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Andreikos D, Spandidos DA, Georgakopoulou VE. Telomeres and telomerase in mesothelioma: Pathophysiology, biomarkers and emerging therapeutic strategies (Review). Int J Oncol 2025; 66:23. [PMID: 39981889 PMCID: PMC11844339 DOI: 10.3892/ijo.2025.5729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 02/10/2025] [Indexed: 02/22/2025] Open
Abstract
Malignant mesothelioma (MM) is a rare but aggressive cancer linked to asbestos exposure and characterized by advanced‑stage disease at presentation. Despite advances in treatment, prognosis remains abysmal, highlighting the imperative for the development of novel biomarkers and treatment approaches. Telomere biology plays a pivotal role in the tumorigenic process and has emerged as a key area in oncology research. Short telomeres have been associated with genomic instability, and substantially shorter telomere length (TL) has been identified in MM, showcasing the potential of TL in risk assessment, early detection, and disease progression monitoring. MM predominantly maintains TL through telomerase activity (TA), which in research has been identified in >90% of MM cases, underscoring the potential of TA as a biomarker in MM. Telomerase reverse transcriptase (TERT) polymorphisms may serve as valuable biomarkers, with research identifying associations between single nucleotide polymorphisms (SNPs) and the risk and prognosis of MM. Additionally, TERT promoter mutations have been associated with poor prognosis and advanced‑stage disease, with the non‑canonical functions of TERT hypothesized to contribute to the development of MM. TERT promoter mutations occur in ~12% of MM cases; C228T, C250T and A161C are the most common, while the distribution and frequency differ depending on histological subtype. Research reveals the promise of the various approaches therapeutically targeting telomerase, with favorable results in pre‑clinical models and inconclusive findings in clinical trials. The present review examines the role of telomere biology in MM and its implications in diagnosis, prognosis, and therapy.
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Affiliation(s)
- Dimitrios Andreikos
- School of Medicine, Democritus University of Thrace, 68110 Alexandroupolis, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece
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Baylie T, Jemal M, Baye G, Getinet M, Amare GA, Adugna A, Abebaw D, Hibstu Z, Tegegne BA, Gugsa E, Adane T, Getie G, Ashenef B, Sinamaw D. The role of telomere and telomerase in cancer and novel therapeutic target: narrative review. Front Oncol 2025; 15:1542930. [PMID: 40151802 PMCID: PMC11947687 DOI: 10.3389/fonc.2025.1542930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 01/27/2025] [Indexed: 03/29/2025] Open
Abstract
Telomeres are dynamic complexes at the ends of chromosomes that are made up of protective proteins and tandem repeating DNA sequences. In the large majority of cancer cells, telomere length is maintained by telomerase, an enzyme that elongates telomeres. Telomerase activation is seen in the majority of cancer, which permits uncontrol cell proliferation. About 90% of human malignancies show telomere dysfunction and telomerase reactivation; as a result, telomerase activation plays a special role as a practically universal stage on the way to malignancy. This review understands the structural and functional of telomere and telomerase, mechanisms of telomerase activation in oncogenesis, biomarkers and therapeutic targets. Therapeutic strategies targeting telomerase, including antisense oligonucleotides, G-quadruplex stabilizers, immunotherapy, small-molecule inhibitors, gene therapy, Telomerase-Responsive Drug Release System, have shown promise in preclinical and clinical settings. Advances in telomere biology not only illuminate the complex interplay between telomeres, telomerase, and cancer progression but also open avenues for innovative, targeted cancer therapies.
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Affiliation(s)
- Temesgen Baylie
- Department of Biomedical Sciences, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Mohammed Jemal
- Department of Biomedical Sciences, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Gelagay Baye
- Department of Biomedical Sciences, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Mamaru Getinet
- Department of Biomedical Sciences, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Gashaw Azanaw Amare
- Medical Laboratory Science, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Adane Adugna
- Medical Laboratory Science, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Desalegn Abebaw
- Medical Laboratory Science, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Zigale Hibstu
- Medical Laboratory Science, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Bantayehu Addis Tegegne
- Department of Pharmacy, College of Medicine and Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Endalkachew Gugsa
- Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Tadegew Adane
- Department of Biomedical Sciences, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Gedefaw Getie
- Department of Biomedical Sciences, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Baye Ashenef
- Department of Biomedical Sciences, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Deresse Sinamaw
- Department of Biomedical Sciences, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
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Long W, Zeng YX, Zheng BX, Li YB, Wang YK, Chan KH, She MT, Lu YJ, Cao C, Wong WL. Targeting hTERT Promoter G-Quadruplex DNA Structures with Small-Molecule Ligand to Downregulate hTERT Expression for Triple-Negative Breast Cancer Therapy. J Med Chem 2024; 67:13363-13382. [PMID: 38987863 DOI: 10.1021/acs.jmedchem.4c01255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
Human telomerase reverse transcriptase (hTERT) may have noncanonical functions in transcriptional regulation and metabolic reprogramming in cancer cells, but it is a challenging target. We thus developed small-molecule ligands targeting hTERT promoter G-quadruplex DNA structures (hTERT G4) to downregulate hTERT expression. Ligand 5 showed high affinity toward hTERT G4 (Kd = 1.1 μM) and potent activity against triple-negative breast cancer cells (MDA-MB-231, IC50 = 1 μM). In cell-based assays, 5 not only exerts markedly inhibitory activity on classical telomere functions including decreased telomerase activity, shortened telomere length, and cellular senescence but also induces DNA damage, acute cellular senescence, and apoptosis. This study reveals that hTERT G4-targeting ligand may cause mitochondrial dysfunction, disrupt iron metabolism and activate ferroptosis in cancer cells. The in vivo antitumor efficacy of 5 was also evaluated in an MDA-MB-231 xenograft mouse model and approximately 78.7% tumor weight reduction was achieved. No observable toxicity against the major organs was observed.
