title: Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses.
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.
authors.affiliation: 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.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Roberts
authors.affiliation: BioMed Valley Discoveries Inc., 4520 Main Street, Kansas City, MO 64111, USA.
authors.forename: Linping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: BioMed Valley Discoveries Inc., 4520 Main Street, Kansas City, MO 64111, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Collins
authors.affiliation: Department of Neurosurgery, The Johns Hopkins Medical Institutes, Baltimore, MD 21231, USA.
authors.forename: Ren-Yuan
authors.initials: RY
authors.lastname: Bai
authors.affiliation: Department of Neurosurgery, The Johns Hopkins Medical Institutes, Baltimore, MD 21231, USA.|Department of Neurology, The Johns Hopkins Medical Institutes, Baltimore, MD 21231, USA.
authors.forename: Verena
authors.initials: V
authors.lastname: Staedtke
authors.affiliation: Animal Clinical Investigation LLC, 4926 Wisconsin Avenue, NW Washington, DC 20016, USA.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Rusk
authors.affiliation: BioMed Valley Discoveries Inc., 4520 Main Street, Kansas City, MO 64111, USA.
authors.forename: David
authors.initials: D
authors.lastname: Tung
authors.affiliation: BioMed Valley Discoveries Inc., 4520 Main Street, Kansas City, MO 64111, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Miller
authors.affiliation: BioMed Valley Discoveries Inc., 4520 Main Street, Kansas City, MO 64111, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Roix
authors.affiliation: Animal Clinical Investigation LLC, 4926 Wisconsin Avenue, NW Washington, DC 20016, USA.
authors.forename: Kristen V
authors.initials: KV
authors.lastname: Khanna
authors.affiliation: Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Murthy
authors.affiliation: Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Benjamin
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Thorunn
authors.initials: T
authors.lastname: Helgason
authors.affiliation: Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ariel D
authors.initials: AD
authors.lastname: Szvalb
authors.affiliation: Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Bird
authors.affiliation: Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Sinchita
authors.initials: S
authors.lastname: Roy-Chowdhuri
authors.affiliation: BioMed Valley Discoveries Inc., 4520 Main Street, Kansas City, MO 64111, USA.
authors.forename: Halle H
authors.initials: HH
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Molecular and Comparative Pathobiology, The Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Baktiar
authors.initials: B
authors.lastname: Karim
authors.affiliation: The Veterinary Cancer Center, 129 Glover Avenue, Norwalk, CT 06850, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: McDaniel
authors.affiliation: VCA Great Lakes Veterinary Specialists, 5035 Richmond Road, Bedford Heights, OH 44146, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Elpiner
authors.affiliation: The Oncology Service, Friendship Hospital for Animals, 4105 Brandywine Street, NW, Washington, DC 20016, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sahora
authors.affiliation: BluePearl Veterinary Partners, 410 West 55th Street, New York, NY 10019, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Lachowicz
authors.affiliation: Veterinary Specialty Hospital of San Diego, 10435 Sorrento Valley Road, San Diego, CA 92121, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Phillips
authors.affiliation: Veterinary Cancer Group of Los Angeles at City of Angels Veterinary Specialty Center, 9599 Jefferson Boulevard, Culver City, CA 90232, USA.
authors.forename: Avenelle
authors.initials: A
authors.lastname: Turner
authors.affiliation: Southern Arizona Veterinary Specialty and Emergency Center, 141 East Fort Lowell, Tucson, AZ 85705, USA.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Klein
authors.affiliation: The Veterinary Cancer Center, 129 Glover Avenue, Norwalk, CT 06850, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Post
authors.affiliation: 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.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.affiliation: Department of Neurosurgery, The Johns Hopkins Medical Institutes, Baltimore, MD 21231, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
authors.affiliation: 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.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: 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.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: 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.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: 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.
authors.forename: Chetan
authors.initials: C
authors.lastname: Bettegowda
authors.affiliation: Department of Molecular and Comparative Pathobiology, The Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.affiliation: BioMed Valley Discoveries Inc., 4520 Main Street, Kansas City, MO 64111, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Varterasian
authors.affiliation: BioMed Valley Discoveries Inc., 4520 Main Street, Kansas City, MO 64111, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Saha
authors.affiliation: 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.
authors.forename: Shibin
authors.initials: S
authors.lastname: Zhou
mesh_terms: D000818:Animals; D003013:Clostridium / Q000502:physiology*; D004285:Dogs; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000382:microbiology* / Q000473:pathology / Q000628:therapy*; D051381:Rats; D015203:Reproducibility of Results; D012509:Sarcoma / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy; D013171:Spores, Bacterial; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome