Targeting Acute Leukemia and Cancer by High-Affinity T-Cell-Receptor Transfer
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.
KeywordsHigh Avidity Large Scale Clinical Application Limited Copy Number Human CTLs Hdm2 Protein
Unable to display preview. Download preview PDF.
- Molldrem JJ, Dermime S, Parker K, Jiang YZ, Mavroudis D, Hensel N, Fukushima P, Barrett AJ (1996) Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells. Blood 88:2450–2457PubMedGoogle Scholar
- Oka Y, Elisseeva OA, Tsuboi A, Ogawa H, Tamaki H, Li H, Oji Y, Kim EH, Soma T, Asada M, Ueda K, Maruya E, Saji H, Kishimoto T, Udaka K, Sugiyama H (2000) Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms tumor gene (WT1) product. Immunogenetics 51:99–107PubMedCrossRefGoogle Scholar
- Theobald M, Ruppert T, Kuckelkorn U, Hernandez J, Häussler A, Antunes Ferreira E, Liewer U, Biggs J, Levine AJ, Huber C, Koszinowski UH, Kloetzel P-M, Sherman LA (1998) The sequence alteration associated with a mutational hotspot in p53 protects cells from lysis by cytotoxic T lymphocytes specific for a flanking peptide epitope. J Exp Med 188:1017–1028PubMedCrossRefGoogle Scholar