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Affiliation(s)
- Wei Long
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China
| | - Yao-Xun Zeng
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China
| | - Bo-Xin Zheng
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China
| | - Yu-Bo Li
- State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
| | - Ya-Kun Wang
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China
| | - Ka-Hin Chan
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China
| | - Meng-Ting She
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China
| | - Yu-Jing Lu
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology Guangzhou 510006, China
| | - Chunyang Cao
- State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
| | - Wing-Leung Wong
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China
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Wang Y, Zhang X, Chen G, Shao M. Clinical research progress of telomerase targeted cancer immunotherapy: a literature review. Transl Cancer Res 2024; 13:3904-3921. [PMID: 39145070 PMCID: PMC11319969 DOI: 10.21037/tcr-24-196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 08/16/2024]
Abstract
Background and Objective Telomerase is activated or overexpressed in 85-90% of tumors, which maintains the length of telomere and has become an important anti-cancer target. Increasing clinical and preclinical data suggest that telomerase-targeted cancer immunotherapy could achieve effective killing of tumor cells in vivo. This article reviews the research progress of telomerase targeted cancer immunotherapy in clinical and pre-clinical trials, aiming to provide a reference for further clinical research and treatment of cancers. Methods We investigated the research progress of telomerase immunotherapy in the last 20 years from four electronic databases. Key Content and Findings Telomerase-targeted immunotherapies have been developed with the arising of a new era in immuno-oncology, including peptide vaccines, DNA vaccines, dendritic cells (DCs), adoptive cell transfer (ACT) therapies, antibodies, etc. Some of them have been approved for undergoing clinical trials by the Food and Drug Administration (FDA) for the treatment of various cancers, such as pancreatic cancer, non-small cell lung cancer, melanoma, leukaemia. Of all the treatment modalities, vaccines are the primary treatment methods, some of which have been even entered into phase III clinical trials. The main clinical application direction of telomerase vaccine is the combination with other drugs and treatment modalities, including combination with other vaccines targeting human telomerase reverse transcriptase (hTERT), traditional chemotherapy drugs and immunosuppressors. We also summarized the recent findings of immunotherapy targeting hTERT, focusing on various vaccines and the current status of associated clinical trials. We further discussed the advantages, disadvantages and potential developmental directions of various telomerase-targeted immunotherapies. Conclusions Telomerase-targeted cancer immunotherapy has promising prospects in improving patient survival expectancy. This review may provide data support and design ideas for all researchers and pharmaceutical enterprises in this field.
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Affiliation(s)
- Yu Wang
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, School of Medicine, Huzhou University, Huzhou, China
| | - Xiaoying Zhang
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, School of Medicine, Huzhou University, Huzhou, China
| | - Guangming Chen
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, School of Medicine, Huzhou University, Huzhou, China
| | - Mingzhe Shao
- Department of Vascular Surgery, Multidisciplinary Collaboration Group of Diabetic Foot, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
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Tao HY, Zhao CY, Wang Y, Sheng WJ, Zhen YS. Targeting Telomere Dynamics as an Effective Approach for the Development of Cancer Therapeutics. Int J Nanomedicine 2024; 19:3805-3825. [PMID: 38708177 PMCID: PMC11069074 DOI: 10.2147/ijn.s448556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 03/14/2024] [Indexed: 05/07/2024] Open
Abstract
Telomere is a protective structure located at the end of chromosomes of eukaryotes, involved in maintaining the integrity and stability of the genome. Telomeres play an essential role in cancer progression; accordingly, targeting telomere dynamics emerges as an effective approach for the development of cancer therapeutics. Targeting telomere dynamics may work through multifaceted molecular mechanisms; those include the activation of anti-telomerase immune responses, shortening of telomere lengths, induction of telomere dysfunction and constitution of telomerase-responsive drug release systems. In this review, we summarize a wide variety of telomere dynamics-targeted agents in preclinical studies and clinical trials, and reveal their promising therapeutic potential in cancer therapy. As shown, telomere dynamics-active agents are effective as anti-cancer chemotherapeutics and immunotherapeutics. Notably, these agents may display efficacy against cancer stem cells, reducing cancer stem levels. Furthermore, these agents can be integrated with the capability of tumor-specific drug delivery by the constitution of related nanoparticles, antibody drug conjugates and HSA-based drugs.
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Affiliation(s)
- Hong-yu Tao
- Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Chun-yan Zhao
- Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Ying Wang
- Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Wei-jin Sheng
- Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yong-su Zhen
- Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
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Kim JY, Yang DW, Kim S, Choi JG. Retrospective Analysis of the Clinical Characteristics of Patients with Breast Cancer Treated with Telomerase Peptide Immunotherapy Combined with Cytotoxic Chemotherapy. BREAST CANCER (DOVE MEDICAL PRESS) 2023; 15:955-966. [PMID: 38146419 PMCID: PMC10749539 DOI: 10.2147/bctt.s431333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 12/08/2023] [Indexed: 12/27/2023]
Abstract
Purpose Telomerase activation, a critical step in cancer progression, occurs in approximately 95% of breast cancer cases. Telomerase is an attractive therapeutic target for breast cancer owing to its unique expression pattern. GV1001, a telomerase-derived peptide, is loaded onto human leukocyte antigen (HLA) class II antigen-presenting cells and binds to CD4+ T cell activating immune responses. This study aimed to evaluate the effectiveness and safety of co-administration of GV1001 and cytotoxic chemotherapy in patients with heavily-treated metastatic breast cancer. Patients and methods We analyzed 63 patients with breast cancer who received both GV1001 and cytotoxic chemotherapy. The GV 1001 administration methods involves 0.56 mg intradermal injection three times during the first week, one time at weeks 2, 3, 4, and 6, and then once every 28 days. The primary endpoint of this study was quality of life according to EORTC QLO-C30 and EQ-5D, while the secondary endpoint was the antitumor response according to RECIST 1.1, progression-free survival, overall survival, and toxicity profile. Results In 34 patients with HR+ breast cancer evaluable for tumor response, the disease control rate (DCR) and overall response rate (ORR) were 58.8% and 26.4%, respectively. The DCR and ORR were 66.6% and 28.5% in 21 patients with HER-2+ and 50% and 25% in patients with triple-negative breast cancer (TNBC), respectively. The median progression free survival was 10.4, 8.7, and 5.6 months in HR+, HER-2+, TNBC, respectively. The overall survival was 19.7, 13.2, and 9.4 months for patients with HR+, HER-2+, and TNBC, respectively. Most patients had an improved quality of life with statistically significant differences in some variables. The patients in this study experienced no additional toxicities other than the cytotoxic chemotherapy-associated side effects. Conclusion GV1001 is a relatively safe anticancer vaccine for patients with heavily-treated breast cancer and can to improve the quality of life.
