Exploring the T cell receptor genome - the next generation cancer immunotherapeutics

We will generate recombinant T cell receptors (TCRs) that recognize cancer cells. DNA encoding the receptors forms basis for novel drugs for immunotherapy of cancer. Two strategies are followed to select T cells with the desired receptors: 1) T cells that recognize telomerase have been isolated from patients successfully treated by peptide vaccination. A large number of clones that kill tumor cells selectively and efficiently have been isolated. Telomerase is overexpressed in 90% of cancers. The TCRs can therefore be widely applied. 2) A novel strategy has been developed to select T cells that kill specific cell types independently of tumor-associated antigens. Tissue-restricted cytotoxicity is a rational treatment option when cancer occurs in tissues tha t are not essential for the host, or can be replaced by transplantation. Cell type-specific T cells are generated by exposing normal T cells to a foreign HLA molecule with a peptide from a cell type-restricted protein. Fluorescent HLA-peptide complexes ar e used to detect and isolate the specific cells. The strategy allows immunization against a large number of molecules for more efficient immunotherapy. Methods for selecting and cloning T cells with desired reactivity are used in combination with state of the art technology to isolate and amplify DNA encoding TCRs. The research is conducted in a research environment actively involved in several clinical trials for cancer immunotherapy and with a strong record in translational research. The project applied for is planned to enter phase I clinical trials by 2011.