Chimeric antigen receptors for stem cell based immunotherapy.

The retargeting of lymphocytes is an important new strategy in immunotherapy of cancer. One can currently isolate naturally refined, high affinity specificities from antibodies and T-cell receptors (TCRs) to use in engineered applications. We have developed two new molecules that have specificity for the overexpressed tumor antigen HER2/neu. The specificity derived from an anti-HER2 antibody variable fragment was used to create a single chain Fv (scFv). A HER2 reactive TCR was also used to develop a single chain TCR (scTCR). The HER2 binding elements were linked to an intracellular signaling module, active only in the T cell signaling pathway, providing a novel molecule to retarget lymphocytes. We demonstrate here that these molecules can be expressed in several cell lines as well as in hematopoietic stem cells (HSCs). In a transplant setting, these new receptors can be expressed in multiple cells types derived from repopulating HSCs. These new chimeric receptors will be valuable tools for further research of immune function of retargeted hematopoietic cells.