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Affiliation(s)
- Jong Yeup Kim
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon, Republic of Korea
| | - Dong Won Yang
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon, Republic of Korea
| | - Sangjae Kim
- Department of Research and Development, Teloid Inc., Los Angeles, CA, 90010, USA
| | - Jong Gwon Choi
- Department of Oncology-Hematology, Konyang University Hospital, Daejeon, Republic of Korea
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Ellingsen EB, Bjørheim J, Gaudernack G. Therapeutic cancer vaccination against telomerase: clinical developments in melanoma. Curr Opin Oncol 2023; 35:100-106. [PMID: 36700456 PMCID: PMC9894137 DOI: 10.1097/cco.0000000000000922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW Checkpoint inhibitors (CPIs) have revolutionized treatment outcomes for patients with malignant melanoma. Long-term follow-up shows that a substantial subset of patients who exhibit clinical responses achieve extended overall survival. Nevertheless, most patients do not achieve durable benefit from CPIs, and improvements are urgently needed. The clinical efficacy of CPIs depends on highly variable preexisting spontaneous T-cell immune responses. Cancer vaccines represent an independent treatment modality uniquely capable of expanding the repertoire of tumor-specific T cells in cancer patients and thus have the capacity to compensate for the variability in spontaneous T-cell responses. Vaccines are, therefore, considered attractive components in a CPI-combination strategy. RECENT FINDINGS Here we discuss recent results obtained through therapeutic vaccination against telomerase human telomerase reverse transcriptase (hTERT). Recent publications on translational research and clinical results from phase I trials indicate that vaccination against telomerase in combination with CPIs provides relevant immune responses, negligible added toxicity, and signals of clinical efficacy. CONCLUSION In the near future, randomized data from clinical trials involving therapeutic cancer vaccines and checkpoint inhibitors will be available. Positive readout may spark broad development and allow cancer vaccines to find their place in the clinic as an important component in multiple future CPI combinations.
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Kim JH, Cho YR, Ahn EK, Kim S, Han S, Kim SJ, Bae GU, Oh JS, Seo DW. A novel telomerase-derived peptide GV1001-mediated inhibition of angiogenesis: Regulation of VEGF/VEGFR-2 signaling pathways. Transl Oncol 2022; 26:101546. [PMID: 36183673 PMCID: PMC9526227 DOI: 10.1016/j.tranon.2022.101546] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/25/2021] [Accepted: 09/23/2022] [Indexed: 11/21/2022] Open
Abstract
GV1001, a human telomerase reverse transcriptase catalytic subunit-derived 16-mer peptide, has been developed as a novel anticancer vaccine against various cancers including pancreatic cancer. In the current study, we demonstrate the regulatory roles and mechanisms of GV1001 in endothelial cell responses in vitro and microvessel sprouting ex vivo. GV1001 markedly inhibits vascular endothelial growth factor-A (VEGF-A)-stimulated endothelial cell permeability, proliferation, migration, invasion, tube formation as well as microvessel outgrowth from rat aortic rings. These anti-angiogenic effects of GV1001 were associated with the inhibition of VEGF-A/VEGFR-2 signaling pathways, redistribution of vascular endothelial-cadherin to cell-cell contacts, and down-regulation of VEGFR-2 and matrix metalloproteinase-2. Furthermore, GV1001 suppresses the proliferation and invasion of non-small cell lung cancer cells, and the release of VEGF from the cells, suggesting the regulatory role of GV1001 in tumor-derived angiogenesis as well as cancer cell growth and progression. Collectively, our study reports the pharmacological potential of GV1001 in the regulation of angiogenesis, and warrants further evaluation and development of GV1001 as a promising therapeutic agent for a variety of angiogenesis-related diseases including cancer.
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Affiliation(s)
- Jae Hyeon Kim
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea
| | - Young-Rak Cho
- Biocenter, Gyeonggido Business & Science Accelerator, Suwon 16229, Republic of Korea
| | - Eun-Kyung Ahn
- Biocenter, Gyeonggido Business & Science Accelerator, Suwon 16229, Republic of Korea
| | - Sunho Kim
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea
| | - Surim Han
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea
| | - Sung Joon Kim
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea
| | - Gyu-Un Bae
- Department of Pharmacy, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea
| | - Joa Sub Oh
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea
| | - Dong-Wan Seo
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea.
