Dr Searle

Dr Mautner

Nitroreductase converts the prodrug CB1954 to a potent cytotoxic derivative, allowing killing of the cancer cells.

Our initial laboratory based studies led on to the first clinical trials of this enzyme-prodrug combination. Following an initial phase I study of CB1954 alone, phase I trials of the replication-defective adenovirus CTL102, expressing nitroreductase, were conducted in patients with operable tumours (liver, head and neck, and prostate). This established the safety profile of the virus and allowed analysis of the level and distribution of nitroreductase within the surgically excised tumours.

A subsequent phase I/II study in patients with locally recurrent prostate cancer has provided encouraging evidence of anti-tumour activity, including partial regression or

stabilisation of the disease in some patients, as indicated by PSA levels.

We are exploring a number of complementary strategies to improve the gene therapy, including use of adenovirus vectors that are able to replicate selectively within cancer cells, and testing of alternative prodrugs that can be activated by nitroreductase. We have also engineered the nitroreductase enzyme for more efficient prodrug activation.

We are also interested in strategies that can promote immune responses against tumour cells. For example, while tumour cells killed by nitroreductase + CB1954 can induce tumour-specific immunity, we have shown this can be improved by simultaneous expression of the cytokine GM-CSF. Future trials will include improvements in delivery of virus to the tumour, combination with immune stimulation, and use of conditionally-replicating oncolytic virus vectors.

• Chen MJ, et al (2004) Enhanced efficacy of Escherichia coli nitroreductase/CB1954 prodrug activation gene therapy using an E1B-55K-deleted oncolytic adenovirus vector. Gene Ther 11: 1126-36.
• Palmer DH, et al (2004) Virus-directed enzyme prodrug therapy: intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer. J Clin Oncol 22: 1546-52.
• Green NK, et al (2003) Immune enhancement of nitroreductase-induced cytotoxicity: Studies using a bicistronic adenovirus vector. Int J Cancer 104: 104-12.
• Grove JI (2003) Generation of Escherichia coli nitroreductase mutants conferring improved cell sensitization to the prodrug CB1954. Cancer Res 63: 5532-7.