Objective
At the present time several antigens have been identified that are recognised on human tumours by autologous cytolytic T lymphocytes (CTL). Many of these antigens are encoded by genes that are very selectively expressed by tumour cells. Therefore, it is now reasonable to try to immunise cancer patients against such tumour antigens to stimulate or to induce tumour rejection responses. A first part of the project is the identification of new tumour rejection antigens recognised on human tumours by CTL. We intend to identify new antigens by applying to other types of tumours the methods that were successfully used with melanoma antigens. We will derive CTL clones against cell lines derived from renal, bladder, head and neck, and cervical carcinomas, from lung tumours, sarcomas, and leukaemias. After the identification of the HLA molecule which present the antigen recognised by a given CTL clone, the antigen will be identified by cloning the gene coding for the antigenic peptide, using transfection of cDNA libraries derived from the tumour cells. Another approach will involve the elution of the antigenic peptides bound to the HLA molecules expressed by the tumour cells. Using a combination of chromatography and mass spectrometry, it was possible to identify and to sequence individual peptides recognised by CTL clones. The third approach consists in identifying antigenic peptides that are derived from proteins encoded by genes which are known to be selectively expressed in tumours. Candidate peptides that are able to bind to defined HLA molecules will be identified. These peptides will be used in vitro to stimulate T lymphocytes from normal individuals and from cancer patients. The lytic activity of the responder CTL will be tested on tumour cell lines expressing the relevant HLA molecule and the gene encoding the antigenic peptide. The second part of the project consists of attempts to stimulate immune responses of cancer patients against these defined tumour antigens. Several forms of the antigens will be tested, in order to compare their immunogenicity in vivo. Small groups of patients, eligible for such immunisations on the basis of their clinical status of their HLA type and of the expression in their tumour of genes that are known to encode antigens, will be vaccinated with peptide alone or peptide mixed with adjuvant, or with recombinant protein with adjuvant, with irradiated cells expressing the antigen, with naked DNA encoding the antigen, and possibly with adenovirus or vaccinia constructs. These modalities of immunisation will be concomitantly evaluated in mice, using tumour antigen P1A. For the patients, the efficacy of immunisation will be assessed in vitro by measuring specific CTL responses in the blood and, whenever possible, in tumour-infiltrating lymphocytes obtained before and after vaccination. Histology of available tumour biopsies will be evaluated to define the nature of the lymphocytes infiltrated and, by PCR, the repertoire of infiltrating T cells. Larger clinical studies, with progression of the disease as endpoint, will be initiated with those forms of antigens which will prove to generate CTL responses in a significant proportion of patients.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine immunology immunisation
- medical and health sciences clinical medicine oncology skin cancer melanoma
- medical and health sciences clinical medicine oncology leukemia
- natural sciences chemical sciences analytical chemistry mass spectrometry
- natural sciences biological sciences histology
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Coordinator
1200 Brussels
Belgium
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