Peter Searle is developing immuno/gene therapy approaches to treat prostate cancer, using modified Adenoviruses and cytokines.
Senior Lecturer, School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham.
Background and Research focus
Dr Peter Searle is a Senior Lecturer in the School of Cancer Sciences with a long standing interest in developing novel, gene-based therapies for cancer. One strategy utilizes the enzyme nitroreductase, derived from E. coli, to activate prodrugs such as CB1954 to cytotoxic derivatives. In collaboration with Dr Prashant Patel and Professor Nick James, his research has evolved to early phase clinical trials, injecting an adenovirus vector expressing nitroreductase into tumours. This study has demonstrated promising evidence of localised anti-tumour activity when combined with CB1954, and propose that additional optimization may provide an effective treatment for locally relapsed prostate cancer. With this in mind, his team has developed improved nitroreductase mutants that are more efficient at activating CB1954 relative to the natural enzyme. In addition, his group has forged strong links with local groups to design and generate better prodrugs. Peter’s group is also investigating viruses that are engineered to replicate in cancer cells, but not in normal cells. Virus replication contributes direct anti-cancer activity, and can also improve the distribution of nitroreductase through the cancer. Stimulation of tumour-specific immune responses could permit a localized gene therapy to have a systemic benefit; his team plan to assess this by clinical trial of a vector that produces nitroreductase (for CB1954 activation) and the immunostimulatory cytokine GM-CSF. Finally, Peter and his group are interested in the potential of co-stimulatory proteins such as CD80 and 4-1BBL to overcome tumour immune evasion strategies.
Genetic manipulation/genetic modification; gene therapy; cancer gene therapy; tumour immunology.
Peter has published in excess of 70 peer reviewed research articles and has received funding from the Medical Research Council and Cancer Research UK. Alongside his research interests, Peter plays a significant role in teaching both undergraduate and postgraduate students. Most pertinently he currently serves as Programme Director for the new MSc in Translational Medicine course. In addition, he delivers lectures and tutorials on the BMedSc, MBChB and MSc in Clinical Oncology courses. Peter is Member of the Scientific Advisory Committee on Genetic Modification, a national committee which advises the Health and Safety Executive. He also sits on the Biologicals and Vaccines Expert Advisory Group Committee which advises the Medicines and Healthcare Products Regulatory Agency.
Dowell AC, Oldham KA, Bhatt RI, Lee SP, Searle PF. (2012) Long-term proliferation of functional human NK cells, with conversion of CD56(dim) NK cells to a CD56 (bright) phenotype, induced by carcinoma cells co-expressing 4-1BBL and IL-12. Cancer Immunol Immunother. May;61(5):615-28.
Hu L, Wu X, Han J, Chen L, Vass SO, Browne P, Hall BS, Bot C, Gobalakrishnapillai V, Searle PF, Knox RJ, Wilkinson SR. Synthesis and structure-activity relationships of nitrobenzyl phosphoramide mustards as nitroreductase-activated prodrugs. Bioorg Med Chem Lett. 2011 Jul 1;21(13):3986-91.
Rojas JJ, Guedan S, Searle PF, Martinez-Quintanilla J, Gil-Hoyos R, Alcayaga-Miranda F, Cascallo M, Alemany R. Minimal RB-responsive E1A promoter modification to attain potency, selectivity, and transgene-arming capacity in oncolytic adenoviruses. Mol Ther. 2010 Nov;18(11):1960-71.
Jaberipour, M., Vass, S.O., Guise, C.P., Grove, J.I., Knox, R.J., Hu, L., Hyde, E.I., and Searle, P.F. (2010). Testing double mutants of the enzyme nitroreductase for enhanced cell sensitisation to prodrugs: Effects of combining beneficial single mutations. Biochem Pharmacol 79; 102-111.
Elmetwali, T., Searle, P.F., McNeish, I., Young, L.S., and Palmer, D.H. (2010). CD40 ligand induced cytotoxicity in carcinoma cells is enhanced by inhibition of metalloproteinase cleavage and delivery via a conditionally-replicating adenovirus. Mol Cancer 9; 52.
Vass, S.O., Jarrom, D., Wilson, W.R., Hyde, E.I., and Searle, P.F. (2009). E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954. Br J Cancer 100; 1903-1911.
Patel, P., Young, J.G., Mautner, V., Ashdown, D., Bonney, S., Pineda, R.G., Collins, S.I., Searle, P.F., Hull, D., Peers, E., et al. (2009). A phase I/II clinical trial in localized prostate cancer of an adenovirus expressing nitroreductase with CB1954. Mol Ther 17; 1292-1299.
Jarrom, D., Jaberipour, M., Guise, C.P., Daff, S., White, S.A., Searle, P.F., and Hyde, E.I. (2009). Steady-state and stopped-flow kinetic studies of three Escherichia coli NfsB mutants with enhanced activity for the prodrug CB1954. Biochemistry 48; 7665-7672.
Young, J.G., Green, N.K., Mautner, V., Searle, P.F., Young, L.S., and James, N.D. (2008). Combining gene and immunotherapy for prostate cancer. Prostate Cancer Prostatic Dis 11; 187-193.
Race, P.R., Lovering, A.L., White, S.A., Grove, J.I., Searle, P.F., Wrighton, C.W., and Hyde, E. (2007). Kinetic and Structural Characterisation of Escherichia coli Nitroreductase Mutants Showing Improved Efficacy for the Prodrug Substrate CB1954. J Mol Biol 368; 481-492.