Gene therapy

My group is developing novel, gene-based therapies for cancer. One approach involves use of the enzyme nitroreductase, from E. coli, to activate the prodrug CB1954 to cytotoxic derivatives. Our laboratory studies of this prodrug activation gene therapy have progressed to a series of clinical trials, using a replication-defective adenovirus vector to express the enzyme following intratumoural injection. The clinical development of our work is facilitated through close collaboration with Institute clinicians Prof. Nick James, Dr. Emilio Porfiri and Dr. Dan Palmer, and by the Cancer Clinical Trials Unit within the Institute. These trials have shown encouraging evidence of partial anti-tumour activity, and suggest the treatment may delay disease progression in prostate cancer patients with locally relapsed disease. Thus, further development to increase the efficacy is warranted.

We are exploring a number of complementary strategies to improve the gene therapy. One focus of our group has been to engineer the nitroreductase enzyme for more efficient prodrug activation. Based on the crystal structure of nitroreductase, determined through collaboration with Dr. Scott White and Dr. Eva Hyde (School of Biosciences, University of Birmingham), we have developed mutants that are significantly better at activating CB1954 than the natural enzyme. To facilitate further improvement, we have recently developed a direct, positive selection for improved enzymes.

As a complementary approach, we also collaborate with groups developing alternative prodrugs for nitroreductase. We are also interested in using oncolytic adenovirus vectors that are able to replicate selectively within cancer cells, and have shown that these can be advantageous for delivery of nitroreductase to cells. Our work with adenovirus is enhanced by close collaboration with the Institute adenovirus expert, Dr. Vivien Mautner.

The group is 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. Expression of proteins such as CD80 and 4-1BBL that provide costimulatory signals to T-cells also has potential to activate, or re-activate tumour-specific immune responses. We have shown that the combination of both signals allows a greater magnitude and duration of proliferation of T-cells stimulated with anti-CD3 antibodies or with viral peptides and aim to extend these studies to anti-tumour immune responses. These studies involve collaboration with immunology groups in the Institute, and in particular the Immunotherapy Group of Dr. Steve Lee.

Publications

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