In vitro stimulation with WT1 peptide-loaded Epstein-Barr virus-positive B cells elicits high frequencies of WT1 peptide-specific T cells with in vitro and in vivo tumoricidal activity Journal Article

Authors: Doubrovina, E. S.; Doubrovin, M. M.; Lee, S.; Shieh, J.H.; Heller, G.; Pamer, E.; O'Reilly, R. J.
Article Title: In vitro stimulation with WT1 peptide-loaded Epstein-Barr virus-positive B cells elicits high frequencies of WT1 peptide-specific T cells with in vitro and in vivo tumoricidal activity
Abstract: The Wilms tumor protein (WT1) is overexpressed in most acute and chronic leukemias. To develop a practicable, clinically applicable approach for generation of WT1-specific T cells and to comparatively evaluate the immunogenicity of WT1 in normal individuals, we sensitized T cells from 13 HLA-A0201+ and 5 HLA-A2402+ donors with autologous EBV-transformed B cells or cytokine-activated monocytes, loaded with the HLA-A0201-binding WT1 peptides 126-134RMFPNAPYL or 187-195SLGEQQYSV or a newly identified HLA-A2402-binding WT1 peptide 301-310RVPGVAPTL. WT1-specific T cells were regularly generated from each donor. T cells sensitized with peptide-loaded EBV-transformed B cells generated higher numbers of WT1-specific T cells than peptide-loaded cytokine-activated monocytes. Contrary to expectations, the frequencies of WT1 peptide-specific T cells were equivalent to those generated against individual highly immunogenic HLA-A0201-binding EBV peptides. Each of these T-cell lines specifically killed WT1+ leukemias and solid tumors in an HLA-restricted manner but did not lyse autologous or HLA-matched normal CD34+ hematopoietic progenitor cells or reduce their yield of colony-forming unit-granulocyte-macrophage (CFU-GM), burst-forming unit erythroid (BFU-E), or mixed colonies (CFU-mix). Furthermore, WT1 peptide-specific T cells after adoptive transfer into nonobese diabetic-severe combined immunodeficient mice bearing subcutaneous xenografts of WT1+ and WT1- HLA-A0201+ leukemias preferentially accumulated in and induced regressions of WT1+ leukemias that expressed the restricting HLA allele. Such cells are clinically applicable and may prove useful for adoptive cell therapy of WT1+ malignant diseases in humans.
Keywords: leukemia; human cell; nonhuman; positron emission tomography; sensitivity and specificity; cd8 antigen; t lymphocyte; t-lymphocytes; mouse; animals; mice; gene; cd34 antigen; interleukin 2; erythropoietin; granulocyte macrophage colony stimulating factor; interleukin 4; animal model; protein binding; alleles; antineoplastic activity; tumor xenograft; mice, scid; peptide; cell line, tumor; time factors; b lymphocyte; cytokines; tumor necrosis factor alpha; gamma interferon; iodine 131; immunogenicity; tumor protein; cytotoxic t lymphocyte; tumor cell; peptides; cell movement; adoptive transfer; fialuridine; hematopoietic stem cell; neoplasm transplantation; wt1 protein; monocytes; image processing, computer-assisted; hla a antigen; fluorine 18; antigens, cd34; adoptive immunotherapy; antigen presenting cell; scid mouse; epstein barr virus; herpesvirus 4, human; colony forming unit gm; hla system; 5 ethyl 2' fluorouracil arabinoside; recombinant interleukin 3; wt1 proteins; scintillation camera; burst forming unit e; genes, wilms tumor; gamma scintigraphy; wt1 gene; humans; human; priority journal; article; virus cell transformation
Journal Title: Clinical Cancer Research
Volume: 10
Issue: 21
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2004-11-01
Start Page: 7207
End Page: 7219
Language: English
DOI: 10.1158/1078-0432.ccr-04-1040
PROVIDER: scopus
PUBMED: 15534094
Notes: Clin. Cancer Res. -- Cited By (since 1996):33 -- Export Date: 16 June 2014 -- CODEN: CCREF -- Source: Scopus
Citation Impact
MSK Authors
  1. Glenn Heller
    381 Heller
  2. Eric Pamer
    279 Pamer
  3. Sang Yull Lee
    16 Lee
  4. Jae-Hung Shieh
    76 Shieh
  5. Richard O'Reilly
    714 O'Reilly