Composition and method for inducing and enhancing a telomerase reverse transcriptase-reactive cytotoxic T lymphocyte response
Patent Number: US8697836
Executive Summary:
General Description:
The vast majority of contemporary approaches to personalized immunotherapy are based on neoantigen peptides identified by whole-exome sequencing. This invention presents a viable alternative: rationally designed peptides that induce T cell response against telomerase reverse transcriptase (hTRT), an enzyme essential for cell immortalization, which is highly expressed in a variety of cancers. hTRT has been described as a promising target for a universal cancer vaccine. Phase I clinical trials of the peptides from this invention (ref. 6) demonstrated that vaccination against telomerase is safe and that a specific immunological response can be induced in vivo. However, the clinical response was observed only in a limited number of cases. According to the recent review published by the Inventor (ref. 1), development of cancer immunotherapy targeting hTRT is still justified, despite the largely unsuccessful initial attempts. Optimization of immunogenicity and the quality of T-cell responses should be the focus of new research efforts. Furthermore, pre-screening of patients to estimate the potential benefit from the hTRT peptide vaccine can be performed by new generation sequencing and quantifying the existence of T-cells precursors specific for TERT before immunotherapy is attempted.
Scientific Progress:
It has been recently demonstrated that hTRT is expressed at every stage of the cancer process, from the incipient CSCs and/or tumor-initiating cells to advanced metastatic cancer cells, and has essential roles at each stage of tumorigenesis. Whole genome sequencing analyses have established that TERT-promoter mutations are the most-prevalent mutations in noncoding regions of cancer genomes.
Future Directions:
Strengths:
Weaknesses:
Patent Status:
Publications:
1: Zanetti M. A second chance for telomerase reverse transcriptase in anticancer immunotherapy. Nat Rev Clin Oncol. 2017 Feb;14(2):115-128. doi:10.1038/nrclinonc.2016.67. Epub 2016 Jun 1. Review. PubMed PMID: 27245281.
2: Soeiro-de-Souza MG, Teixeira AL, Mateo EC, Zanetti MV, Rodrigues FG, de Paula VJ, Bezerra JF, Moreno RA, Gattaz WF, Machado-Vieira R. Leukocyte telomerase activity and antidepressant efficacy in bipolar disorder. Eur Neuropsychopharmacol. 2014 Jul;24(7):1139-43. doi:10.1016/j.euroneuro.2014.03.005. Epub 2014 Mar 27. PubMed PMID: 24731723.
3: Fenoglio D, Traverso P, Parodi A, Kalli F, Zanetti M, Filaci G. Generation of more effective cancer vaccines. Hum Vaccin Immunother. 2013 Dec;9(12):2543-7. doi: 10.4161/hv.26147. Epub 2013 Aug 26. PubMed PMID: 23978951; PubMed Central PMCID: PMC4162041.
4: Cortez-Gonzalez X, Zanetti M. Identification of immunogenic peptides of the self-tumor antigen: our experience with telomerase reverse transcriptase. Methods Mol Biol. 2010;651:211-25. doi: 10.1007/978-1-60761-786-0_12. PubMed PMID: 20686968.
5: Pellicciotta I, Cortez-Gonzalez X, Sasik R, Reiter Y, Hardiman G, Langlade-Demoyen P, Zanetti M. Presentation of telomerase reverse transcriptase, a self-tumor antigen, is down-regulated by histone deacetylase inhibition. Cancer Res. 2008 Oct 1;68(19):8085-93. doi: 10.1158/0008-5472.CAN-08-1014. PubMed PMID: 18829567.
6: Cortez-Gonzalez X, Zanetti M. Telomerase immunity from bench to bedside: round one. J Transl Med. 2007 Feb 26;5:12. Review. PubMed PMID: 17324292; PubMed Central PMCID: PMC1839079.
7: Cortez-Gonzalez X, Sidney J, Adotevi O, Sette A, Millard F, Lemonnier F, Langlade-Demoyen P, Zanetti M. Immunogenic HLA-B7-restricted peptides of hTRT. Int Immunol. 2006 Dec;18(12):1707-18. Epub 2006 Oct 31. PubMed PMID: 17077179.
