HMCRT CANCER RESEARCH EFFORT

Since Harry's passing, the HMCRT has supported numerous events and in 2003 donated £20,000 towards the acquisition of a £100,000 Laser Dissecting Microscope currently in daily use at the John Radcliffe Hospital in Oxford.

 

RESEARCH EFFORT LEADERSHIP

Harry looked to his close Canadian friend, John Bell, for much of his guidance on combating his cancer. As Regius Professor of Medicine, at Oxford University, where he was a Rhodes Scholar, Prof. Sir Bell is well positioned to lead the HMCRT. The Regius Professor of Medicine, one of the oldest medical chairs in the world, is an appointment held at the University of Oxford founded by Henry VIII of England by 1546. As head of the Nuffield Department of Medicine over the past decade, Dr. Bell has driven the development of the new biomedical "Research Crescent" at Oxford, comprising eight institutes and a projected Centre for Cancer Medicine.

Oxford University Professor of Immunology Vincenzo Cerundolo oversees the daily research and use of equipment provided by the HMCRT. Vincenzo is a graduate of the University of Padua (M.D., PhD) and Oxford (M.A.) and among his many honors is a fellow of the Academy of Medical Sciences and the Royal College of Pathologists while currently a Consultant in Medical Oncology to the NHS Trust.


RESEARCH PROGRESS - WORDS FROM VINCENZO (SEPTEMBER 2005)

The overall aim of my research programme is to build up a detailed picture of the mechanisms controlling the immune response to tumours and to develop vaccination strategies to enhance tumour specific responses. Our previous results have indicated that in vivo generation of tumour specific responses occurs mostly in advanced metastatic disease (1), hence justifying early immunotherapeutic approaches.

Over the last few years we have identified novel vaccination strategies capable of generating large numbers of tumour specific responses. These protocols are based on the use of compounds that enhance the interplay between innate and adaptive immune response and assist the expansion of tumour specific T cells (2,3,4,5,6). It is my intention to translate these results into clinical trial protocols to vaccinate cancer patients.

The purchase of a laser-microdissection microscope has provided a tremedous opportunity to monitor the interplay between tumour cells and the immune system and to identify genetic changes of tumour cells in the presence of tumour specific killer cells.

Over the next 12 months, it is my intention to complete optimizing the current vaccination strategy and to compare a broad range of different compounds for their ability to assist in vivo the expansion of tumour specific immune responses.


SUMMARY OF CURRENT IDO WORK

The immune system is important for protection not only from pathogens but also from development of tumours. Cells from the immune system patrol the body looking for the presence of viruses, bacteria or cancerous cells and under normal circumstances, eradicating them. However, cancers can develop different mechanisms allowing them to hide or prevent the immune system from attacking them, which allows the cancer to grow. One of the methods that cancers sometimes use is by producing a protein, an enzyme called IDO (Indoleamine-2,3 dioxygenase). IDO is commonly found in a large number of different types of cancer cells, including liver cancer and melanoma (skin cancer), and studies have shown that patients whose cancers expressed IDO had a worse prognosis than those in whom the tumours did not.

The function of IDO is to degrade tryptophan, an essential amino acid that cannot be synthesised within the body and must be supplied through the diet. The supply of amino acids such as tryptophan is critical for all cells to make proteins, allowing them to function properly. The presence of IDO within a tumour means that it degrades tryptophan and as a result the amount of tryptophan present near to the tumour is dramatically reduced. In such a hostile environment, other cells are essentially starved of this key nutrient and are unable to survive and function properly, while the tumour remains resistant. This includes cells from the immune system and the tumour can grow and the immune system is unable to do anything about it.

In our laboratory, we are currently researching ways to inhibit IDO function to allow the immune system to effectively target such cancers. The state-of-the-art HPLC (High Performance Liquid Chromatography) machine purchased through kind donation from the Henry Mahon Cancer Research Trust will allow us measure with a high degree of accuracy the function of IDO using cell culture based assays and also with patient samples and allow us to screen for effective novel IDO inhibitors. These novel treatments could hopefully be used in combination with existing therapies such as chemotherapeutic agents and also potentially with cancer vaccines that are currently being developed within our laboratory.


CURRENT FUNDRAISING GOALS

Fast Protein Liquid Chromatography (FPLC): A tool in the development of anti-cancer vaccines

My laboratory focuses on ways to stimulate the body's immune system to fight cancer in the same way that vaccination helps protect against diseases such as meningitis and tuberculosis.

