Attenuated Salmonella engineered to produce human cytokine LIGHT inhibit tumor growth.
Intravenously administered bacteria reportedly accumulate in tumors. Furthermore, systemic administration of attenuated Salmonella typhimurium has little or no significant side-effects in humans. Consequently, we engineered such bacteria to improve their oncolytic activity by stably inserting a gene encoding LIGHT, a cytokine known to promote tumor rejection. Unlike control bacteria, attenuated S. typhimurium expressing LIGHT inhibited growth of primary tumors, as well as the dissemination of pulmonary metastases, in various mouse tumor models employing murine carcinoma cell lines in immunocompetent mice. Antitumor activity was achieved without significant toxicity and was associated with infiltration of inflammatory cells and dependent on the LIGHT receptors, herpes virus entry mediator (HVEM), and lymphotoxin-beta receptor (LTbetaR). These findings provide evidence that nonvirulent bacteria can be exploited as targeting vehicles for local generation of therapeutic proteins in tumors.
Loeffler
Markus
M
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Le'Negrate
Gaelle
G
Krajewska
Maryla
M
Reed
John C
JC
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D015202:Protein Engineering; D012486:Salmonella typhimurium / Q000235:genetics / Q000378:metabolism*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics / Q000378:metabolism*
C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14