8: Adotévi O, Mollier K, Neuveut C, Cardinaud S, Boulanger E, Mignen B, Fridman WH, Zanetti M, Charneau P, Tartour E, Lemonnier F, Langlade-Demoyen P. Immunogenic HLA-B*0702-restricted epitopes derived from human telomerase reverse transcriptase that elicit antitumor cytotoxic T-cell responses. Clin Cancer Res. 2006 May 15;12(10):3158-67. PubMed PMID: 16707616.
9: Filaci G, Fravega M, Setti M, Traverso P, Millo E, Fenoglio D, Negrini S, Ferrera F, Romagnoli A, Basso M, Contini P, Rizzi M, Ghio M, Benatti U, Damonte G, Ravetti JL, Carmignani G, Zanetti M, Indiveri F. Frequency of
telomerase-specific CD8+ T lymphocytes in patients with cancer. Blood. 2006 Feb 15;107(4):1505-12. Epub 2005 Oct 25. PubMed PMID: 16249379.
10: Zanetti M, Hernandez X, Langlade-Demoyen P. Telomerase reverse transcriptase as target for anti-tumor T cell responses in humans. Springer Semin Immunopathol. 2005 Jun;27(1):87-104. Epub 2005 Feb 15. Review. PubMed PMID: 15711953.
11: Hernández J, Schoeder K, Blondelle SE, Pons FG, Lone YC, Simora A, Langlade-Demoyen P, Wilson DB, Zanetti M. Antigenicity and immunogenicity of peptide analogues of a low affinity peptide of the human telomerase reverse transcriptase tumor antigen. Eur J Immunol. 2004 Aug;34(8):2331-41. PubMed PMID: 15259031.
12: Hernandez J, Garcia-Pons F, Lone YC, Firat H, Schmidt JD, Langlade-Demoyen P, Zanetti M. Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12275-80. Epub 2002 Sep 6. PubMed PMID: 12218171; PubMed Central PMCID: PMC129435.
13: Minev B, Hipp J, Firat H, Schmidt JD, Langlade-Demoyen P, Zanetti M. Cytotoxic T cell immunity against telomerase reverse transcriptase in humans. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4796-801. PubMed PMID: 10759561; PubMed Central PMCID: PMC18312.
14: Dosset M, Godet Y, Vauchy C, Beziaud L, Lone YC, Sedlik C, Liard C, Levionnois E, Clerc B, Sandoval F, Daguindau E, Wain-Hobson S, Tartour E, Langlade-Demoyen P, Borg C, Adotévi O. Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor. Clin Cancer Res. 2012 Nov 15;18(22):6284-95. doi: 10.1158/1078-0432.CCR-12-0896. Epub 2012 Oct 2. PubMed PMID: 23032748
Inventor Bio: Maurizio Zanetti
http://moores.ucsd.edu/zanettilab/
Executive Summary:
- Invention Type: Therapeutic (Vaccine)
- Patent Status: Granted
- Patent Link: https://patents.google.com/patent/US8697836/en
- Research Institute: University of California, San Diego
- Disease Focus: Cancer
- Basis of Invention: Human telomerase reverse transcriptase (hTRT) is a nuclear enzyme highly expressed in cancer cells. hTRT works in the cell nucleus. Therefore, T cells can recognize it only as short (8–16 amino acids) peptides, which are processed inside the cell before being exported to, and presented at, the cell surface in the context of MHC (HLA) complex
- How it works: This invention describes several peptides derived from hTRT sequence that illicit immune response in mice, healthy volunteers, and prostate cancer patients. The high immunogenicity was achieved by modifications of the original sequence that increases their affinity to antigen-presenting complexes.
