Circumventing antigen-specific self-tolerance in A2.1 transgenic mice allows the generation of A2.1-restricted TCR with high affnity for universal human tumor-and leukemia-associated peptide epitopes (TAA) (i.e., MDM2, p53).Retroviral transduction of human T lympocytes with wild-type and partially humanized mouse-derived TCR leads to the equipment of the otherwise tolerant T cell repertoire with effective CTL with high avidity for a wide range of A2.1-positive tumors and leukemias.However, implementing TCR-based gene therapy of malignant disease requires further molecular optimization.To prevent or impair potentially harmful recombination of transduced and endogenous TCR chains, we have modified the interface of TCR and chains.Designing various single chain TCR constructs met the same purpose.Developing CD8-independent TCR allowed not only the reprograming of CD4+ T helper cells (Th), but also turned human CD8+ CTL into hyper-avidity effector cells.