Abstract
Telomerase reverse transcriptase hTERT is an attractive target for cancer immunotherapy given its broad expression in human tumors and its demonstrated immunogenicity. Human and murine model systems demonstrate that CD8+ cytotoxic T-lymphocytes (CTL) and CD4+ helper T-lymphocytes can recognize dominant epitopes derived from TERT. CTL kill TERT-positive tumor cells of multiple histologies, although there is some disagreement regarding the level of processing and presentation of certain TERT peptides within the context of MHC class I molecules. CTL recognizing modified, low-affinity cryptic TERT epitopes have also been generated that protect against tumor challenge in a murine model. Several phase I clinical trials testing hTERT as a cancer vaccine target have shown the induction of T-cell immune responses but minimal toxicities, including bone marrow toxicity, in patients with multiple types of cancer. Several studies report some patients experiencing clinical benefit, including partial tumor regression, providing further encouragement for hTERT as broadly applicable target for cancer immunotherapy.
Similar content being viewed by others
Abbreviations
- CTL:
-
cytotoxic T-lymphocyte
- DC:
-
dendritic cells
- HLA:
-
human leukocyte antigen
- LAMP:
-
lysosome associated membrane protein
- MHC:
-
major histocompatibility complex
- TAA:
-
tumor-associated antigen
References
J. Arai M. Yasukawa H. Ohminami M. Kakimoto A. Hasegawa S. Fujita (2001) ArticleTitleIdentification of human telomerase reverse transcriptase-derived peptides that induce HLA-A24-restricted antileukemia cytotoxic T lymphocytes Blood 97 2903–2907 Occurrence Handle10.1182/blood.V97.9.2903 Occurrence Handle11313288
M. Ayyoub M. Migliaccio P. Guillaume D. Lienard J.C. Cerottini P. Romero F. Levy D.E. Speiser D. Valmori (2001) ArticleTitleLack of tumor recognition by hTERT peptide 540–548-specific CD8(+) T cells from melanoma patients reveals inefficient antigen processing Eur. J. Immunol. 31 2642–2651 Occurrence Handle10.1002/1521-4141(200109)31:9<2642::AID-IMMU2642>3.0.CO;2-6 Occurrence Handle11536162
D. Broccoli J.W. Young T. de Lange (1995) ArticleTitleTelomerase activity in normal and malignant hematopoietic cells Proc. Natl. Acad. Sci. USA 92 9082–9086 Occurrence Handle7568077
A.G. Bodnar M. Ouellette M. Frolkis S.E. Holt C.P. Chiu G.B. Morin C.B. Harley J.W. Shay S. Lichtsteiner W.E. Wright (1998) ArticleTitleExtension of life-span by introduction of telomerase into normal human cells Science 279 349–352 Occurrence Handle9454332
C.M. Counter A.A. Avilion C.E. LeFeuvre N.G. Stewart C.W. Greider C.B. Harley S. Bacchetti (1992) ArticleTitleTelomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity EMBO J 11 1921–1929 Occurrence Handle1582420
C.M. Counter F.M. Botelho P. Wang C.B. Harley S. Bacchetti (1994) ArticleTitleStabilization of short telomeres and telomerase activity accompany immortalization of Epstein–Barr virus-transformed human B lymphocytes J. Virol. 68 3410–3414 Occurrence Handle8151802
C.M. Counter M. Meyerson E.N. Eaton L.W. Ellisen S.D. Caddle D.A. Haber R.A. Weinberg (1998) ArticleTitleTelomerase activity is restored in human cells by ectopic expression of hTERT (hEST2), the catalytic subunit of telomerase Oncogene 16 1217–1222 Occurrence Handle9528864
G. Gaudernack T. Buanes M. Meo S. Aamdal P. Brunsvig L.R. Braathen K. Kernland M.K. Gjertsen J.A. Eriksen M. Moller (2003) ArticleTitleClinical trials of a peptide based vaccine targeting telomerase Proc. Am. Soc. Clin. Oncol. 22 166
