Bacteriolytic Therapy Can Generate a Potent Immune Response against Experimental Tumors

When spores of the anaerobic bacterium Clostridium novyi-NT are systemically injected into animals, they germinate exclusively within the hypoxic regions of cancers. The germinated bacteria destroy adjacent tumor cells but spare a rim of well oxygenated tumor cells that subsequently expand. Surprisi...

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Published in	Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 42; pp. 15172 - 15177
Main Authors	Agrawal, Nishant, Bettegowda, Chetan, Cheong, Ian, Geschwind, Jean-Francois, Drake, Charles G., Hipkiss, Edward L., Tatsumi, Mitsuaki, Dang, Long H., Diaz, Luis A., Pomper, Martin, Abusedera, Mohammad, Wahl, Richard L., Kinzler, Kenneth W., Zhou, Shibin, Huso, David L., Vogelstein, Bert
Format	Journal Article
Language	English
Published	United States National Academy of Sciences 19.10.2004 National Acad Sciences
Subjects	Adoptive Transfer Animals Bacteria Bacterial spores Bacteriolysis Biological Sciences Cell Line, Tumor Clostridium - immunology Clostridium Infections - immunology Clostridium novyi Cytokines Experiments Immune response Immune system Inflammation Lesions Lymphocytes Mice Mice, Inbred BALB C Models, Immunological Neoplasms, Experimental - immunology Neoplasms, Experimental - pathology Neoplasms, Experimental - therapy Rabbits Spores Spores, Bacterial - immunology Therapy Tumors
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Abstract	When spores of the anaerobic bacterium Clostridium novyi-NT are systemically injected into animals, they germinate exclusively within the hypoxic regions of cancers. The germinated bacteria destroy adjacent tumor cells but spare a rim of well oxygenated tumor cells that subsequently expand. Surprisingly, we found that ≈30% of mice treated with such spores were cured of their cancers despite the viable tumor rim initially remaining after spore germination. The mechanism underlying this effect was shown to be immune-mediated, because cured animals rejected a subsequent challenge of the same tumor. Similar effects were observed in rabbits with intrahepatic tumors. It was particularly notable that the induced immune response, when combined with the bacteriolytic effects of C. novyi-NT, could eradicate large established tumors.
AbstractList	When spores of the anaerobic bacterium Clostridium novyi-NT are systemically injected into animals, they germinate exclusively within the hypoxic regions of cancers. The germinated bacteria destroy adjacent tumor cells but spare a rim of well oxygenated tumor cells that subsequently expand. Surprisingly, we found that approximately 30% of mice treated with such spores were cured of their cancers despite the viable tumor rim initially remaining after spore germination. The mechanism underlying this effect was shown to be immune-mediated, because cured animals rejected a subsequent challenge of the same tumor. Similar effects were observed in rabbits with intrahepatic tumors. It was particularly notable that the induced immune response, when combined with the bacteriolytic effects of C. novyi-NT, could eradicate large established tumors. When spores of the anaerobic bacterium Clostridium novyi-NT are systemically injected into animals, they germinate exclusively within the hypoxic regions of cancers. The germinated bacteria destroy adjacent tumor cells but spare a rim of well oxygenated tumor cells that subsequently expand. Surprisingly, we found that {approx}30% of mice treated with such spores were cured of their cancers despite the viable tumor rim initially remaining after spore germination. The mechanism underlying this effect was shown to be immune-mediated, because cured animals rejected a subsequent challenge of the same tumor. Similar effects were observed in rabbits with intrahepatic tumors. It was particularly notable that the induced immune response, when combined with the bacteriolytic effects of C. novyi-NT, could eradicate large established tumors. [PUBLICATION ABSTRACT] When spores of the anaerobic bacterium Clostridium novyi-NT are systemically injected into animals, they germinate exclusively within the hypoxic regions of cancers. The germinated bacteria destroy adjacent tumor cells but spare a rim of well oxygenated tumor cells that subsequently expand. Surprisingly, we found that ≈30% of mice treated with