Immune response manipulation: recombinant immunoreceptors endow T-cells with predefined specificity

The application of immunotherapy for the treatment of malignant diseases has attracted growing interest in recent years. Because T-cell immunity plays a major part in the control of tumor growth, strategies have been developed to specifically target and activate T-cells towards tumor cells by circumventing major histocompatibility complex (MHC)-restricted antigen recognition. Here we review the immunoreceptor ("T-body") strategy based on grafting cytolytic T-cells with an antigen-specific, recombinant receptor with signalling properties. The extracellular domain of the receptor molecule consists of a single-chain antibody fragment (scFv) derived from a monoclonal antibody that binds to a tumor associated antigen. The intracellular domain is derived from a signalling receptor for cellular activation, e.g., the Fc epsilon RI receptor gamma-chain or the CD3 zeta-chain. Thereby, the immunoreceptor strategy combines the advantages of MHC-independent binding of antibodies to antigens with efficient T-cell activation. Due to the receptor design, T-cells grafted with immunoreceptors can be directed virtually against every cell defined by the particular antigen, including tumor cells and virally infected cells. This review summarizes the current knowledge about redirecting T-cell functions by grafting in recombinant immunoreceptors with specificity for tumor associated antigens and discusses the limitations and perspectives of the strategy for use in adoptive immunotherapy of malignant diseases.