E. Gilboa (1999) ArticleTitleThe makings of a tumor rejection antigen Immunity 11 263–70 Occurrence Handle10.1016/S1074-7613(00)80101-6 Occurrence Handle10514004
D.A. Gross S. Graff-Dubois P. Opolon S. Cornet P. Alves A. Bennaceur-Griscelli O. Faure P. Guillaume H. Firat S. Chouaib F.A. Lemonnier J. Davoust I. Miconnet R.H. Vonderheide K. Kosmatopoulos (2004) ArticleTitleHigh vaccination efficiency of low-affinity epitopes in antitumor immunotherapy J. Clin. Invest. 113 425–433 Occurrence Handle10.1172/JCI200419418 Occurrence Handle14755339
W.C. Hahn C.M. Counter A.S. Lundberg R.L. Beijersbergen M.W. Brooks R.A. Weinberg (1999a) ArticleTitleCreation of human tumour cells with defined genetic elements Nature 400 464–468 Occurrence Handle10.1038/22780
W.C. Hahn S.A. Stewart M.W. Brooks S.G. York E. Eaton A. Kurachi R.L. Beijersbergen J.H. Knoll M. Meyerson R.A. Weinberg (1999b) ArticleTitleInhibition of telomerase limits the growth of human cancer cells Nat. Med. 5 1164–1170 Occurrence Handle10.1038/13495
C. Harle-Bachor P. Boukamp (1996) ArticleTitleTelomerase activity in the regenerative basal layer of the epidermis in human skin and in immortal and carcinoma-derived skin keratinocytes Proc. Natl. Acad. Sci. USA 93 6476–6481 Occurrence Handle10.1073/pnas.93.13.6476 Occurrence Handle8692840
C.B. Harley N.W. Kim K.R. Prowse S.L. Weinrich K.S. Hirsch M.D. West S. Bacchetti H.W. Hirte C.M. Counter C.W. Greider et al. (1994) ArticleTitleTelomerasecell immortality, and cancer Cold Spring Harb. Symp. Quant. Biol. 59 307–315 Occurrence Handle7587082
L. Harrington W. Zhou T. McPhail R. Oulton D.S. Yeung V. Mar M.B. Bass M.O. Robinson (1997) ArticleTitleHuman telomerase contains evolutionarily conserved catalytic and structural subunits Genes Dev. 11 3109–3115 Occurrence Handle9389643
A. Heiser M.A. Maurice D.R. Yancey D.M. Coleman P. Dahm J. Vieweg (2001a) ArticleTitleHuman dendritic cells transfected with renal tumor RNA stimulate polyclonal T-cell responses against antigens expressed by primary and metastatic tumors Cancer Res. 61 3388–3393
A. Heiser M.A. Maurice D.R. Yancey N.Z. Wu P. Dahm S.K. Pruitt D. Boczkowski S.K. Nair M.S. Ballo E. Gilboa J. Vieweg (2001b) ArticleTitleInduction of polyclonal prostate cancer-specific CTL using dendritic cells transfected with amplified tumor RNA J. Immunol. 166 2953–2960
B. Herbert A.E. Pitts S.I. Baker S.E. Hamilton W.E. Wright J.W. Shay D.R. Corey (1999) ArticleTitleInhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death Proc. Natl. Acad. Sci. USA 96 14276–14281 Occurrence Handle10.1073/pnas.96.25.14276 Occurrence Handle10588696
K. Hiyama Y. Hirai S. Kyoizumi M. Akiyama E. Hiyama M.A. Piatyszek J.W. Shay S. Ishioka M. Yamakido (1995) ArticleTitleActivation of telomerase in human lymphocytes and hematopoietic progenitor cells J. Immunol. 155 3711–3715 Occurrence Handle7561072
K. Hung R. Hayashi A. Lafond-Walker C. Lowenstein D. Pardoll H. Levitsky (1998) ArticleTitleThe central role of CD4(+) T cells in the antitumor immune response J. Exp. Med. 188 2357–2368 Occurrence Handle10.1084/jem.188.12.2357 Occurrence Handle9858522
E.M. Janssen E.E. Lemmens T. Wolfe U. Christen M.G. von Herrath S.P. Schoenberger (2003) ArticleTitleCD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes Nature 421 852–856 Occurrence Handle10.1038/nature01441 Occurrence Handle12594515
