IL-18-producing Salmonella inhibit tumor growth.
Previous studies have shown that intravenously applied bacteria can accumulate in tumors and lead to sporadic tumor regression. Recently, systemic administration of attenuated Salmonella typhimurium was demonstrated to generate no significant side effects in humans, but also no antitumor responses. We report the enhanced antitumor activity in preclinical mouse cancer models of nonvirulent S. typhimurium engineered to synthesize the cytokine Interleukin-18 (IL-18). IL-18-producing bacteria (but not control bacteria) inhibit the growth of primary subcutaneous tumors as well as pulmonary metastases in immunocompetent mice challenged with syngeneic multidrug-resistant clones of murine carcinoma cell lines, without overt toxicity to normal tissues. Antitumor activity was associated with increased accumulation of T-lymphocytes and NK cells in tumors, and massive infiltration of granulocytes, as well as increased intra-tumoral production of several cytokines. In summary, these findings provide evidence of promising preclinical antitumor activity of IL-18-expressing, attenuated S. typhimurium, suggesting a novel strategy for cancer immunotherapy.
Loeffler
M
M
Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Le'Negrate
G
G
Krajewska
M
M
Reed
J C
JC
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D020382:Interleukin-18 / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D015202:Protein Engineering; D012475:Salmonella / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016207:Cytokines; D020382:Interleukin-18