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
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-20444498276&partnerID=40&md5=727c03a3e986ef703467e440b32d2eeb
Notes:	--- - "Cited By (since 1996): 35" - "Export Date: 24 October 2012" - "CODEN: CNREA" - "Source: Scopus"

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