N.W. Kim M.A. Piatyszek K.R. Prowse C.B. Harley M.D. West P.L. Ho G.M. Coviello W.E. Wright S.L. Weinrich J.W. Shay (1994) ArticleTitleSpecific association of human telomerase activity with immortal cells and cancer Science 266 2011–2015 Occurrence Handle7605428
A. Lev G. Denkberg C.J. Cohen M. Tzukerman K.L. Skorecki P. Chames H.R. Hoogenboom Y. Reiter (2002) ArticleTitleIsolation and characterization of human recombinant antibodies endowed with the antigen-specific, major histocompatability complex-restricted specificity of T cells directed toward the widely expressed tumor T-cell epitopes of the telomerase catalytic subunit Cancer Res. 62 3184–3194 Occurrence Handle12036932
K. Masutomi E.Y. Yu S. Khurts I. Ben-Porath J.L. Currier G.B. Metz M.W. Brooks S. Kaneko S. Murakami J.A. DeCaprio R.A. Weinberg S.A. Stewart W.C. Hahn (2003) ArticleTitleTelomerase maintains telomere structure in normal human cells Cell 114 241–253 Occurrence Handle10.1016/S0092-8674(03)00550-6 Occurrence Handle12887925
M. Meyerson C.M. Counter E.N. Eaton L.W. Ellisen P. Steiner S.D. Caddle L. Ziaugra R.L. Beijersbergen M.J. Davidoff Q. Liu S. Bacchetti D.A. Haber R.A. Weinberg (1997) ArticleTitlehEST2, the putative human telomerase catalytic subunit geneis up-regulated in tumor cells and during immortalization Cell 90 785–795 Occurrence Handle9288757
B. Minev J. Hipp H. Firat J.D. Schmidt P. Langlade-Demoyen M. Zanetti (2000) ArticleTitleCytotoxic T cell immunity against telomerase reverse transcriptase in humans Proc. Natl. Acad. Sci. USA 97 4796–4801 Occurrence Handle10.1073/pnas.070560797 Occurrence Handle10759561
S.K. Nair A. Heiser D. Boczkowski A. Majumdar M. Naoe J.S. Lebkowski J. Vieweg E. Gilboa (2000) ArticleTitleInduction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells Nat. Med. 6 1011–1017 Occurrence Handle10.1038/79519 Occurrence Handle10973321
T.M. Nakamura G.B. Morin K.B. Chapman S.L. Weinrich W.H. Andrews J. Lingner C.B. Harley T.R. Cech (1997) ArticleTitleTelomerase catalytic subunit homologs from fission yeast and human Science 277 955–959
S. Ramakrishnan U. Eppenberger H. Mueller Y. Shinkai R. Narayanan (1998) ArticleTitleExpression profile of the putative catalytic subunit of the telomerase gene Cancer Res. 58 622–625 Occurrence Handle9485011
S.A. Rosenberg (1997) ArticleTitleCancer vaccines based on the identification of genes encoding cancer regression antigens Immunol. Today 18 175–182 Occurrence Handle10.1016/S0167-5699(97)84664-6 Occurrence Handle9136454
S.A. Rosenberg (2001) ArticleTitleProgress in human tumour immunology and immunotherapy Nature 411 380–384 Occurrence Handle10.1038/35077246 Occurrence Handle11357146
A. Scardino D.A. Gross P. Alves J.L. Schultze S. Graff-Dubois O. Faure S. Tourdot S. Chouaib L.M. Nadler F.A. Lemonnier R.H. Vonderheide A.A. Cardoso K. Kosmatopoulos (2002) ArticleTitleHER-2/neu and hTERT cryptic epitopes as novel targets for broad spectrum tumor immunotherapy J. Immunol. 168 5900–5906 Occurrence Handle12023395
R. Schroers X.F. Huang J. Hammer J. Zhang S.Y. Chen (2002) ArticleTitleIdentification of HLA DR7-restricted epitopes from human telomerase reverse transcriptase recognized by CD4+ T-helper cells Cancer Res. 62 2600–2605 Occurrence Handle11980655
R. Schroers L. Shen L. Rollins C.M. Rooney K. Slawin G. Sonderstrup X.F. Huang S.Y. Chen (2003) ArticleTitleHuman telomerase reverse transcriptase-specific T-helper responses induced by promiscuous major histocompatability complex class II-restricted epitopes Clin. Cancer Res. 9 4743–4755 Occurrence Handle14581345
