Most recently, the Trust has raised £2.5 million towards a new Cancer Clinical Research Facility (CRF). The CRF will open at University College London www.uclh.nhs.uk in 2009, and be
a state-of-the-art facility for early phase clinical trials, as well as first-in-man trials of new anti-cancer drugs.
During the last 10 years, the Trust has funded personnel, facilities and equipment and collaborates with Cancer Research UK and other charities in developing the research.
Key achievements are:
Novel antibodies
Our researchers were the first in the world to make clinically relevant single chain Fv antibodies and antibodies from phage libraries and give them to patients. The genetic engineering techniques involved enable antibodies to be used as building blocks to guide treatments or scanning agents to cancer anywhere in the body. They are now being used in our group and by several others in new treatments for cancer and other researchers have been shown them to be of benefit in rheumatoid arthritis. As part of this work the Trust funded the first academic production unit for these products to be licensed by the UK Government.
Key publications
- Chester, K.A., Begent, R.H.J., Robson, L., Keep, P., Pedley, R.B., Boden, J.A., Boxer, G., Green, A., Winter, G., Cochet, O. and Hawkins, R.E. (1994) Phage libraries for generation of clinically useful antibodies. Lancet 343, 455 456.
- Verhaar, M.J., Chester, K.A., Keep, P.A., Robson, L., Pedley, R.B., Boden, J.A., Hawkins, R.E. and Begent, R.H.J. (1995) A single chain Fv derived from a filamentous phage library has distinct tumour targeting advantages over one derived from a hybridoma. Int. J. Cancer 61, 497 501
- Begent, R.H.J., Verhaar, M.J., Chester, K.A., Casey, J.L., Green, A.J., Napier, M.P., Hope Stone, L.D., Cushen, N., Keep, P.A., Johnson, C.J., Hawkins, R.E., Hilson, A.J.W. and Robson, L. (1996) Clinical evidence of efficient tumor targeting based on single chain Fv antibody selected from a combinatorial library. Nature Medicine 2, 979 984.
- Mayer, A., Begent, R.H.J., Chester, K.A. and et al (1998) Exemplifying guidelines for preparation of recombinant DNA products in phase I trials in cancer: preparation of a genetically engineered anti CEA single chain Fv antibody. European Journal of Cancer 34, 968-976.
- Mayer A, Tsiompanou E, O'Malley D, Boxer GM, Bhatia J, Flynn AA, Chester KA, Davidson BR, Lewis AA, Winslet MC, Dhillon AP, Hilson AJ, Begent RH. Radioimmunoguided surgery in colorectal cancer using a genetically engineered anti-CEA single-chain Fv antibody.Clin Cancer Res. 2000 May;6:1711-9
ADEPT
Antibody Directed Enzyme Prodrug Therapy (ADEPT) is a new system for treatment of cancer in which an anticancer drug is generated within the cancer. An enzyme is delivered to the cancer by an antibody to which it is linked and then a harmless prodrug is given which is converted by the enzyme to a cancer-killing drug selectively within deposits of cancer. This reduces side effects and can improve effectiveness. The antibody technology described above has been used for this. We are the only group to have conducted clinical trials with the system which shows evidence of benefit in patients with bowel and related cancers whose tumour is resistant to other treatments.
Key publications
- Napier MP, Sharma SK, Springer CJ, Bagshawe KD, Green AJ, Martin J, Stribbling SM, Cushen N, O'Malley D, Begent RHJ (2000) Antibody-directed enzyme prodrug therapy: efficacy and mechanism of action in colorectal carcinoma. Clin Cancer Res. 6:765-72.
- Francis RJ, Sharma SK, Springer C, Green AJ, Hope-Stone LD, Sena L, Martin J, Adamson KL, Robbins A, Gumbrell L, O'Malley D, Tsiompanou E, Shahbakhti H,Webley S, Hochhauser D, Hilson AJ, Blakey D, Begent RH. A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours.Br J Cancer. 2002 Sep 9;87(6):600-7.
- Sharma SK, Pedley RB, Bhatia J, Boxer GM, El-Emir E, Qureshi U, Tolner B,Lowe H, Michael NP, Minton N, Begent RH, Chester KA. Sustained tumor regression of human colorectal cancer xenografts using a multifunctional mannosylated fusion protein in antibody-directed enzyme prodrug therapy. Clin Cancer Res. 2005 ;11:814-25.
