Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 31, Pages 12879-12883Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0701959104
Keywords
cancer therapy; immunotherapy; tumor homing
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Funding
- NCI NIH HHS [P01 CA069381, CA 69381] Funding Source: Medline
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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 (LT beta R). These findings provide evidence that nonvirulent bacteria can be exploited as targeting vehicles for local generation of therapeutic proteins in tumors.
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