificity for ERBB2 receptor-expre ssing tumor cells. A binding function was conferred directly on the ze ta chain of the T-cell receptor (TCR) complex to circumvent major hist ocompatibility complex-restricted antigen recognition through the alph a and beta chains of the TCR. A chimeric gene was constructed which en coded a single-chain Fv antibody (scFv, consisting of the joined heavy - and light-chain variable domains of a monoclonal antibody against th e extracellular domain of the ERBB2 receptor), a hinge region as a spa cer, and the zeta chain of the TCR. This gene was introduced into CTLs by retroviral gene transfer. The signaling potential of the scFv/hing e/zeta receptors was demonstrated by secretion of interferon gamma upo n coincubation with ERBB2-expressing cells. Target cells expressing th e ERBB2 gene were lysed in vitro with high specificity by the scFv/hin ge/zeta-expressing T cells. The growth of ERBB2-transformed cells in a thymic nude mice was retarded by adoptively transferred scFv/hinge/zet a-expressing CTLs. Transduced CTLs labeled with a fluorescent dye were specifically detected in tumor sections. Our results suggest that tum or cell lysis by CTLs grafted in vitro with a major histocompatibility complex-independent recognition could become a gene-therapy approach to cancer treatment.