6533b835fe1ef96bd129f395

RESEARCH PRODUCT

Targeting Acute Leukemia and Cancer by High-Affinity T-Cell-Receptor Transfer

subject

description

Accumulation and subsequent overexpression of human mdm2 (hdm2) and altered p53 protein is associated with high-level presentation of hdm2 and wild-type (wt) p53 derived peptides by major histocompatibility complex (MHC) class I molecules on a wide range of malignant cells. A major barrier to the design of broad-spectrum hdm2 and p53 specific immunotherapeutics for leukemia and cancer, however, has been the observation that low-level expression of hdm2 and wt p53 peptides by non-transformed tissues and cells results in self-tolerance of T-lymphocytes with high avidity for self-class I MHC / self-peptide complexes. Although the peripheral T-cell repertoire is mostly devoid of such high-avidity hdm2 and wt p53 epitope-specific cytotoxic T-lymphocytes (CTLs) due to self-tolerance, this does not necessarily preclude the possibility of designing strategies to tackle these universal leukemia and tumor-associated CTL-epitopes. HLA-A*0201 (A2.1) transgenic (Tg) mice models provide a conceptual basis that exploits species differences between human and murine protein sequences in order to circumvent self-tolerance and obtain A2.1-restricted CTLs specific for epitopes derived from hdm2 and p53 self-proteins. High-affinity hdm2 and p53 specific T-cell-receptors (TCRs) have been gained from A2.1-restricted Tg-CTLs and delivered into human T-lymphocytes in order to transfer antigen specificity, affinity, and class I MHC restriction. TCR-transduced human T-cells were able to recognize limited copy numbers of antigen and to efficiently kill a wide variety of human leukemia and tumor targets while preserving the integrity of non-transformed cells.