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Zhou M, Zou X, Cheng K, Zhong S, Su Y, Wu T, Tao Y, Cong L, Yan B, Jiang Y. The role of cell-penetrating peptides in potential anti-cancer therapy. Clin Transl Med 2022; 12:e822. [PMID: 35593206 PMCID: PMC9121317 DOI: 10.1002/ctm2.822] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 03/28/2022] [Accepted: 04/04/2022] [Indexed: 12/19/2022] Open
Abstract
Due to the complex physiological structure, microenvironment and multiple physiological barriers, traditional anti-cancer drugs are severely restricted from reaching the tumour site. Cell-penetrating peptides (CPPs) are typically made up of 5-30 amino acids, and can be utilised as molecular transporters to facilitate the passage of therapeutic drugs across physiological barriers. Up to now, CPPs have widely been used in many anti-cancer treatment strategies, serving as an excellent potential choice for oncology treatment. However, their drawbacks, such as the lack of cell specificity, short duration of action, poor stability in vivo, compatibility problems (i.e. immunogenicity), poor therapeutic efficacy and formation of unwanted metabolites, have limited their further application in cancer treatment. The cellular uptake mechanisms of CPPs involve mainly endocytosis and direct penetration, but still remain highly controversial in academia. The CPPs-based drug delivery strategy could be improved by clever design or chemical modifications to develop the next-generation CPPs with enhanced cell penetration capability, stability and selectivity. In addition, some recent advances in targeted cell penetration that involve CPPs provide some new ideas to optimise CPPs.
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Affiliation(s)
- Meiling Zhou
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China.,School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Xi Zou
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China.,School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Kexin Cheng
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China.,School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Suye Zhong
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China.,School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Yangzhou Su
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China.,School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Tao Wu
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China.,School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Yongguang Tao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, School of Basic Medicine, Central South University, Changsha, Hunan, China
| | - Li Cong
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China.,School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Bin Yan
- Department of Pathology, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, China
| | - Yiqun Jiang
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, Hunan, China.,School of Medicine, Hunan Normal University, Changsha, Hunan, China
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Telomeres and Cancer. Life (Basel) 2021; 11:life11121405. [PMID: 34947936 PMCID: PMC8704776 DOI: 10.3390/life11121405] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/01/2021] [Accepted: 12/06/2021] [Indexed: 12/18/2022] Open
Abstract
Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation. This review describes the telomere functions, the role of functional modulators, the implications in cancer development, and the future therapeutic opportunities.
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Nardin C, Laheurte C, Puzenat E, Boullerot L, Ramseyer M, Marguier A, Jacquin M, Godet Y, Aubin F, Adotevi O. Naturally occurring Telomerase-specific CD4 T cell Immunity in Melanoma. J Invest Dermatol 2021; 142:435-444. [PMID: 34352265 DOI: 10.1016/j.jid.2021.07.160] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 06/19/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023]
Abstract
CD4 T cells play a key role in anticancer immunity. Here, we investigate the clinical relevance of circulating CD4 Th1 response against telomerase (anti-TERT Th1 response) in melanoma patients. The spontaneous anti-TERT Th1 response was detected in 54.5% (85/156) of melanoma patients before treatment. The prevalence of this systemic response was inversely related to Breslow thickness above 1mm and AJCC stage ≥ II (P = 0.001 and 0.032). In contrast to patients treated by targeted therapies, the anti-TERT Th1 immunity was associated with objective response after immune checkpoint inhibitors (ICI) treatment. Hence 86% (18/21) of responder patients exhibited pre-existing anti-TERT Th1 versus 35% (6/19) in non-responders (P = 0.001). This response was also associated with increased progression free survival and overall survival in melanoma patients treated with ICI (P = 0.0008 and 0.012 respectively). Collectively, the presence of circulating anti-TERT Th1 response is inversely related to melanoma evolution and appears to be a predictive factor of response to immunotherapy. Our results highlight the interest of telomerase-specific CD4 Th1 response as a promising blood based biomarker of immune checkpoint inhibitors therapy in melanoma.
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Affiliation(s)
- Charlée Nardin
- University Hospital of Besançon, department of Dermatology, F-25000 Besançon, France; University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, F-25000 Besançon, France
| | - Caroline Laheurte
- University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, F-25000 Besançon, France; INSERM CIC-1431, Clinical Investigation Center in Biotherapy, Plateforme de Biomonitoring F-25000 Besançon, France
| | - Eve Puzenat
- University Hospital of Besançon, department of Dermatology, F-25000 Besançon, France
| | - Laura Boullerot
- University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, F-25000 Besançon, France; INSERM CIC-1431, Clinical Investigation Center in Biotherapy, Plateforme de Biomonitoring F-25000 Besançon, France
| | - Mélanie Ramseyer
- University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, F-25000 Besançon, France
| | - Amélie Marguier
- University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, F-25000 Besançon, France
| | - Marion Jacquin
- INSERM CIC-1431, Clinical Investigation Center in Biotherapy, Plateforme de Biomonitoring F-25000 Besançon, France
| | - Yann Godet
- University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, F-25000 Besançon, France
| | - François Aubin
- University Hospital of Besançon, department of Dermatology, F-25000 Besançon, France; University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, F-25000 Besançon, France
| | - Olivier Adotevi
- University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, F-25000 Besançon, France; INSERM CIC-1431, Clinical Investigation Center in Biotherapy, Plateforme de Biomonitoring F-25000 Besançon, France; University Hospital of Besançon, department of medical Oncology, F-25000 Besançon, France.
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12
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Ellingsen EB, Mangsbo SM, Hovig E, Gaudernack G. Telomerase as a Target for Therapeutic Cancer Vaccines and Considerations for Optimizing Their Clinical Potential. Front Immunol 2021; 12:682492. [PMID: 34290704 PMCID: PMC8288190 DOI: 10.3389/fimmu.2021.682492] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/21/2021] [Indexed: 12/14/2022] Open
Abstract
Telomerase-based therapeutic cancer vaccines (TCVs) have been under clinical investigation for the past two decades. Despite past failures, TCVs have gained renewed enthusiasm for their potential to improve the efficacy of checkpoint inhibition. Telomerase stands as an attractive target for TCVs due to its almost universal presence in cancer and its essential function promoting tumor growth. Herein, we review tumor telomerase biology that may affect the efficacy of therapeutic vaccination and provide insights on optimal vaccine design and treatment combinations. Tumor types possessing mechanisms of increased telomerase expression combined with an immune permissive tumor microenvironment are expected to increase the therapeutic potential of telomerase-targeting cancer vaccines. Regardless, rational treatment combinations, such as checkpoint inhibitors, are likely necessary to bring out the true clinical potential of TCVs.
