Virus-directed enzyme prodrug therapy: Intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer

Daniel H. Palmer, Vivien Mautner, Darius Mirza, Simon Oliff, Winald Gerritsen, Joost R M Van der Sijp, Stefan Hubscher, Gary Reynolds, Sarah Bonney, Ratna Rajaratnam, Diana Hull, Mark Horne, John Ellis, Andrew Mountain, Simon Hill, Peter A. Harris, Peter F. Searle, Lawrence S. Young, Nicholas D. James, David J. Kerr

Research output: Contribution to journalArticle

Abstract

Purpose Virus-directed enzyme prodrug therapy depends on selective delivery of virus encoding a prodrug-activating enzyme to tumor, followed by systemic treatment with prodrug to achieve high levels of the activated cytotoxic at the intended site of action. The use of the bacterial enzyme nitroreductase to activate CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) to a short lived, highly toxic DNA cross-linking agent has been demonstrated in tumor xenografts. In this study, we report the first clinical trial investigating the feasibility, safety, and transgene expression of a replication-defective adenovirus encoding nitroreductase (CTL102) in patients with liver tumors. Patients and Methods Patients with resectable primary or secondary (colorectal) liver cancer received a single dose of CTL102 delivered by direct intratumoral inoculation 3 to 8 days before surgical resection. Results Eighteen patients were treated with escalating doses of CTL102 (range, 108-5 × 1011 virus particles). The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Dose-related increases in tumoral nitroreductase expression measured by immunohistochemical analysis have been observed. Conclusion Direct intratumoral inoculation of CTL102 to patients with primary and secondary liver cancer is feasible and well tolerated. The high level of nitroreductase expression observed at 1 to 5 × 1011 virus particles mandates further studies in patients with inoperable tumors who will receive CTL102 and CB1954.

Original languageEnglish (US)
Pages (from-to)1546-1552
Number of pages7
JournalJournal of Clinical Oncology
Volume22
Issue number9
DOIs
StatePublished - 2004
Externally publishedYes

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Nitroreductases
Enzyme Therapy
Prodrugs
Liver Neoplasms
Adenoviridae
Viruses
Virion
Neoplasms
Poisons
Enzymes
Transgenes
Heterografts
Antibody Formation
Half-Life
Colorectal Neoplasms
Clinical Trials
Safety
Liver
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Virus-directed enzyme prodrug therapy : Intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer. / Palmer, Daniel H.; Mautner, Vivien; Mirza, Darius; Oliff, Simon; Gerritsen, Winald; Van der Sijp, Joost R M; Hubscher, Stefan; Reynolds, Gary; Bonney, Sarah; Rajaratnam, Ratna; Hull, Diana; Horne, Mark; Ellis, John; Mountain, Andrew; Hill, Simon; Harris, Peter A.; Searle, Peter F.; Young, Lawrence S.; James, Nicholas D.; Kerr, David J.

In: Journal of Clinical Oncology, Vol. 22, No. 9, 2004, p. 1546-1552.

Research output: Contribution to journalArticle

Palmer, DH, Mautner, V, Mirza, D, Oliff, S, Gerritsen, W, Van der Sijp, JRM, Hubscher, S, Reynolds, G, Bonney, S, Rajaratnam, R, Hull, D, Horne, M, Ellis, J, Mountain, A, Hill, S, Harris, PA, Searle, PF, Young, LS, James, ND & Kerr, DJ 2004, 'Virus-directed enzyme prodrug therapy: Intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer', Journal of Clinical Oncology, vol. 22, no. 9, pp. 1546-1552. https://doi.org/10.1200/JCO.2004.10.005
Palmer, Daniel H. ; Mautner, Vivien ; Mirza, Darius ; Oliff, Simon ; Gerritsen, Winald ; Van der Sijp, Joost R M ; Hubscher, Stefan ; Reynolds, Gary ; Bonney, Sarah ; Rajaratnam, Ratna ; Hull, Diana ; Horne, Mark ; Ellis, John ; Mountain, Andrew ; Hill, Simon ; Harris, Peter A. ; Searle, Peter F. ; Young, Lawrence S. ; James, Nicholas D. ; Kerr, David J. / Virus-directed enzyme prodrug therapy : Intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer. In: Journal of Clinical Oncology. 2004 ; Vol. 22, No. 9. pp. 1546-1552.
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abstract = "Purpose Virus-directed enzyme prodrug therapy depends on selective delivery of virus encoding a prodrug-activating enzyme to tumor, followed by systemic treatment with prodrug to achieve high levels of the activated cytotoxic at the intended site of action. The use of the bacterial enzyme nitroreductase to activate CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) to a short lived, highly toxic DNA cross-linking agent has been demonstrated in tumor xenografts. In this study, we report the first clinical trial investigating the feasibility, safety, and transgene expression of a replication-defective adenovirus encoding nitroreductase (CTL102) in patients with liver tumors. Patients and Methods Patients with resectable primary or secondary (colorectal) liver cancer received a single dose of CTL102 delivered by direct intratumoral inoculation 3 to 8 days before surgical resection. Results Eighteen patients were treated with escalating doses of CTL102 (range, 108-5 × 1011 virus particles). The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Dose-related increases in tumoral nitroreductase expression measured by immunohistochemical analysis have been observed. Conclusion Direct intratumoral inoculation of CTL102 to patients with primary and secondary liver cancer is feasible and well tolerated. The high level of nitroreductase expression observed at 1 to 5 × 1011 virus particles mandates further studies in patients with inoperable tumors who will receive CTL102 and CB1954.",
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T1 - Virus-directed enzyme prodrug therapy

T2 - Intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer

AU - Palmer, Daniel H.

AU - Mautner, Vivien

AU - Mirza, Darius

AU - Oliff, Simon

AU - Gerritsen, Winald

AU - Van der Sijp, Joost R M

AU - Hubscher, Stefan

AU - Reynolds, Gary

AU - Bonney, Sarah

AU - Rajaratnam, Ratna

AU - Hull, Diana

AU - Horne, Mark

AU - Ellis, John

AU - Mountain, Andrew

AU - Hill, Simon

AU - Harris, Peter A.

AU - Searle, Peter F.

AU - Young, Lawrence S.

AU - James, Nicholas D.

AU - Kerr, David J.

PY - 2004

Y1 - 2004

N2 - Purpose Virus-directed enzyme prodrug therapy depends on selective delivery of virus encoding a prodrug-activating enzyme to tumor, followed by systemic treatment with prodrug to achieve high levels of the activated cytotoxic at the intended site of action. The use of the bacterial enzyme nitroreductase to activate CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) to a short lived, highly toxic DNA cross-linking agent has been demonstrated in tumor xenografts. In this study, we report the first clinical trial investigating the feasibility, safety, and transgene expression of a replication-defective adenovirus encoding nitroreductase (CTL102) in patients with liver tumors. Patients and Methods Patients with resectable primary or secondary (colorectal) liver cancer received a single dose of CTL102 delivered by direct intratumoral inoculation 3 to 8 days before surgical resection. Results Eighteen patients were treated with escalating doses of CTL102 (range, 108-5 × 1011 virus particles). The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Dose-related increases in tumoral nitroreductase expression measured by immunohistochemical analysis have been observed. Conclusion Direct intratumoral inoculation of CTL102 to patients with primary and secondary liver cancer is feasible and well tolerated. The high level of nitroreductase expression observed at 1 to 5 × 1011 virus particles mandates further studies in patients with inoperable tumors who will receive CTL102 and CB1954.

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