Artificial antigen-presenting cells transduced with telomerase efficiently expand epitope-specific, human leukocyte antigen-restricted cytotoxic T cells Journal Article

Authors: Dupont, J.; Latouche, J. B.; Ma, C.; Sadelain, M.
Article Title: Artificial antigen-presenting cells transduced with telomerase efficiently expand epitope-specific, human leukocyte antigen-restricted cytotoxic T cells
Abstract: Human telomerase reverse transcriptase (hTERT) is overexpressed in most human tumors, making it a potential target for cancer immunotherapy. hTERT-derived CTL epitopes have been identified previously, including p865 (RLVDDFLLV) and p540 (ILAKFLHWL), which are restricted by the human leukocyte antigen (HLA) class I A*0201 allele. However, it remains a major challenge to efficiently and consistently expand hTERT-specific CTLs from donor peripheral blood T lymphocytes. To bypass the need for generating conventional antigen-presenting cells (APCs) on an autologous basis, we investigated the potential ability of fibroblast-derived artificial APCs (AAPCs) to activate and expand HLA-A*0201-restricted CTLs. We show here that AAPCs stably expressing HLA-A*0201, human β 2-microglobulin, B7.1, intercellular adhesion molecule-1, and LFA-3, together with either p540 and p865 minigenes or the full-length hTERT, effectively stimulate tumoricidal, hTERT-specific CTLs. hTERT-expressing AAPCs stimulated both p540 and p865 CTLs as shown by peptide-specific cytolysis and tetramer staining, indicating that hTERT is processed by the AAPCs and that the two peptides are presented as codominant epitopes. The level of cytotoxic activity against a panel of tumors comprising hematologic and epithelial malignancies varied, correlating overall with the level of HLA-A2 and hTERT expression by the target cell. Starting from 100 mL blood, ∼ 100 million hTERT-specific CTLs could be generated over the course of five sequential stimulations, representing an expansion of ∼ 1 × 10 5. Our data show that AAPCs process hTERT antigen and efficiently stimulate hTERT-specific CTLs from human peripheral blood T lymphocytes and suggest that sufficient expansion could be achieved to be clinically useful for adoptive cell therapy. © 2005 American Association for Cancer Research.
Keywords: controlled study; unclassified drug; human cell; dna-binding proteins; animals; mice; allele; cancer immunotherapy; cytotoxicity; cell line, tumor; transfection; telomerase; transduction, genetic; lymphocyte activation; hematologic malignancy; amino acid sequence; molecular sequence data; peptide fragments; epitope; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; telomerase reverse transcriptase; cytolysis; target cell; beta 2 microglobulin; epitopes, t-lymphocyte; intercellular adhesion molecule 1; lymphocyte function associated antigen 3; adoptive immunotherapy; antigen presenting cell; hla-a antigens; immunotherapy, adoptive; antigen-presenting cells; cd45 antigen; b7 antigen; hla a2 antigen; k562 cells; phenylalanine derivative; arginylleucylvalylaspartylaspartylphenylalanylleucylleucylvalyl; hla a1 antigen; isoleucylleucylalanyllysylphenylalanylleucylhistidyltryptophylleucyl; tryptophan derivative
Journal Title: Cancer Research
Volume: 65
Issue: 12
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2005-06-15
Start Page: 5417
End Page: 5427
Language: English
DOI: 10.1158/0008-5472.can-04-2991
PUBMED: 15958591
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 35" - "Export Date: 24 October 2012" - "CODEN: CNREA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Jakob Dupont
    65 Dupont
  2. Michel W J Sadelain
    540 Sadelain
  3. Chia Ma
    4 Ma