ABSTRACT
Summary The Wilms tumor antigen 1 (WT1) is expressed at elevated levels in most leukemias compared with normal hematopoietic cells. Furthermore, WT1 is also activated in a variety of solid cancers, while the corresponding normal cells do not express this protein. Hence, WT1 is an attractive target molecule for tumor immunotherapy. However, low levels of expression in normal tissues is likely to cause immunological tolerance, which may lead to the inactivation of high avidity T lymphocytes. The allo-restricted strategy was developed to avoid tolerance and to isolate high avidity cytotoxic T lymphocytes (CTL) specific for selfproteins, such as WT1. In vitro studies have shown that allo-restricted CTL kill WT1 expressing tumor cell lines and leukemic progenitor cells isolated from patients. The expression level in normal hematopoietic cells is insufficient to trigger killing by WT1-specific CTL. However, a major drawback of immunotherapy with allo-restricted CTL is the HLA mismatch between CTL and tumor patients, leading to rejection of infused CTL in immunocompetent recipients. To overcome this limitation, the transfer of cloned T cell receptors (TCR) into patients CD8 T cells provides a strategy to equip autologous CTL with high avidity receptors specific for defined tumor-associated proteins.
