Salmonella typhimurium engineered to produce CCL21 inhibit tumor growth.
Intravenously-applied bacteria tend to accumulate in tumors and can sporadically lead to tumor regression. Systemic administration of attenuated Salmonella typhimurium is safe and has shown no significant adverse effects in humans. The purpose of this study was to test the hypothesis that engineering S. typhimurium to express a chemokine, CCL21, would increase anti-tumor activity. We engineered an attenuated strain of S. typhimurium to produce the chemokine CCL21. Attenuated S. typhimurium expressing CCL21 significantly inhibited the growth of primary tumors and pulmonary metastases in preclinical models of multi-drug-resistant murine carcinomas, while control bacteria did not. Histological analysis of tumors showed marked inflammatory cell infiltrates in mice treated with CCL21-expressing but not control bacteria. Levels of cytokines and chemokines known to be induced by CCL21 [e.g., interferon-gamma (INFgamma), CXCL9, and CXCL10] were significantly elevated in tumors of mice treated with CCL21-expressing but not control S. typhimurium. The anti-tumor activity was found to be dependent on CD4- and CD8-expressing cells, based on antibody-mediated in vivo immuno-depletion experiments. Anti-tumor activity was achieved without evidence of toxicity. In summary, chemokine-expressing, attenuated bacteria may provide a novel approach to cancer immunotherapy for effective and well-tolerated in vivo delivery of immunomodulatory proteins.
Loeffler
Markus
M
Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Le'Negrate
Gaelle
G
Krajewska
Maryla
M
Reed
John C
JC
D000230:Adenocarcinoma / Q000737:chemistry / Q000276:immunology / Q000517:prevention & control / Q000556:secondary / Q000628:therapy*; D000818:Animals; D001428:Bacterial Vaccines / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D045744:Cell Line, Tumor / Q000637:transplantation; D054421:Chemokine CCL21 / Q000235:genetics / Q000502:physiology*; D018925:Chemokines / Q000032:analysis; D003110:Colonic Neoplasms / Q000473:pathology; D016207:Cytokines / Q000032:analysis; D005260:Female; D016233:Immunotherapy, Active; D008175:Lung Neoplasms / Q000737:chemistry / Q000276:immunology / Q000517:prevention & control / Q000556:secondary / Q000628:therapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000737:chemistry / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012486:Salmonella typhimurium / Q000235:genetics* / Q000378:metabolism; D014613:Vaccines, Attenuated / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D001428:Bacterial Vaccines; D019496:Cancer Vaccines; D054421:Chemokine CCL21; D018925:Chemokines; D016207:Cytokines; D011993:Recombinant Fusion Proteins; D014613:Vaccines, Attenuated