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Clinical Trials: Immunotherapy

Intratumoral Injection of Clostridium novyi-NT Spores in Patients with Treatment-refractory Advanced Solid Tumors

Filip Janku, Halle Huihong Zhang, Abdulmohammad Pezeshki, Sanjay Goel, Ravi Murthy, Andrea Wang-Gillam, Dale R. Shepard, Thorunn Helgason, Tyler Masters, David S. Hong, Sarina A. Piha-Paul, Daniel D. Karp, Mark Klang, Steven Y. Huang, Divya Sakamuri, Anjali Raina, Jean Torrisi, Stephen B. Solomon, Alice Weissfeld, Ernest Trevino, Gary DeCrescenzo, Amanda Collins, Maria Miller, Jennifer L. Salstrom, Ronald L. Korn, Linping Zhang, Saurabh Saha, Alexey A. Leontovich, David Tung, Brent Kreider, Mary Varterasian, Khashayarsha Khazaie and Mrinal M. Gounder
Filip Janku
1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • ORCID record for Filip Janku
  • For correspondence: fjanku@mdanderson.org khazaie@mayo.edu gounderm@mskcc.org
Halle Huihong Zhang
2BioMed Valley Discoveries Inc., Kansas City, Missouri.
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Abdulmohammad Pezeshki
3Department of Immunology, Mayo Clinic, Rochester, Minnesota.
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Sanjay Goel
4Montefiore/Albert Einstein Cancer Center, Bronx, New York.
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  • ORCID record for Sanjay Goel
Ravi Murthy
1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
5Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Andrea Wang-Gillam
6Washington University in St. Louis, St. Louis, Missouri.
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Dale R. Shepard
7Cleveland Clinic, Cleveland, Ohio.
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Thorunn Helgason
1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Tyler Masters
8Early Drug Development Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
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David S. Hong
1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • ORCID record for David S. Hong
Sarina A. Piha-Paul
1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Daniel D. Karp
1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Mark Klang
8Early Drug Development Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
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Steven Y. Huang
5Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Divya Sakamuri
1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Anjali Raina
1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jean Torrisi
8Early Drug Development Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
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Stephen B. Solomon
8Early Drug Development Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
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Alice Weissfeld
9Microbiology Specialists Inc., Houston, Texas.
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Ernest Trevino
9Microbiology Specialists Inc., Houston, Texas.
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Gary DeCrescenzo
2BioMed Valley Discoveries Inc., Kansas City, Missouri.
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Amanda Collins
2BioMed Valley Discoveries Inc., Kansas City, Missouri.
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Maria Miller
2BioMed Valley Discoveries Inc., Kansas City, Missouri.
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Jennifer L. Salstrom
10PAREXEL International, Waltham, Massachusetts.
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Ronald L. Korn
11Imaging Endpoints, Scottsdale, Arizona.
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Linping Zhang
2BioMed Valley Discoveries Inc., Kansas City, Missouri.
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Saurabh Saha
2BioMed Valley Discoveries Inc., Kansas City, Missouri.
12Atlas Venture, Boston, Massachusetts.
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Alexey A. Leontovich
13Biomedical Informatics, Mayo Clinic, Rochester, Minnesota.
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David Tung
2BioMed Valley Discoveries Inc., Kansas City, Missouri.
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Brent Kreider
2BioMed Valley Discoveries Inc., Kansas City, Missouri.
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Mary Varterasian
2BioMed Valley Discoveries Inc., Kansas City, Missouri.
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Khashayarsha Khazaie
3Department of Immunology, Mayo Clinic, Rochester, Minnesota.
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  • For correspondence: fjanku@mdanderson.org khazaie@mayo.edu gounderm@mskcc.org
Mrinal M. Gounder
8Early Drug Development Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
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  • For correspondence: fjanku@mdanderson.org khazaie@mayo.edu gounderm@mskcc.org
DOI: 10.1158/1078-0432.CCR-20-2065 Published January 2021
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Abstract

Purpose: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation.

Patients and Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 × 104 to 3 × 106 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose.

Results: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n = 2) and grade 4 gas gangrene (n = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n = 1), limb abscess (n = 1), soft-tissue infection (n = 1), respiratory insufficiency (n = 1), and rash (n = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses.

Conclusions: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2021;27:96–106

  • Received May 27, 2020.
  • Revision received July 24, 2020.
  • Accepted October 7, 2020.
  • Published first October 12, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 27 (1)
January 2021
Volume 27, Issue 1
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Intratumoral Injection of Clostridium novyi-NT Spores in Patients with Treatment-refractory Advanced Solid Tumors
Filip Janku, Halle Huihong Zhang, Abdulmohammad Pezeshki, Sanjay Goel, Ravi Murthy, Andrea Wang-Gillam, Dale R. Shepard, Thorunn Helgason, Tyler Masters, David S. Hong, Sarina A. Piha-Paul, Daniel D. Karp, Mark Klang, Steven Y. Huang, Divya Sakamuri, Anjali Raina, Jean Torrisi, Stephen B. Solomon, Alice Weissfeld, Ernest Trevino, Gary DeCrescenzo, Amanda Collins, Maria Miller, Jennifer L. Salstrom, Ronald L. Korn, Linping Zhang, Saurabh Saha, Alexey A. Leontovich, David Tung, Brent Kreider, Mary Varterasian, Khashayarsha Khazaie and Mrinal M. Gounder
Clin Cancer Res January 1 2021 (27) (1) 96-106; DOI: 10.1158/1078-0432.CCR-20-2065

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Intratumoral Injection of Clostridium novyi-NT Spores in Patients with Treatment-refractory Advanced Solid Tumors
Filip Janku, Halle Huihong Zhang, Abdulmohammad Pezeshki, Sanjay Goel, Ravi Murthy, Andrea Wang-Gillam, Dale R. Shepard, Thorunn Helgason, Tyler Masters, David S. Hong, Sarina A. Piha-Paul, Daniel D. Karp, Mark Klang, Steven Y. Huang, Divya Sakamuri, Anjali Raina, Jean Torrisi, Stephen B. Solomon, Alice Weissfeld, Ernest Trevino, Gary DeCrescenzo, Amanda Collins, Maria Miller, Jennifer L. Salstrom, Ronald L. Korn, Linping Zhang, Saurabh Saha, Alexey A. Leontovich, David Tung, Brent Kreider, Mary Varterasian, Khashayarsha Khazaie and Mrinal M. Gounder
Clin Cancer Res January 1 2021 (27) (1) 96-106; DOI: 10.1158/1078-0432.CCR-20-2065
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