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Affiliation(s)
- Espen Basmo Ellingsen
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway.,Research and Development, Ultimovacs ASA, Oslo, Norway
| | - Sara M Mangsbo
- Research and Development, Ultimovacs AB, Uppsala, Sweden.,Department of Pharmaceutical Biosciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Eivind Hovig
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.,Centre for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway
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13
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Inderberg-Suso EM, Trachsel S, Lislerud K, Rasmussen AM, Gaudernack G. Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001. Oncoimmunology 2021; 1:670-686. [PMID: 22934259 PMCID: PMC3429571 DOI: 10.4161/onci.20426] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Understanding the basis of a successful clinical response after treatment with therapeutic cancer vaccines is essential for the development of more efficacious therapy. After vaccination with the single telomerase (hTERT) 16-mer peptide, GV1001, some patients experienced clinical responses and long-term survival. This study reports in-depth immunological analysis of the T-cell response against telomerase (hTERT) in clinically responding patients compared with clinical non-responders following vaccination with the single hTERT 16-mer peptide, GV1001. Extensive characterization of CD4+ T-cell clones specific for GV1001 generated from a lung cancer patient in complete remission after vaccination demonstrated a very broad immune response to this single peptide vaccine with differences in fine specificity, HLA restriction, affinity and function. Some CD4+ T-cell clones were cytotoxic against peptide-loaded target cells and also recognized processed recombinant hTERT protein. Furthermore, T-cell responses against several unrelated hTERT epitopes, some of which are novel, were detected, indicating extensive epitope spreading which was confirmed in other clinical responders. In contrast, patients responding immunologically, but not clinically, after vaccination did not display this intramolecular epitope spreading. Multifunctional CD4+ T-cell clones specific for novel hTERT epitopes were generated and shown to recognize a melanoma cell line. Pentamer analysis of T cells in peripheral blood also demonstrated the presence of an important CD8+ T-cell response recognizing an HLA-B7 epitope embedded in GV1001 not previously described. These results indicate that the highly diverse hTERT-specific T-cell response, integrating both T helper and CTL responses, is essential for tumor regression and the generation of long-term T-cell memory.
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Affiliation(s)
- Else-Marit Inderberg-Suso
- Unit for Immunotherapy; Section for Immunology; Institute for Cancer Research; Oslo University Hospital; Norwegian Radium Hospital; Oslo, Norway
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14
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Relitti N, Saraswati AP, Federico S, Khan T, Brindisi M, Zisterer D, Brogi S, Gemma S, Butini S, Campiani G. Telomerase-based Cancer Therapeutics: A Review on their Clinical Trials. Curr Top Med Chem 2020; 20:433-457. [PMID: 31894749 DOI: 10.2174/1568026620666200102104930] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 12/02/2019] [Accepted: 12/03/2019] [Indexed: 12/11/2022]
Abstract
Telomeres are protective chromosomal ends that shield the chromosomes from DNA damage, exonucleolytic degradation, recombination, and end-to-end fusion. Telomerase is a ribonucleoprotein that adds TTAGGG tandem repeats to the telomeric ends. It has been observed that 85 to 90% of human tumors express high levels of telomerase, playing a crucial role in the development of cancers. Interestingly, the telomerase activity is generally absent in normal somatic cells. This selective telomerase expression has driven scientists to develop novel anti-cancer therapeutics with high specificity and potency. Several advancements have been made in this area, which is reflected by the enormous success of the anticancer agent Imetelstat. Since the discovery of Imetelstat, several research groups have contributed to enrich the therapeutic arsenal against cancer. Such contributions include the application of new classes of small molecules, peptides, and hTERT-based immunotherapeutic agents (p540, GV1001, GRNVAC1 or combinations of these such as Vx-001). Many of these therapeutic tools are under different stages of clinical trials and have shown promising outcomes. In this review, we highlight the current status of telomerase-based cancer therapeutics and the outcome of these investigations.
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Affiliation(s)
- Nicola Relitti
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, via Aldo Moro 2, I- 53100 Siena, University of Siena, Siena, Italy
| | - Akella P Saraswati
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, via Aldo Moro 2, I- 53100 Siena, University of Siena, Siena, Italy
| | - Stefano Federico
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, via Aldo Moro 2, I- 53100 Siena, University of Siena, Siena, Italy
| | - Tuhina Khan
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, via Aldo Moro 2, I- 53100 Siena, University of Siena, Siena, Italy
| | - Margherita Brindisi
- Department of Pharmacy, Department of Excellence 2018-2022, University of Napoli Federico II, via D. Montesano 49, I-80131 Napoli, Italy
| | - Daniela Zisterer
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160, Pearse Street, Dublin 2, Ireland
| | - Simone Brogi
- Department of Pharmacy, University of Pisa, via Bonanno Pisano 6, I-56126 Pisa, Italy
| | - Sandra Gemma
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, via Aldo Moro 2, I- 53100 Siena, University of Siena, Siena, Italy
| | - Stefania Butini
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, via Aldo Moro 2, I- 53100 Siena, University of Siena, Siena, Italy
| | - Giuseppe Campiani
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, via Aldo Moro 2, I- 53100 Siena, University of Siena, Siena, Italy
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15
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Dratwa M, Wysoczańska B, Łacina P, Kubik T, Bogunia-Kubik K. TERT-Regulation and Roles in Cancer Formation. Front Immunol 2020; 11:589929. [PMID: 33329574 PMCID: PMC7717964 DOI: 10.3389/fimmu.2020.589929] [Citation(s) in RCA: 165] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/16/2020] [Indexed: 12/16/2022] Open
Abstract
Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase. Telomerase complex plays a key role in cancer formation by telomere dependent or independent mechanisms. Telomere maintenance mechanisms include complex TERT changes such as gene amplifications, TERT structural variants, TERT promoter germline and somatic mutations, TERT epigenetic changes, and alternative lengthening of telomere. All of them are cancer specific at tissue histotype and at single cell level. TERT expression is regulated in tumors via multiple genetic and epigenetic alterations which affect telomerase activity. Telomerase activity via TERT expression has an impact on telomere length and can be a useful marker in diagnosis and prognosis of various cancers and a new therapy approach. In this review we want to highlight the main roles of TERT in different mechanisms of cancer development and regulation.