- Lead Challenge Inventor: Maurizio Zanetti
- Inventors: Maurizio Zanetti
- Development Stage: Pre-clinical/Phase I trials
- Novelty:
- Use of peptides derived from hTRT sequence and modified to optimize their interaction with antigen-presenting complexes as cancer vaccines
- Clinical Applications:
- Treatment of cancers with increased hTRT: sporadic melanoma, hepatocellular carcinoma, bladder carcinoma, glioblastoma, neuroblastoma, and prostate adenocarcinoma
- Treatment of other cancers with elevated hTRT as determined by whole genome or promoter-targeted sequencing
General Description:
The vast majority of contemporary approaches to personalized immunotherapy are based on neoantigen peptides identified by whole-exome sequencing. This invention presents a viable alternative: rationally designed peptides that induce T cell response against telomerase reverse transcriptase (hTRT), an enzyme essential for cell immortalization, which is highly expressed in a variety of cancers. hTRT has been described as a promising target for a universal cancer vaccine. Phase I clinical trials of the peptides from this invention (ref. 6) demonstrated that vaccination against telomerase is safe and that a specific immunological response can be induced in vivo. However, the clinical response was observed only in a limited number of cases. According to the recent review published by the Inventor (ref. 1), development of cancer immunotherapy targeting hTRT is still justified, despite the largely unsuccessful initial attempts. Optimization of immunogenicity and the quality of T-cell responses should be the focus of new research efforts. Furthermore, pre-screening of patients to estimate the potential benefit from the hTRT peptide vaccine can be performed by new generation sequencing and quantifying the existence of T-cells precursors specific for TERT before immunotherapy is attempted.
Scientific Progress:
It has been recently demonstrated that hTRT is expressed at every stage of the cancer process, from the incipient CSCs and/or tumor-initiating cells to advanced metastatic cancer cells, and has essential roles at each stage of tumorigenesis. Whole genome sequencing analyses have established that TERT-promoter mutations are the most-prevalent mutations in noncoding regions of cancer genomes.
Future Directions:
- Whole genome or promoter-targeted sequencing to guide the selection of patients on the basis of hTRT-promoter mutations
- Combination of vaccination with hTRT peptides and immune-checkpoint inhibitors treatment
Strengths:
- 23 clinical studies on hTRT-based cancer vaccines performed so far showed no major adverse effects of hTRT targeting
- New findings on hTRT biology in cancer (reviewed in ref. 1) suggest alternative ways to identify patients that will benefit from vaccination with the peptides from this invention
Weaknesses:
- The patent expires in May 2021
- 23 clinical studies performed so far showed only a modest effect of hTRT immunotherapy on cancer outcome
Patent Status:
- Priority date: 2000-02-15
- Filing date: 2008-04-25
- Publication date and Grant date: 2014-04-15
- Other versions: US20090074741A1 (Application)
Publications:
1: Zanetti M. A second chance for telomerase reverse transcriptase in anticancer immunotherapy. Nat Rev Clin Oncol. 2017 Feb;14(2):115-128. doi:10.1038/nrclinonc.2016.67. Epub 2016 Jun 1. Review. PubMed PMID: 27245281.
2: Soeiro-de-Souza MG, Teixeira AL, Mateo EC, Zanetti MV, Rodrigues FG, de Paula VJ, Bezerra JF, Moreno RA, Gattaz WF, Machado-Vieira R. Leukocyte telomerase activity and antidepressant efficacy in bipolar disorder. Eur Neuropsychopharmacol. 2014 Jul;24(7):1139-43. doi:10.1016/j.euroneuro.2014.03.005. Epub 2014 Mar 27. PubMed PMID: 24731723.
3: Fenoglio D, Traverso P, Parodi A, Kalli F, Zanetti M, Filaci G. Generation of more effective cancer vaccines. Hum Vaccin Immunother. 2013 Dec;9(12):2543-7. doi: 10.4161/hv.26147. Epub 2013 Aug 26. PubMed PMID: 23978951; PubMed Central PMCID: PMC4162041.
4: Cortez-Gonzalez X, Zanetti M. Identification of immunogenic peptides of the self-tumor antigen: our experience with telomerase reverse transcriptase. Methods Mol Biol. 2010;651:211-25. doi: 10.1007/978-1-60761-786-0_12. PubMed PMID: 20686968.
