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

  • M. Theobald
  • R.-H. Voss
  • F. Schmitz
  • J. Kuball
  • C. Lotz
Conference paper
Part of the Haematology and Blood Transfusion Hämatologie und Bluttransfusion book series (HAEMATOLOGY, volume 41)

Summary

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.

Keywords

Toxicity Leukemia Myeloma Geted 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • M. Theobald
    • 1
  • R.-H. Voss
    • 1
  • F. Schmitz
    • 1
  • J. Kuball
    • 1
  • C. Lotz
    • 1
  1. 1.Department of Hematology & OncologyJohannes Gutenberg-UniversityMainzGermany

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