Telomerase As a Tumor-associated Antigen for Cancer Immunotherapy

Overview

Journal Cytotechnology

Specialties Biotechnology
Genetics

Date 2008 Nov 13

PMID 19003246

Citations 7

Authors

Kunal P Patel

Robert H Vonderheide

Affiliations

Soon will be listed here.

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.

Citing Articles

Cytotoxic lymphocytes induced by engineered human dendritic cells mediate potent anti-leukemia activity.

Zhao C, Jia B, Jiang Y, Shike H, Annageldiyev C, Cioccio J Cancer Immunol Immunother. 2025; 74(4):117.

PMID: 39998689 PMC: 11861774. DOI: 10.1007/s00262-025-03971-y.

TERT Promoter Mutation in Benign and Malignant Salivary Gland Tumors; A Cross-Sectional Study.

Zare-Mirzaie A, Mollazadehghomi S, Heshmati S, Mehrtash A, Mollazadehghomi S Iran J Pathol. 2023; 18(1):64-74.

PMID: 37383158 PMC: 10293604. DOI: 10.30699/IJP.ijp.2023.556651.2927.

Expression of the Reverse Transcriptase Domain of Telomerase Reverse Transcriptase Induces Lytic Cellular Response in DNA-Immunized Mice and Limits Tumorigenic and Metastatic Potential of Murine Adenocarcinoma 4T1 Cells.

Jansons J, Bayurova E, Skrastina D, Kurlanda A, Fridrihsone I, Kostyushev D Vaccines (Basel). 2020; 8(2).

PMID: 32570805 PMC: 7350266. DOI: 10.3390/vaccines8020318.

An Overview of Candidate Therapeutic Target Genes in Ovarian Cancer.

Alexandrova E, Pecoraro G, Sellitto A, Melone V, Ferravante C, Rocco T Cancers (Basel). 2020; 12(6).

PMID: 32512900 PMC: 7352306. DOI: 10.3390/cancers12061470.

In Vitro Assessment of the Expression and T Cell Immunogenicity of the Tumor-Associated Antigens BORIS, MUC1, hTERT, MAGE-A3 and Sp17 in Uterine Cancer.

Vanderstraeten A, Tuyaerts S, Everaert T, Van Bree R, Verbist G, Luyten C Int J Mol Sci. 2016; 17(9).

PMID: 27618037 PMC: 5037800. DOI: 10.3390/ijms17091525.

References

Van den Eynde B, van der Bruggen P . T cell defined tumor antigens. Curr Opin Immunol. 1997; 9(5):684-93. DOI: 10.1016/s0952-7915(97)80050-7. View

Counter C, Botelho F, Wang P, Harley C, Bacchetti S . Stabilization of short telomeres and telomerase activity accompany immortalization of Epstein-Barr virus-transformed human B lymphocytes. J Virol. 1994; 68(5):3410-4. PMC: 236835. DOI: 10.1128/JVI.68.5.3410-3414.1994. View

Ramakrishnan S, Eppenberger U, Mueller H, Shinkai Y, Narayanan R . Expression profile of the putative catalytic subunit of the telomerase gene. Cancer Res. 1998; 58(4):622-5. View

Boukamp P . Telomerase activity in the regenerative basal layer of the epidermis inhuman skin and in immortal and carcinoma-derived skin keratinocytes. Proc Natl Acad Sci U S A. 1996; 93(13):6476-81. PMC: 39048. DOI: 10.1073/pnas.93.13.6476. View

Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyama E, Piatyszek M . Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol. 1995; 155(8):3711-5. View

Arai J, Yasukawa M, Ohminami H, Kakimoto M, Hasegawa A, Fujita S . Identification of human telomerase reverse transcriptase-derived peptides that induce HLA-A24-restricted antileukemia cytotoxic T lymphocytes. Blood. 2001; 97(9):2903-7. DOI: 10.1182/blood.v97.9.2903. View

Hahn W, Counter C, Lundberg A, Beijersbergen R, Brooks M, Weinberg R . Creation of human tumour cells with defined genetic elements. Nature. 1999; 400(6743):464-8. DOI: 10.1038/22780. View

Hahn W, Stewart S, Brooks M, York S, Eaton E, Kurachi A . Inhibition of telomerase limits the growth of human cancer cells. Nat Med. 1999; 5(10):1164-70. DOI: 10.1038/13495. View

Scardino A, Gross D, Alves P, Schultze J, Graff-Dubois S, Faure O . HER-2/neu and hTERT cryptic epitopes as novel targets for broad spectrum tumor immunotherapy. J Immunol. 2002; 168(11):5900-6. DOI: 10.4049/jimmunol.168.11.5900. View

10.

Broccoli D, Young J, de Lange T . Telomerase activity in normal and malignant hematopoietic cells. Proc Natl Acad Sci U S A. 1995; 92(20):9082-6. PMC: 40928. DOI: 10.1073/pnas.92.20.9082. View

11.

Herbert B, Pitts A, Baker S, Hamilton S, Wright W, Shay J . Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc Natl Acad Sci U S A. 1999; 96(25):14276-81. PMC: 24427. DOI: 10.1073/pnas.96.25.14276. View

12.

Rosenberg S . Progress in human tumour immunology and immunotherapy. Nature. 2001; 411(6835):380-4. DOI: 10.1038/35077246. View

13.

Nakamura T, Morin G, Chapman K, Weinrich S, Andrews W, Lingner J . Telomerase catalytic subunit homologs from fission yeast and human. Science. 1997; 277(5328):955-9. DOI: 10.1126/science.277.5328.955. View

14.

Yasumoto S, Kunimura C, Kikuchi K, Tahara H, Ohji H, Yamamoto H . Telomerase activity in normal human epithelial cells. Oncogene. 1996; 13(2):433-9. View

15.

Su Z, Dannull J, Heiser A, Yancey D, Pruitt S, Madden J . Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res. 2003; 63(9):2127-33. View

16.

Kim N, Piatyszek M, Prowse K, Harley C, WEST M, Ho P . Specific association of human telomerase activity with immortal cells and cancer. Science. 1994; 266(5193):2011-5. DOI: 10.1126/science.7605428. View

17.

Vaziri H, Benchimol S . Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr Biol. 1998; 8(5):279-82. DOI: 10.1016/s0960-9822(98)70109-5. View

18.

Bodnar A, Ouellette M, Frolkis M, Holt S, Chiu C, Morin G . Extension of life-span by introduction of telomerase into normal human cells. Science. 1998; 279(5349):349-52. DOI: 10.1126/science.279.5349.349. View

19.

Vonderheide R, Schultze J, Anderson K, Maecker B, Butler M, Xia Z . Equivalent induction of telomerase-specific cytotoxic T lymphocytes from tumor-bearing patients and healthy individuals. Cancer Res. 2001; 61(23):8366-70. View

20.

Nair S, Heiser A, Boczkowski D, Majumdar A, Naoe M, Lebkowski J . Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells. Nat Med. 2000; 6(9):1011-7. DOI: 10.1038/79519. View