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Enhanced efficacy of Escherichia coli nitroreductase/CB1954 prodrug activation gene therapy using an E1B-55K-deleted
M-J Chen1, N K Green, G M Reynolds
1Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK.
Abstract:
Viruses that replicate selectively in cancer cells constitute an exciting new class of anticancer agent. The conditionally replicating adenovirus (CRAd) dl1520, which lacks the E1B-55K gene, has elicited significant clinical responses in humans when used in combination with chemotherapy. A convergent development has been to use replication-defective viruses to express prodrug-activating enzymes in cancer cells. This can sensitize the cancer to prodrug, but depends upon achieving sufficient level, distribution and specificity of enzyme expression within the tumour. In this study, we have expressed the prodrug-activating enzyme nitroreductase (NTR) in the context of an E1B-55K-deleted adenovirus, CRAd-NTR(PS1217H6). We show that CRAd-NTR(PS1217H6) retains oncolytic growth properties, and expresses substantially more NTR than a comparable, replication-defective adenovirus. The combination of viral oncolysis and NTR expression results in significantly greater sensitization of SW480 and WiDr colorectal cancer cells to the prodrug CB1954 in vitro. In vivo, CRAd-NTR(PS1217H6) was shown to replicate in subcutaneous SW480 tumour xenografts in immunodeficient mice, resulting in more NTR expression and greater sensitization to CB1954 than with replication-defective virus. Combination therapy of CRAd-NTR(PS1217H6) with CB1954 reduced tumour growth from 13.5- to 2.8-fold over 5 weeks, and extended median survival from 42 to 81 days, compared with no treatment.
Insights
This study introduces a novel oncolytic virus, CRAd-NTR(PS1217H6), that selectively replicates in cancer cells and expresses nitroreductase (NTR) to enhance prodrug therapy. The combined approach significantly reduced tumor growth and extended survival in preclinical models.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Cancer treatment
Background:
- Conditionally replicating adenoviruses (CRAd) are promising anticancer agents.
- CRAd dl1520, lacking E1B-55K, shows clinical efficacy with chemotherapy.
- Replication-defective viruses can express prodrug-activating enzymes but require sufficient expression levels.
Purpose of the Study:
- To develop and evaluate a novel CRAd vector expressing nitroreductase (NTR) for enhanced cancer prodrug therapy.
- To assess the oncolytic properties and NTR expression of CRAd-NTR(PS1217H6).
- To determine the efficacy of CRAd-NTR(PS1217H6) in combination with the prodrug CB1954 in vitro and in vivo.
Main Methods:
- Construction of CRAd-NTR(PS1217H6), an E1B-55K-deleted adenovirus expressing NTR.
- In vitro studies using SW480 and WiDr colorectal cancer cells to assess viral replication, NTR expression, and sensitization to CB1954.
- In vivo studies using subcutaneous SW480 tumor xenografts in immunodeficient mice to evaluate viral replication, NTR expression, tumor growth, and survival following combination therapy with CB1954.
Main Results:
- CRAd-NTR(PS1217H6) demonstrated oncolytic activity and higher NTR expression compared to replication-defective adenovirus vectors.
- In vitro, the combination of CRAd-NTR(PS1217H6) and CB1954 significantly sensitized colorectal cancer cells to the prodrug.
- In vivo, CRAd-NTR(PS1217H6) replication led to enhanced NTR expression, greater CB1954 sensitization, reduced tumor growth (13.5-fold to 2.8-fold), and extended median survival (42 to 81 days).
Conclusions:
- CRAd-NTR(PS1217H6) is a potent oncolytic virus expressing NTR, effectively sensitizing cancer cells to CB1954.
- The combination of CRAd-NTR(PS1217H6) and CB1954 represents a promising therapeutic strategy for colorectal cancer.
- This dual-action approach, combining viral oncolysis with targeted enzyme expression, offers significant therapeutic potential against solid tumors.
