Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses

Nicholas Roberts, Linping Zhang, Filip Janku, Amanda Collins, Renyuan Bai, Verena Staedtke, Anthony W. Rusk, David Tung, Maria Miller, Jeffrey Roix, Kristen V. Khanna, Ravi Murthy, Robert S. Benjamin, Thorunn Helgason, Ariel D. Szvalb, Justin E. Bird, Sinchita Roy-Chowdhuri, Halle H. Zhang, Yuan Qiao, Baktiar Karim & 18 others Jennifer McDaniel, Amanda Elpiner, Alexandra Sahora, Joshua Lachowicz, Brenda Phillips, Avenelle Turner, Mary K. Klein, Gerald Post, Luis A. Diaz, Gregory J Riggins, Nickolas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein, Chetan Bettegowda, David L. Huso, Mary Varterasian, Saurabh Saha, Shibin Zhou

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number249ra111
JournalScience Translational Medicine
Volume6
Issue number249
DOIs
StatePublished - Aug 13 2014

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Clostridium
Spores
Injections
Neoplasms
Canidae
Dogs
Leiomyosarcoma
Bacterial Infections
Brain Neoplasms
Theoretical Models
Clinical Trials
Bacteria
Bone and Bones
Mutation
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. / Roberts, Nicholas; Zhang, Linping; Janku, Filip; Collins, Amanda; Bai, Renyuan; Staedtke, Verena; Rusk, Anthony W.; Tung, David; Miller, Maria; Roix, Jeffrey; Khanna, Kristen V.; Murthy, Ravi; Benjamin, Robert S.; Helgason, Thorunn; Szvalb, Ariel D.; Bird, Justin E.; Roy-Chowdhuri, Sinchita; Zhang, Halle H.; Qiao, Yuan; Karim, Baktiar; McDaniel, Jennifer; Elpiner, Amanda; Sahora, Alexandra; Lachowicz, Joshua; Phillips, Brenda; Turner, Avenelle; Klein, Mary K.; Post, Gerald; Diaz, Luis A.; Riggins, Gregory J; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Bettegowda, Chetan; Huso, David L.; Varterasian, Mary; Saha, Saurabh; Zhou, Shibin.

In: Science Translational Medicine, Vol. 6, No. 249, 249ra111, 13.08.2014.

Research output: Contribution to journalArticle

Roberts, N, Zhang, L, Janku, F, Collins, A, Bai, R, Staedtke, V, Rusk, AW, Tung, D, Miller, M, Roix, J, Khanna, KV, Murthy, R, Benjamin, RS, Helgason, T, Szvalb, AD, Bird, JE, Roy-Chowdhuri, S, Zhang, HH, Qiao, Y, Karim, B, McDaniel, J, Elpiner, A, Sahora, A, Lachowicz, J, Phillips, B, Turner, A, Klein, MK, Post, G, Diaz, LA, Riggins, GJ, Papadopoulos, N, Kinzler, KW, Vogelstein, B, Bettegowda, C, Huso, DL, Varterasian, M, Saha, S & Zhou, S 2014, 'Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses', Science Translational Medicine, vol. 6, no. 249, 249ra111. https://doi.org/10.1126/scitranslmed.3008982
Roberts, Nicholas ; Zhang, Linping ; Janku, Filip ; Collins, Amanda ; Bai, Renyuan ; Staedtke, Verena ; Rusk, Anthony W. ; Tung, David ; Miller, Maria ; Roix, Jeffrey ; Khanna, Kristen V. ; Murthy, Ravi ; Benjamin, Robert S. ; Helgason, Thorunn ; Szvalb, Ariel D. ; Bird, Justin E. ; Roy-Chowdhuri, Sinchita ; Zhang, Halle H. ; Qiao, Yuan ; Karim, Baktiar ; McDaniel, Jennifer ; Elpiner, Amanda ; Sahora, Alexandra ; Lachowicz, Joshua ; Phillips, Brenda ; Turner, Avenelle ; Klein, Mary K. ; Post, Gerald ; Diaz, Luis A. ; Riggins, Gregory J ; Papadopoulos, Nickolas ; Kinzler, Kenneth W ; Vogelstein, Bert ; Bettegowda, Chetan ; Huso, David L. ; Varterasian, Mary ; Saha, Saurabh ; Zhou, Shibin. / Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. In: Science Translational Medicine. 2014 ; Vol. 6, No. 249.
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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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AU - Roberts, Nicholas

AU - Zhang, Linping

AU - Janku, Filip

AU - Collins, Amanda

AU - Bai, Renyuan

AU - Staedtke, Verena

AU - Rusk, Anthony W.

AU - Tung, David

AU - Miller, Maria

AU - Roix, Jeffrey

AU - Khanna, Kristen V.

AU - Murthy, Ravi

AU - Benjamin, Robert S.

AU - Helgason, Thorunn

AU - Szvalb, Ariel D.

AU - Bird, Justin E.

AU - Roy-Chowdhuri, Sinchita

AU - Zhang, Halle H.

AU - Qiao, Yuan

AU - Karim, Baktiar

AU - McDaniel, Jennifer

AU - Elpiner, Amanda

AU - Sahora, Alexandra

AU - Lachowicz, Joshua

AU - Phillips, Brenda

AU - Turner, Avenelle

AU - Klein, Mary K.

AU - Post, Gerald

AU - Diaz, Luis A.

AU - Riggins, Gregory J

AU - Papadopoulos, Nickolas

AU - Kinzler, Kenneth W

AU - Vogelstein, Bert

AU - Bettegowda, Chetan

AU - Huso, David L.

AU - Varterasian, Mary

AU - Saha, Saurabh

AU - Zhou, Shibin

PY - 2014/8/13

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N2 - 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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