Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses.

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Abstract

Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.

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Journal

Journal ID (iso-abbrev): Sci Transl Med

Title: Science translational medicine

ISSN (Electronic): 1946-6242

ISSN (Print): 1946-6234

Publication date (Electronic): Aug 13 2014

Volume: 6

Issue: 249

Affiliations

[1 ] The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA.

[2 ] BioMed Valley Discoveries Inc., 4520 Main Street, Kansas City, MO 64111, USA.

[3 ] Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

[4 ] Department of Neurosurgery, The Johns Hopkins Medical Institutes, Baltimore, MD 21231, USA.

[5 ] Department of Neurosurgery, The Johns Hopkins Medical Institutes, Baltimore, MD 21231, USA. Department of Neurology, The Johns Hopkins Medical Institutes, Baltimore, MD 21231, USA.

[6 ] Animal Clinical Investigation LLC, 4926 Wisconsin Avenue, NW Washington, DC 20016, USA.

[7 ] Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

[8 ] Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

[9 ] Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

[10 ] Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

[11 ] Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

[12 ] Department of Molecular and Comparative Pathobiology, The Johns Hopkins University, Baltimore, MD 21205, USA.

[13 ] The Veterinary Cancer Center, 129 Glover Avenue, Norwalk, CT 06850, USA.

[14 ] VCA Great Lakes Veterinary Specialists, 5035 Richmond Road, Bedford Heights, OH 44146, USA.

[15 ] The Oncology Service, Friendship Hospital for Animals, 4105 Brandywine Street, NW, Washington, DC 20016, USA.

[16 ] BluePearl Veterinary Partners, 410 West 55th Street, New York, NY 10019, USA.

[17 ] Veterinary Specialty Hospital of San Diego, 10435 Sorrento Valley Road, San Diego, CA 92121, USA.

[18 ] Veterinary Cancer Group of Los Angeles at City of Angels Veterinary Specialty Center, 9599 Jefferson Boulevard, Culver City, CA 90232, USA.

[19 ] Southern Arizona Veterinary Specialty and Emergency Center, 141 East Fort Lowell, Tucson, AZ 85705, USA.

[20 ] The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA.The Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21231, USA.

[21 ] The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA. Department of Neurosurgery, The Johns Hopkins Medical Institutes, Baltimore, MD 21231, USA.

[22 ] BioMed Valley Discoveries Inc., 4520 Main Street, Kansas City, MO 64111, USA. saurabh.saha@gmail.com.

Article

Publisher Item ID: 6/249/249ra111 Mid ID: NIHMS659033

DOI: 10.1126/scitranslmed.3008982

PubMed ID: 25122639

SO-VID: e1c392b4-8e08-4316-9549-8431a925a3f2

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