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Affiliation(s)
- Marta Dratwa
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Barbara Wysoczańska
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Piotr Łacina
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Tomasz Kubik
- Department of Computer Engineering, Faculty of Electronics, Wrocław University of Science and Technology, Wroclaw, Poland
| | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
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16
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Anti-cancer Immunotherapies Targeting Telomerase. Cancers (Basel) 2020; 12:cancers12082260. [PMID: 32806719 PMCID: PMC7465444 DOI: 10.3390/cancers12082260] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 02/06/2023] Open
Abstract
Telomerase is a reverse transcriptase that maintains telomeres length, compensating for the attrition of chromosomal ends that occurs during each replication cycle. Telomerase is expressed in germ cells and stem cells, whereas it is virtually undetectable in adult somatic cells. On the other hand, telomerase is broadly expressed in the majority of human tumors playing a crucial role in the replicative behavior and immortality of cancer cells. Several studies have demonstrated that telomerase-derived peptides are able to bind to HLA (human leukocyte antigen) class I and class II molecules and effectively activate both CD8+ and CD4+ T cells subsets. Due to its broad and selective expression in cancer cells and its significant immunogenicity, telomerase is considered an ideal universal tumor-associated antigen, and consequently, a very attractive target for anti-cancer immunotherapy. To date, different telomerase targeting immunotherapies have been studied in pre-clinical and clinical settings, these approaches include peptide vaccination and cell-based vaccination. The objective of this review paper is to discuss the role of human telomerase in cancer immunotherapy analyzing recent developments and future perspectives in this field.
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17
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Fernandes SG, Dsouza R, Pandya G, Kirtonia A, Tergaonkar V, Lee SY, Garg M, Khattar E. Role of Telomeres and Telomeric Proteins in Human Malignancies and Their Therapeutic Potential. Cancers (Basel) 2020; 12:E1901. [PMID: 32674474 PMCID: PMC7409176 DOI: 10.3390/cancers12071901] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/10/2020] [Accepted: 07/13/2020] [Indexed: 12/19/2022] Open
Abstract
Telomeres are the ends of linear chromosomes comprised of repetitive nucleotide sequences in humans. Telomeres preserve chromosomal stability and genomic integrity. Telomere length shortens with every cell division in somatic cells, eventually resulting in replicative senescence once telomere length becomes critically short. Telomere shortening can be overcome by telomerase enzyme activity that is undetectable in somatic cells, while being active in germline cells, stem cells, and immune cells. Telomeres are bound by a shelterin complex that regulates telomere lengthening as well as protects them from being identified as DNA damage sites. Telomeres are transcribed by RNA polymerase II, and generate a long noncoding RNA called telomeric repeat-containing RNA (TERRA), which plays a key role in regulating subtelomeric gene expression. Replicative immortality and genome instability are hallmarks of cancer and to attain them cancer cells exploit telomere maintenance and telomere protection mechanisms. Thus, understanding the role of telomeres and their associated proteins in cancer initiation, progression and treatment is very important. The present review highlights the critical role of various telomeric components with recently established functions in cancer. Further, current strategies to target various telomeric components including human telomerase reverse transcriptase (hTERT) as a therapeutic approach in human malignancies are discussed.
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Affiliation(s)
- Stina George Fernandes
- Sunandan Divatia School of Science, SVKM’s NMIMS (Deemed to be University), Vile Parle West, Mumbai 400056, India; (S.G.F.); (R.D.)
| | - Rebecca Dsouza
- Sunandan Divatia School of Science, SVKM’s NMIMS (Deemed to be University), Vile Parle West, Mumbai 400056, India; (S.G.F.); (R.D.)
| | - Gouri Pandya
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida 201313, India; (G.P.); (A.K.)
| | - Anuradha Kirtonia
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida 201313, India; (G.P.); (A.K.)
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology (IMCB), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; (V.T.); (S.Y.L.)
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore 117597, Singapore
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore 117597, Singapore
| | - Sook Y. Lee
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology (IMCB), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; (V.T.); (S.Y.L.)
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida 201313, India; (G.P.); (A.K.)
| | - Ekta Khattar
- Sunandan Divatia School of Science, SVKM’s NMIMS (Deemed to be University), Vile Parle West, Mumbai 400056, India; (S.G.F.); (R.D.)
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18
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Choi YM, Kim H, Lee SA, Lee SY, Kim BJ. A Telomerase-Derived Peptide Exerts an Anti-Hepatitis B Virus Effect via Mitochondrial DNA Stress-Dependent Type I Interferon Production. Front Immunol 2020; 11:652. [PMID: 32508804 PMCID: PMC7253625 DOI: 10.3389/fimmu.2020.00652] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 03/23/2020] [Indexed: 01/14/2023] Open
Abstract
Previously, a telomerase-derived 16-mer peptide, GV1001, developed as an anticancer vaccine, was reported to exert antiviral effects on human immunodeficiency virus or hepatitis C virus in a heat shock protein-dependent manner. Here we investigated whether GV1001 exerts antiviral effects on hepatitis B virus (HBV) and elucidated its underlying mechanisms. GV1001 inhibited HBV replication and hepatitis B surface antigen (HBsAg) secretion in a dose-dependent manner, showing synergistic antiviral effects with nucleos(t)ide analogs (NAs) including entecavir and lamivudine. This peptide also inhibited viral cccDNA and pgRNA. The intravenous GV1001 treatment of transgenic mice had anti-HBV effects. Our mechanistic studies revealed that GV1001 suppresses HBV replication by inhibiting capsid formation via type I interferon-mediated induction of heme oxygenase-1 (HO-1). GV1001 promoted the mitochondrial DNA stress-mediated release of oxidized DNA into the cytosol, resulting in IFN-I-dependent anti-HBV effects via the STING-IRF3 axis. We found that the anti-HBV effect of GV1001 was due to its ability to penetrate into the cytosol via extracellular heat shock protein, leading to phagosomal escape-mediated mtDNA stress. We demonstrated that the cell-penetrating and cytosolic localization capacity of GV1001 results in antiviral effects on HBV infections via mtDNA stress-mediated IFN-I production. Thus, GV1001, a peptide proven to be safe for human use, may be an anti-HBV drug that can be synergistically used with nucleot(s)ide analog.
