Cancer cells are by definition abnormal and contain proteins which might be recognized by the immune system as foreign because they are not present in normal tissues. However, for some reason the immune system often seems to ignore this abnormality and fails to attack tumours. At the British Society for Annual Congress in Brighton this week, Dr Graham Pawelec of the University of Tuebingen, Germany will explain how he is attempting to wake immune cells up to this abnormality to develop cancer immunotherapy.
The foreign proteins produced by the cancer cell reveal their presence because they are broken into short fragments which are displayed on the surface of the cell. These fragments are known as tumour antigens. The tumour antigens are held on the cell surface by molecules called MHC.
There are two types of MHC molecule, class I and II. Tumour antigens in association with MHC class I molecules are recognized by cytotoxic T cells, white blood cells which can kill tumour cells directly.
Antigen-MHC class II complexes, however, are recognized by a second subset of T cells called helper cells. These cells secrete messenger molecules called cytokines, which slow or stop tumour growth and help another type of white blood cell, B cells, to make antibodies against the tumour cells. In general much less is known about these tumour antigens, which tend to be slightly longer than those presented by MHC class I.
Dr Pawelec's approach to treating cancer is called adoptive immunotherapy. Outside the body, T cells are stimulated using the tumour antigens and are then reinfused into the patient where they attack the cancerous cells. Research has shown that using both cytotoxic and helper T cells is far more effective than using either subset alone.
Before they can be used for adoptive immunotherapy the tumour antigens must be identified. The technology to do this has recently been developed at several centres in Europe and the US. The MHC molecules are removed from the surface of the cancer cells and the tumour antigens separated from them. The antigens' amino acid sequences are then worked out and compared with proteins made by the tumour to check that they really are markers of cancer, and not from proteins produced by all cells, including healthy ones!
Once identified and characterised the tumour antigens can be reproduced synthetically in the laboratory. Dr Pawelec's team has done this for antigens from two different cancers, melanoma and chronic myelogenous leukaemia. They have shown that they can use the synthetic antigens to sensitize T cells and that the T cells then recognise cancer cells. Dr Pawelec suggests that these synthetic antigens could also be used as vaccines, by injecting them straight into the patient.
However, the cancer cells have a trick up their sleeves to try to prevent the T cells destroying them. The make a cell surface molecule, called fas ligand, which can kill the attacking T cells. Dr Pawelec suggests using an antibody against fas ligand to block its action against the T cells to increase their effectiveness. He says, "Treatment of patients with T cells specifically sensitized to their tumour cell antigens together with this antibody might therefore be especially effective at controlling the cancer."
Dr Pawelec is the co-ordinator of a new Europe-wide initiative, European Union Concerted Action on Peptide Sensitization (EUCAPS), which is holding its inaugral meeting in Brighton on Monday 1 December. The new network aims to share best practise to improve cancer vaccination protocols for use in clinical trials. It is to be hoped that with such a support network in place it is not long before immunotherapy becomes a widely-used weapon in the fight against cancer.
Notes:
1. Dr Pawelec will be speaking in the Immunity and Cancer session on Tuesday 2 December. The BSI 5th
Annual Congress will take place at the Brighton Centre, Brighton, UK from 2-5 December.
2. Dr Pawelec can be contacted at Medizinische Klinik, D-72076 Tuebingen, Germany. Tel: + 49 7071 298 2805
Fax: + 49 7071 294 464 graham.pawelec@uni-tuebingen.de
3. There will be a press office at the Congress, in operation from 9am on Tuesday 2 December.
Tel: +44 1273 724 320. Journalists are welcome to attend but are requested to contact Kirstie Urquhart
in advance to register.