Telomerase (hTERT 611-626) serves as a tumor antigen in B-cell chronic lymphocytic leukemia and generates spontaneously antileukemic, cytotoxic T cells.
OBJECTIVE
Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase. In B-cell chronic lymphocytic leukemia (B-CLL), telomerase activity is increased in about 75% of patients. The aim of this study was to analyze whether B-CLL patients with telomerase-positive leukemic cells had naturally occurring, telomerase-specific T cells that might be utilized for immune-mediated lysis of autologous tumor cells.


METHODS
Spontaneous T-cell immunity and cytotoxicity against hTERT was explored in B-CLL. Nineteen of 25 B-CLL patients (76%) expressed hTERT (reverse transcriptase polymerase chain reaction) and 10 were selected for specific T-cell analysis against hTERT.


RESULTS
The stimulation index (SI) of T cells from seven telomerase-positive patients stimulated with a 16aa hTERT peptide (611-626) loaded onto dendritic cells (DC) was 33.9 +/- 15.4 (mean SI +/- standard error of mean) and 13.2 +/- 5.6 against a Ras control peptide (p = 0.05), whereas the corresponding SI values for three telomerase-negative patients were 5.3 +/- 5.3 against the hTERT 611-626 peptide and 10.3 +/- 6.5 against the Ras peptide, respectively; and for three healthy controls, 5.4 +/- 0.9 against the hTERT 611-626 peptide and 4.5 +/- 1.0 against the Ras peptide (both not significant). Blocking experiments revealed that the specific responses were major histocompatibility complex (MHC) class I and MHC class II restricted. DC pulsed with the hTERT-peptide generated MHC class I-restricted, hTERT-specific cytotoxic T lymphocytes in six of seven telomerase-positive patients; mean cytotoxicity of hTERT-stimulated T cells was 49.8% +/- 9.3% vs 13.1 +/- 2.9% for Ras-stimulated T cells (p < 0.05). In three of three telomerase-negative patients, no hTERT-specific cytotoxic T lymphocytes could be expanded.


CONCLUSIONS
Telomerase-positive B-CLL patients have spontaneously occurring cytotoxic hTERT-specific T cells. This antigen might be explored as a therapeutic vaccine in B-CLL.
Kokhaei
Parviz
P
Immune and Gene Therapy Lab, Cancer Centre Karolinska, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
Palma
Marzia
M
Hansson
Lotta
L
Osterborg
Anders
A
Mellstedt
Håkan
H
Choudhury
Aniruddha
A
D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019098:Telomerase / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology
D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; C514987:GV1001 peptide; D019098:Telomerase