The immune system fights infections, but could also help target and destroy cancer. Until recently it has been difficult to measure this anti-cancer immune response and therefore impossible to test whether different anti-cancer vaccines are effective. This is now changing.

Results generated in my laboratory show that the body’s immune responses to cancer cells might be inefficient, particularly as there are often a large number of varied cancer cells that can evade the body's defences. 'Priming' the immune system with anti-cancer vaccines early in the course of disease could help tip the balance in favour of the patient's own immune system.

Purchase of an FPLC will allow us to develop new ways to monitor the body's immune response to cancer. This will significantly speed up our ability to develop vaccination strategies in the laboratory, and then use this knowledge to treat patients.


CANCER RESEARCH EQUIPMENT PURCHASES

2007 - 2009

  1. FACS Canto ii benchtop analyzer
  2. Refrigerated Microfuge
  3. Fast Protein Liquid Chromatogrpaher (FPLC)

2004 - 2005
Fundraising Contribution of £7,000 funded wish list of research equipment including:

  1. Gibson pipetman kit x1
  2. P2 Gilson pipetman for Tissue culture laboratory
  3. M10 Gilson positive displacement pipette 1-10µl
  4. Drummond Pipet Aids x4
  5. Grant 2 litre waterbath sonicator x1
  6. Protein gel kit
  7. SD200 column for FPLC
  8. Large DNA gel tank
  9. 2 pipetteaids: Fisher bibbijet cat no:PMR-430-0100
  10. P10 pipette: Anachem Cat no: F144802
  11. Ion Exchange columns: Amersham Biosciences HiTrap Q HP pack of 5x5ml columns Cat no: 17-1154-01
  12. DNA gel tank: VWR Gator Horizontal gel system model A3-1 Cat no:306/7318/70
  13. -20° freezer: Jencons Cat no 538-057
  14. Racks for -80° freezer Racking plus boxes

2002/2003
Fundraising Contribution of £20,000 funded Laser Dissecting Microscope


REFERENCES

1) Dunbar, C. L. Smith, D. Chao, M. Salio, D. Shepherd, F. Mirza, M.Lipp, A. Lanzavecchia, F. Sallusto, A. Evans, R. Russell-Jones, A. L. Harris, V. Cerundolo .A shift in the phenotype of melan-A-specific CTL identifies melanoma patients with an active tumour-specific immune response. J. Immunology 2000, 165:6644-6652.

2) Koch M, Stronge VS, Shepherd D, Gadola SD, Mathew B, Ritter G, Fersht AR, Besra GS, Schmidt RR, Jones EY, Cerundolo V. The crystal structure of human CD1d with and without alpha-galactosylceramide. Nat Immunol. 2005 Aug;6(8):819-26.

3) Chen JL, Stewart-Jones G, Bossi G, Lissin NM, Wooldridge L, Choi EM, Held G, Dunbar PR, Esnouf RM, Sami M, Boulter JM, Rizkallah P, Renner C, Sewell A, van der Merwe PA, Jakobsen BK, Griffiths G, Jones EY, Cerundolo V. Structural and kinetic basis for heightened immunogenicity of T cell vaccines. J Exp Med. 2005 Apr 18;201(8):1243-55.

4) Smith, C., Dunbar, R., Mirza F., Palmowski JM., Shepherd D., Gilbert S., Coulie P., Schneider J., Hoffman, E., Hawkins R., Old L., Harris A., and Cerundolo, V.. Recombinant Modified Vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence. International Journal of Cancer Int J Cancer. 2005 Jan 10;113(2):259-66.

5) Silk, J. Hermans, I, Gileadi, U., Chong, W., Shepherd,D., Salio, M., Mathew, B., Schmidt, R.R., Lunt, S. Williams, K., Stratford, I., Harris A., and Cerundolo V. Utilizing the adjuvant properties of CD1d-dependent NKT cells in T cell-mediated immunotherapy. J. Clinical Investigation 2004 Dec;114(12):1800-11.

6) Salio, M., Palmowski, M. J., Atzberger, A., Hermans I.F., and Cerundolo V. CpG-matured murine Plasmacytoid Dendritic Cells: professional antigen presenting cells capable of in vivo priming functional antigen-specific CD8 T cell responses to endogenous but not exogenous antigens. J. Exp. Medicine Feb 16;199(4):567-579, 2004.


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