such spores were cured of their cancers despite the viable tumor rim initially remaining after spore germination. The mechanism underlying this effect was shown to be immune-mediated, because cured animals rejected a subsequent challenge of the same tumor. Similar effects were observed in rabbits with intrahepatic tumors. It was particularly notable that the induced immune response, when combined with the bacteriolytic effects of C. novyi-NT , could eradicate large established tumors. When spores of the anaerobic bacterium Clostridium novyi-NT are systemically injected into animals, they germinate exclusively within the hypoxic regions of cancers. The germinated bacteria destroy adjacent tumor cells but spare a rim of well oxygenated tumor cells that subsequently expand. Surprisingly, we found that ≈30% of mice treated with such spores were cured of their cancers despite the viable tumor rim initially remaining after spore germination. The mechanism underlying this effect was shown to be immune-mediated, because cured animals rejected a subsequent challenge of the same tumor. Similar effects were observed in rabbits with intrahepatic tumors. It was particularly notable that the induced immune response, when combined with the bacteriolytic effects of C. novyi-NT , could eradicate large established tumors. When spores of the anaerobic bacterium Clostridium novyi-NT are systemically injected into animals, they germinate exclusively within the hypoxic regions of cancers. The germinated bacteria destroy adjacent tumor cells but spare a rim of well oxygenated tumor cells that subsequently expand. Surprisingly, we found that ~30% of mice treated with such spores were cured of their cancers despite the viable tumor rim initially remaining after spore germination. The mechanism underlying this effect was shown to be immune-mediated, because cured animals rejected a subsequent challenge of the same tumor. Similar effects were observed in rabbits with intrahepatic tumors. It was particularly notable that the induced immune response, when combined with the bacteriolytic effects of C. novyi-NT, could eradicate large established tumors.
Author	Abusedera, Mohammad Agrawal, Nishant Cheong, Ian Geschwind, Jean-Francois Tatsumi, Mitsuaki Vogelstein, Bert Drake, Charles G. Pomper, Martin Wahl, Richard L. Huso, David L. Kinzler, Kenneth W. Bettegowda, Chetan Dang, Long H. Zhou, Shibin Hipkiss, Edward L. Diaz, Luis A.
AuthorAffiliation	Howard Hughes Medical Institute, † Sidney Kimmel Cancer Center, and Departments of ‡ Otolaryngology-Head and Neck Surgery, ¶ Radiology and Radiological Sciences, and ∥ Comparative Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21231
AuthorAffiliation_xml	– name: Howard Hughes Medical Institute, † Sidney Kimmel Cancer Center, and Departments of ‡ Otolaryngology-Head and Neck Surgery, ¶ Radiology and Radiological Sciences, and ∥ Comparative Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21231
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Notes	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 To whom correspondence should be addressed. E-mail: vogelbe@jhmi.edu. Abbreviations: CT, computed tomography; PET, positron emission tomography; FDG, [18F]fluorodeoxyglucose. C.B. and I.C. contributed equally to this work. Contributed by Bert Vogelstein, August 25, 2004
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Snippet	When spores of the anaerobic bacterium Clostridium novyi-NT are systemically injected into animals, they germinate exclusively within the hypoxic regions of... When spores of the anaerobic bacterium Clostridium novyi-NT are systemically injected into animals, they germinate exclusively within the hypoxic regions of...
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SubjectTerms	Adoptive Transfer Animals Bacteria Bacterial spores Bacteriolysis Biological Sciences Cell Line, Tumor Clostridium - immunology Clostridium Infections - immunology Clostridium novyi Cytokines Experiments Immune response Immune system Inflammation Lesions Lymphocytes Mice Mice, Inbred BALB C Models, Immunological Neoplasms, Experimental - immunology Neoplasms, Experimental - pathology Neoplasms, Experimental - therapy Rabbits Spores Spores, Bacterial - immunology Therapy Tumors
Title	Bacteriolytic Therapy Can Generate a Potent Immune Response against Experimental Tumors
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