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Affiliation(s)
| | | | | | | | - Bum-Joon Kim
- Department of Microbiology and Immunology, Biomedical Sciences, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, South Korea
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19
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Berei J, Eckburg A, Miliavski E, Anderson AD, Miller RJ, Dein J, Giuffre AM, Tang D, Deb S, Racherla KS, Patel M, Vela MS, Puri N. Potential Telomere-Related Pharmacological Targets. Curr Top Med Chem 2020; 20:458-484. [DOI: 10.2174/1568026620666200109114339] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/21/2019] [Accepted: 11/21/2019] [Indexed: 12/22/2022]
Abstract
Telomeres function as protective caps at the terminal portion of chromosomes, containing
non-coding nucleotide sequence repeats. As part of their protective function, telomeres preserve genomic
integrity and minimize chromosomal exposure, thus limiting DNA damage responses. With
continued mitotic divisions in normal cells, telomeres progressively shorten until they reach a threshold
at a point where they activate senescence or cell death pathways. However, the presence of the enzyme
telomerase can provide functional immortality to the cells that have reached or progressed past
senescence. In senescent cells that amass several oncogenic mutations, cancer formation can occur due
to genomic instability and the induction of telomerase activity. Telomerase has been found to be expressed
in over 85% of human tumors and is labeled as a near-universal marker for cancer. Due to this
feature being present in a majority of tumors but absent in most somatic cells, telomerase and telomeres
have become promising targets for the development of new and effective anticancer therapeutics.
In this review, we evaluate novel anticancer targets in development which aim to alter telomerase
or telomere function. Additionally, we analyze the progress that has been made, including preclinical
studies and clinical trials, with therapeutics directed at telomere-related targets. Furthermore, we review
the potential telomere-related therapeutics that are used in combination therapy with more traditional
cancer treatments. Throughout the review, topics related to medicinal chemistry are discussed,
including drug bioavailability and delivery, chemical structure-activity relationships of select therapies,
and the development of a unique telomere assay to analyze compounds affecting telomere elongation.
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Affiliation(s)
- Joseph Berei
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Adam Eckburg
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Edward Miliavski
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Austin D. Anderson
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Rachel J. Miller
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Joshua Dein
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Allison M. Giuffre
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Diana Tang
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Shreya Deb
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Kavya Sri Racherla
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Meet Patel
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Monica Saravana Vela
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
| | - Neelu Puri
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, United States
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20
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Giangaspero F, Minasi S, Gianno F, Alzoubi H, Antonelli M, Buttarelli F. Mechanisms of telomere maintenance in pediatric brain tumors: Promising targets for therapy – A narrative review. GLIOMA 2020. [DOI: 10.4103/glioma.glioma_20_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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21
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Chen X, Tang WJ, Shi JB, Liu MM, Liu XH. Therapeutic strategies for targeting telomerase in cancer. Med Res Rev 2019; 40:532-585. [PMID: 31361345 DOI: 10.1002/med.21626] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 07/12/2019] [Accepted: 07/16/2019] [Indexed: 12/13/2022]
Abstract
Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere-based therapies such as nucleoside analogs, non-nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere-based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.
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Affiliation(s)
- Xing Chen
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, People's Republic of China
| | - Wen-Jian Tang
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, People's Republic of China
| | - Jing Bo Shi
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, People's Republic of China
| | - Ming Ming Liu
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, People's Republic of China
| | - Xin-Hua Liu
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, People's Republic of China
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22
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Telomerase-Targeted Cancer Immunotherapy. Int J Mol Sci 2019; 20:ijms20081823. [PMID: 31013796 PMCID: PMC6515163 DOI: 10.3390/ijms20081823] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 04/05/2019] [Accepted: 04/10/2019] [Indexed: 01/03/2023] Open
Abstract
Telomerase, an enzyme responsible for the synthesis of telomeres, is activated in many cancer cells and is involved in the maintenance of telomeres. The activity of telomerase allows cancer cells to replicate and proliferate in an uncontrolled manner, to infiltrate tissue, and to metastasize to distant organs. Studies to date have examined the mechanisms involved in the survival of cancer cells as targets for cancer therapeutics. These efforts led to the development of telomerase inhibitors as anticancer drugs, drugs targeting telomere DNA, viral vectors carrying a promoter for human telomerase reverse transcriptase (hTERT) genome, and immunotherapy targeting hTERT. Among these novel therapeutics, this review focuses on immunotherapy targeting hTERT and discusses the current evidence and future perspectives.