J.L. Schultze R.H. Vonderheide (2001) ArticleTitleFrom cancer genomics to cancer immunotherapy: toward second-generation tumor antigens Trends Immunol. 22 516–523 Occurrence Handle10.1016/S1471-4906(01)02015-4 Occurrence Handle11525943
D.E. Speiser J.C. Cerottini P. Romero (2002) ArticleTitleCan hTERT peptide (540–548)-specific CD8 T cells recognize and kill tumor cells? Cancer Immun. 2 14 Occurrence Handle12747759
Z. Su J. Dannull P. Dahm B. Yang D. Coleman D. Yancey S. Sichi J. Higgins E. Gilboa J. Vieweg (2003a) ArticleTitleVaccination of patients with hormone-refractory prostate cancer using telomerase RNA transfected DC: results from a phase I clinical trial Blood 102S 11
Z. Su J. Dannull A. Heiser D. Yancey S. Pruitt J. Madden D. Coleman D. Niedzwiecki E. Gilboa J. Vieweg (2003b) ArticleTitleImmunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells Cancer Res. 63 2127–2133
B.J. Van den Eynde P. van der Bruggen (1997) ArticleTitleT cell defined tumor antigens Curr. Opin. Immunol. 9 684–693 Occurrence Handle10.1016/S0952-7915(97)80050-7 Occurrence Handle9368778
A. Van Pel P. van der Bruggen P.G. Coulie V.G. Brichard B. Lethe B. van den Eynde C. Uyttenhove J.C. Renauld T. Boon (1995) ArticleTitleGenes coding for tumor antigens recognized by cytolytic T lymphocytes Immunol. Rev. 145 229–250 Occurrence Handle7590828
H. Vaziri S. Benchimol (1998) ArticleTitleReconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span Curr. Biol. 8 279–382 Occurrence Handle10.1016/S0960-9822(98)70109-5 Occurrence Handle9501072
R.H. Vonderheide W.C. Hahn J.L. Schultze L.M. Nadler (1999) ArticleTitleThe telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes Immunity 10 673–679 Occurrence Handle10.1016/S1074-7613(00)80066-7 Occurrence Handle10403642
R.H. Vonderheide K.S. Anderson W.C. Hahn M.O. Butler J.L. Schultze L.M. Nadler (2001b) ArticleTitleCharacterization of HLA-A3-restricted cytotoxic T lymphocytes reactive against the widely expressed tumor antigen telomerase Clin. Cancer Res. 7 3343–3348
R.H. Vonderheide S.M. Domchek J.L. Schultze D.J. George K.M. Hoar D.Y. Chen K.F. Stephans K. Masutomi M. Loda Z. Xia K.S. Anderson W.C. Hahn L.M. Nadler (2004) ArticleTitleVaccination of cancer patients against telomerase induces functional antitumor CD8+ T lymphocytes Clin. Cancer Res. 10 828–839 Occurrence Handle14871958
R.H. Vonderheide J.L. Schultze K.S. Anderson B. Maecker M.O. Butler Z. Xia M.J. Kuroda M.S. von Bergwelt-Baildon M.M. Bedor K.M. Hoar D.R. Schnipper M.W. Brooks N.L. Letvin K.F. Stephans K.W. Wucherpgennig W.C. Hahn L.M. Nadler (2001a) ArticleTitleEquivalent induction of telomerase-specific cytotoxic T lymphocytes from tumor-bearing patients and healthy individuals Cancer Res. 61 8366–8370
S. Yasumoto C. Kunimura K. Kikuchi H. Tahara H. Ohji H. Yamamoto T. Ide T. Utakoji (1996) ArticleTitleTelomerase activity in normal human epithelial cells Oncogene 13 433–439 Occurrence Handle8710384
X. Zhang V. Mar W. Zhou L. Harrington M.O. Robinson (1999) ArticleTitleTelomere shortening and apoptosis in telomere-inhibited human tumor cells Genes Dev. 13 2388–2399 Occurrence Handle10.1101/gad.13.18.2388 Occurrence Handle10500096
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Patel, K., Vonderheide, R. Telomerase as a tumor-associated antigen for cancer immunotherapy. Cytotechnology 45, 91–99 (2004). https://doi.org/10.1007/s10616-004-5132-2
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10616-004-5132-2