Immunization of patients with the hTERT:540-548 peptide induces peptide-reactive T lymphocytes that do not recognize tumors endogenously expressing telomerase.
OBJECTIVE
Telomerase is an attractive target antigen for cancer immunotherapies because it is expressed in >85% of human tumors but is rarely found in normal tissues. A HLA-A*0201-restricted T-cell epitope was previously identified within telomerase reverse transcriptase hTERT:540-548. This peptide was reported to induce CTL that recognized tumor cells and transfectants that endogenously expressed telomerase. Therefore, we initiated a clinical protocol to evaluate the therapeutic and immunological efficacy of this peptide.


METHODS
Fourteen patients with metastatic cancers were vaccinated with hTERT:540-548 emulsified in incomplete Freund's adjuvant.


RESULTS
In 7 patients, peripheral blood mononuclear cells collected after immunization recognized hTERT:540-548, whereas those collected before vaccination did not. However, none of these CTLs recognized tumors that endogenously expressed telomerase, and none of the patients had an objective clinical response. Several highly avid T-cell clones were generated that recognized T2 cells pulsed with <or=1 nm hTERT:540-548, but none of these recognized HLA-A*0201(+) hTERT(+) tumors or cells transduced with the human telomerase reverse transcriptase (hTERT) gene. Also, an antibody specific for hTERT:540-548/HLA-A*0201 complexes stained peptide-pulsed cells but not telomerase(+) tumors.


CONCLUSIONS
Our results are discordant with previous studies and those of a clinical trial that claimed peripheral blood mononuclear cells from patients vaccinated with peptide-pulsed dendritic cells lysed hTERT(+) tumors. However, our findings are consistent with a previous study that demonstrated that the hTERT:540-548 peptide is cleaved in the proteasome. These results suggest that hTERT:540-548 is not presented on the surfaces of tumor cells in the context of HLA-A*0201 and will not be useful for the immunotherapy of patients with cancer.
Parkhurst
Maria R
MR
National Cancer Institute, Surgery Branch and National Heart, Lung, and Blood Institute, Hematology Branch, NIH, Bethesda, Maryland 20892-1502, USA. Maria_Parkhurst@nih.gov
Riley
John P
JP
Igarashi
Takehito
T
Li
Yong
Y
Robbins
Paul F
PF
Rosenberg
Steven A
SA
D000328:Adult; D000368:Aged; D002460:Cell Line; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007114:Immunization; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000628:therapy; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019098:Telomerase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D012333:RNA, Messenger; C437311:telomerase reverse transcriptase (540-548); D019098:Telomerase