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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Dall
Peter
P
Department of Obstetrics/Gynaecology, University of Duesseldorf Medical Center, Moorenstrasse 5, 40225 Duesseldorf, Germany. dall@med.uni-duesseldorf.de
Herrmann
Isabell
I
Durst
Bettina
B
Stoff-Khalili
Mariam A
MA
Bauerschmitz
Gerd
G
Hanstein
Bettina
B
Niederacher
Dieter
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000276:immunology*; D002460:Cell Line; D005260:Female; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*; D013997:Time Factors; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D018960:Hyaluronan Receptors; D011948:Receptors, Antigen, T-Cell