- Tolner B, Smith L, Begent RHJ, Chester KA. Production of recombinant protein in Pichia pastoris by fermentation Nature Protocols 1, 1006 - 1021 (2006)
- Tolner B, Smith L, Begent RHJ, Chester KA Expanded-bed adsorption immobilized-metal affinity chromatography. Nature Protocols 1, 1213 - 1222 (2006)
- Mayer A, Francis RJ, Sharma SK, Tolner B, Springer CJ, Martin J, Boxer GM, Bell J, Green AJ, Hartley JA, Cruickshank C, Wren J, Chester KA and Begent RHJ. A Phase I Study of Single Administration of Antibody-Directed Enzyme Prodrug Therapy with the Recombinant Anti−Carcinoembryonic Antigen Antibody-Enzyme Fusion Protein MFECP1 and a Bis-Iodo Phenol Mustard Prodrug Clinical Cancer Research 12, 6509-6516, 2006
Radioimmunotherapy for Bowel Cancer and Hodgkin´s Disease
We have developed this treatment in which an antibody is linked to a radioactive isotope. The antibody delivers the isotope to the cancer where it selectively destroys the cancer cells. This has proved effective in over 60% of patients with Hodgkin´s disease and 10% of patients with bowel cancer whose disease was resistant to conventional therapies. The focus is on more extensive trials of the treatment for Hodgkin´s disease and on further laboratory development for bowel cancer.
Key publications
- Lane, D.M., Eagle, K.F., Begent, R.H.J., Hope Stone, L.D., Green, A.J., Casey, J.L., Keep, P.A., Kelly, A.M.B., Ledermann, J.A., Glaser, M.G. and Hilson, A.J.W. (1994) Radioimmunotherapy of metastatic colorectal tumours with iodine 131 labelled antibody to carcinoembryonic antigen: phase i/ii study with comparative biodistribution of intact and f(ab') 2 antibodies. Br. J. Cancer 70, 521 525.
- El Emir E, Qureshi U, Dearling JL, Boxer GM, Clatworthy I, Folarin AA, Robson MP, Nagl S, Konerding MA, Pedley RB. Predicting response to radioimmunotherapy from the tumor microenvironment of colorectal carcinomas. Cancer Res. 2007 15;67(24):11896-905
- Fidarova EF, El-Emir E, Boxer GM, Qureshi U, Dearling JL, Robson MP, Begent RH, Trott KR, Pedley RB. Microdistribution of targeted, fluorescently labeled anti-carcinoembryonic antigen antibody in metastatic colorectal cancer: implications for radioimmunotherapy. Clin Cancer Res. 2008;14:2639-46
Targeting blood vessels within cancers
Many common cancers have a poor blood supply making it difficult to deliver effective therapy to affected parts of the cancer. Our studies showed that a combined treatment should be effective. This comprised giving antibodies to treat the parts of the cancer with a good blood supply and together with a treatment which blocks the abnormal blood vessels which give a poor supply to the rest of the cancer. Both treatments given in the appropriate sequence eliminate experimental cancers and have been used in a preliminary clinical trial in our centre. The same principle in which conventional anticancer drugs replace the antibody treatment is also now being used in clinical trials by other researchers with promising results in lung cancer.
Key references
- Pedley, R.B., Boden, J.A., Boden, R., Boxer, G.M., Flynn, A.A., Keep, P.A. and Begent, R.H.J. (1996) Ablation of colorectal xenografts with combined radioimmunotherapy and tumor blood flow modifying agents. Cancer Research 56, 3293 3300.
- Pedley RB, Sharma SK, Boxer GM, Boden R, Stribbling SM, Davies L, Springer CJ, Begent RH (1999). Enhancement of antibody-directed enzyme prodrug therapy in colorectal xenografts by an antivascular agent. Cancer Res. 15;59:3998-4003.
- Pedley RB, El-Emir E, Flynn AA, Boxer GM, Dearling J, Raleigh JA, Hill SA, Stuart S, Motha R, Begent RH. Synergy between vascular targeting agents and antibody-directed therapy. Int J Radiat Oncol Biol Phys. 2002 Dec 1;54(5):1524-31