"Active" cancer immunotherapy by anti-Met antibody gene transfer.
Gene therapy provides a still poorly explored opportunity to treat cancer by "active" immunotherapy as it enables the transfer of genes encoding antibodies directed against specific oncogenic proteins. By a bidirectional lentiviral vector, we transferred the cDNA encoding the heavy and light chains of a monoclonal anti-Met antibody (DN-30) to epithelial cancer cells. In vitro, the transduced cells synthesized and secreted correctly assembled antibodies with the expected high affinity, inducing down-regulation of the Met receptor and strong inhibition of the invasive growth response. The inhibitory activity resulted (a) from the interference of the antibody with the Met receptor intracellular processing ("cell autonomous activity," in cis) and (b) from the antibody-induced cleavage of Met expressed at the cell surface ("bystander effect," in trans). The monoclonal antibody gene transferred into live animals by systemic administration or by local intratumor delivery resulted in substantial inhibition of tumor growth. These data provide proof of concept both for targeting the Met receptor and for a gene transfer-based immunotherapy strategy.
Vigna
Elisa
E
Laboratory for Gene Transfer and Therapy,Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Turin, Italy.
Pacchiana
Giovanni
G
Mazzone
Massimiliano
M
Chiriaco
Cristina
C
Fontani
Lara
L
Basilico
Cristina
C
Pennacchietti
Selma
S
Comoglio
Paolo M
PM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met