In vivo cervical cancer growth inhibition by genetically engineered cytotoxic T cells

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2005-01, Vol.54 (1), p.51-60
• Main Authors: DALL, Peter, HERRMANN, Isabell, DURST, Bettina, STOFF-KHALILI, Mariam A, BAUERSCHMITZ, Gerd, HANSTEIN, Bettina, NIEDERACHER, Dieter
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - genetics; Antigen-Presenting Cells - immunology; Antineoplastic agents; Biological and medical sciences; Cell Line; Cervical cancer; Female; Genetic Engineering; Genetic Therapy - methods; Hyaluronan Receptors - genetics; Hyaluronan Receptors - immunology; Immunohistochemistry; Immunotherapy, Adoptive - methods; Medical sciences; Mice; Mice, Inbred BALB C; Models, Animal; Original; Pharmacology. Drug treatments; Receptors, Antigen, T-Cell - genetics; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - transplantation; Time Factors; Uterine Cervical Neoplasms - immunology; Uterine Cervical Neoplasms - therapy; Xenograft Model Antitumor Assays
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-004-0569-x

The CD44 v7/8 splice variant that is frequently expressed in cervical carcinoma and rarely expressed in normal tissues displays promising properties as a target antigen for cancer immune therapy. In this study, cytotoxic T lymphocytes (CTLs) were genetically engineered to gain CD44v7/8 target specificity. Clone 96 (Cl96), an established murine cytotoxic T-cell line, and naïve murine T cells were retrovirally transduced with a fusion gene construct encoding for the single chain fragment scFv of the monoclonal antibody VFF17 and for the zeta chain of the T-cell receptor (TCR). The therapeutic potential of genetically engineered T cells was tested in vitro and in vivo. Surface expression of the chimeric TCR on infected Cl96 and naïve T cells was shown by FACS analysis. CD44v7/8-positive target cells were efficiently lysed by transduced Cl96 and naïve T cells, demonstrating the functionality and specificity of the chimeric TCR. In a xenograft BALB/c mouse model, efficient growth retardation of CD44v7/8-positive tumours was mediated by genetically engineered Cl96(VFF17)cyYZ cells. We were able to reprogramme the target specificity of recombinant Cl96 and naïve CTLs resulting in efficient cytolysis of CD44v7/8-positive cervical cancer cells. High transduction rates and the specific cytolysis of CD44v7/8-redirected CTLs are promising tools for an immune gene therapy approach for advanced cervical cancer.