5: Pellicciotta I, Cortez-Gonzalez X, Sasik R, Reiter Y, Hardiman G, Langlade-Demoyen P, Zanetti M. Presentation of telomerase reverse transcriptase, a self-tumor antigen, is down-regulated by histone deacetylase inhibition. Cancer Res. 2008 Oct 1;68(19):8085-93. doi: 10.1158/0008-5472.CAN-08-1014. PubMed PMID: 18829567.
6: Cortez-Gonzalez X, Zanetti M. Telomerase immunity from bench to bedside: round one. J Transl Med. 2007 Feb 26;5:12. Review. PubMed PMID: 17324292; PubMed Central PMCID: PMC1839079.
7: Cortez-Gonzalez X, Sidney J, Adotevi O, Sette A, Millard F, Lemonnier F, Langlade-Demoyen P, Zanetti M. Immunogenic HLA-B7-restricted peptides of hTRT. Int Immunol. 2006 Dec;18(12):1707-18. Epub 2006 Oct 31. PubMed PMID: 17077179.
8: Adotévi O, Mollier K, Neuveut C, Cardinaud S, Boulanger E, Mignen B, Fridman WH, Zanetti M, Charneau P, Tartour E, Lemonnier F, Langlade-Demoyen P. Immunogenic HLA-B*0702-restricted epitopes derived from human telomerase reverse transcriptase that elicit antitumor cytotoxic T-cell responses. Clin Cancer Res. 2006 May 15;12(10):3158-67. PubMed PMID: 16707616.
9: Filaci G, Fravega M, Setti M, Traverso P, Millo E, Fenoglio D, Negrini S, Ferrera F, Romagnoli A, Basso M, Contini P, Rizzi M, Ghio M, Benatti U, Damonte G, Ravetti JL, Carmignani G, Zanetti M, Indiveri F. Frequency of
telomerase-specific CD8+ T lymphocytes in patients with cancer. Blood. 2006 Feb 15;107(4):1505-12. Epub 2005 Oct 25. PubMed PMID: 16249379.
10: Zanetti M, Hernandez X, Langlade-Demoyen P. Telomerase reverse transcriptase as target for anti-tumor T cell responses in humans. Springer Semin Immunopathol. 2005 Jun;27(1):87-104. Epub 2005 Feb 15. Review. PubMed PMID: 15711953.
11: Hernández J, Schoeder K, Blondelle SE, Pons FG, Lone YC, Simora A, Langlade-Demoyen P, Wilson DB, Zanetti M. Antigenicity and immunogenicity of peptide analogues of a low affinity peptide of the human telomerase reverse transcriptase tumor antigen. Eur J Immunol. 2004 Aug;34(8):2331-41. PubMed PMID: 15259031.
12: Hernandez J, Garcia-Pons F, Lone YC, Firat H, Schmidt JD, Langlade-Demoyen P, Zanetti M. Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12275-80. Epub 2002 Sep 6. PubMed PMID: 12218171; PubMed Central PMCID: PMC129435.
13: Minev B, Hipp J, Firat H, Schmidt JD, Langlade-Demoyen P, Zanetti M. Cytotoxic T cell immunity against telomerase reverse transcriptase in humans. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4796-801. PubMed PMID: 10759561; PubMed Central PMCID: PMC18312.
14: Dosset M, Godet Y, Vauchy C, Beziaud L, Lone YC, Sedlik C, Liard C, Levionnois E, Clerc B, Sandoval F, Daguindau E, Wain-Hobson S, Tartour E, Langlade-Demoyen P, Borg C, Adotévi O. Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor. Clin Cancer Res. 2012 Nov 15;18(22):6284-95. doi: 10.1158/1078-0432.CCR-12-0896. Epub 2012 Oct 2. PubMed PMID: 23032748
Inventor Bio: Maurizio Zanetti
http://moores.ucsd.edu/zanettilab/