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23
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Kim KS, Yang HY, Chang SC, Kim YM, Lee KY, Lee BM, Kim HS. Potential repositioning of GV1001 as a therapeutic agent for testosterone‑induced benign prostatic hyperplasia. Int J Mol Med 2018; 42:2260-2268. [PMID: 30015834 DOI: 10.3892/ijmm.2018.3759] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 06/18/2018] [Indexed: 11/06/2022] Open
Abstract
Benign prostatic hyperplasia (BPH) is one of the leading causes of male reproductive disorders. Therapeutic agents currently in use have severe side effects; therefore, alternative drugs that exhibit improved therapeutic activity without side effects are required. The present study investigated the protective effect of GV1001 against testosterone‑induced BPH in rats. BPH in castrated rats was established via daily subcutaneous (s.c.) injections of testosterone propionate (TP, 3 mg/kg) dissolved in corn oil for 4 weeks. GV1001 (0.01, 0.1 and 1 mg/kg, s.c.) was administered 3 times per week for 4 weeks, together with TP (3 mg/kg) injection. The rats were sacrificed on the last day of treatment, and their prostates were excised and weighed for biochemical and histological studies. Serum levels of testosterone and dihydrotestosterone (DHT) were also measured. In rats with TP‑induced BPH, a significant increase in prostate weight (PW) and prostatic index (PI), accompanied by a decrease in antioxidant enzyme activity, was observed. Histological studies revealed clearly enlarged glandular cavities in rats with BPH. GV1001 (0.01 and 0.1 mg/kg) treatment significantly decreased PW and PI in rats with TP‑induced BPH. In addition, GV1001 demonstrated a potent inhibitory effect on 5α‑reductase in prostate. The present data suggest that the protective role of GV1001 against testosterone‑induced BPH is closely associated with its antioxidant potential. Additional studies are required to identify the mechanisms by which GV1001 protects against BPH to determine its clinical application.
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Affiliation(s)
- Kyeong Seok Kim
- Department of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi‑do 16419, Republic of Korea
| | - Hun Yong Yang
- Department of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi‑do 16419, Republic of Korea
| | - Seung-Cheol Chang
- Institute of Bio-Physio Sensor Technology, Center for Proteome Biophysics, Pusan National University, Busan 46241, Republic of Korea
| | - Young-Mi Kim
- College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi‑do 15588, Republic of Korea
| | - Kwang Youl Lee
- College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju, Gwangju 61186, Republic of Korea
| | - Byung Mu Lee
- Department of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi‑do 16419, Republic of Korea
| | - Hyung Sik Kim
- Department of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi‑do 16419, Republic of Korea
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Chang JE, Kim HJ, Jheon S, Lim C. Protective effects of GV1001 on myocardial ischemia‑reperfusion injury. Mol Med Rep 2017; 16:7315-7320. [PMID: 28944828 PMCID: PMC5865859 DOI: 10.3892/mmr.2017.7528] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 08/02/2017] [Indexed: 12/27/2022] Open
Abstract
The potential cardioprotective effects of the novel vaccine peptide GV1001 were evaluated in myocardial ischemia‑reperfusion injury induced rat models. GV1001 is a human telomerase reverse transcriptase derived peptide, which has been reported to possess both anti‑tumor and anti‑inflammatory effects. The normal saline (control group) and various concentrations (0.001‑10 mg/kg) of GV1001 were administered directly to the right ventricle anterior wall before induction of ischemia. The was induced by Tightening the snare around the left anterior descending coronary artery for 40 min, before releasing the snare for 10 min induced the myocardial ischemia‑reperfusion injury and was conducted in Sprague‑Dawley rats. The area at risk, histology, apoptotic cells, neutrophils and inflammatory cytokines were analyzed from the excised heart tissue following myocardial ischemia‑reperfusion injury. The area at risk was protected by concentrations of GV1001 equal to or higher than 0.01 mg/kg. At 0.1 mg/kg and higher concentrations of GV1001, the hemorrhage in the heart was attenuated, while severe congestion was reported in the control group. Apoptotic cells, myeloperoxidase activity and inflammatory cytokines [tumor necrosis factor (TNF)‑α and interleukin (IL)‑6] revealed decreased levels in a dose‑dependent manner with respect to GV1001 concentration. The group treated with 10 mg/kg GV1001 demonstrated 59.73% apoptotic cells (P<0.001), 48.14% neutrophil contents (P<0.001), 55.63% TNF‑α (P<0.01) and 42.35% IL‑6 (P<0.01) levels, compared with the control group. The novel vaccine peptide GV1001 provided protective effects on myocardial ischemia‑reperfusion injury and, therefore, it should be considered as an alternative potential anti‑inflammatory agent for myocardial ischemia‑reperfusion injury.
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Affiliation(s)
- Ji-Eun Chang
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do 13620, Republic of Korea
| | - Hyun Jun Kim
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do 13620, Republic of Korea
| | - Sanghoon Jheon
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do 13620, Republic of Korea
- Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Cheong Lim
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do 13620, Republic of Korea
- Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
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25
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Telomerase based anticancer immunotherapy and vaccines approaches. Vaccine 2017; 35:5768-5775. [DOI: 10.1016/j.vaccine.2017.09.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 08/26/2017] [Accepted: 09/01/2017] [Indexed: 12/11/2022]
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Nitschke NJ, Bjoern J, Iversen TZ, Andersen MH, Svane IM. Indoleamine 2,3-dioxygenase and survivin peptide vaccine combined with temozolomide in metastatic melanoma. Stem Cell Investig 2017; 4:77. [PMID: 29057249 DOI: 10.21037/sci.2017.08.06] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 04/25/2017] [Indexed: 11/06/2022]
Abstract
BACKGROUND Indoleamine 2,3-dioxygenase (IDO) and survivin have been identified as potential targets for cancer vaccination. In this phase II study a vaccine using the peptides Sur1M2 and IDO5 was combined with the chemotherapy temozolomide (TMZ) for treatment of metastatic melanoma patients. The aim was to simultaneously target several immune inhibiting mechanisms and the highly malignant cells expressing survivin. METHODS HLA-A2 positive patients with advanced malignant melanoma were treated biweekly with 150 mg/m2 TMZ daily for 7 days followed by subcutaneous vaccination with 250 µg of each peptide in 500 µL Montanide solution at day 8. Granulocyte-macrophage colony-stimulating factor was used as an adjuvant and topical imiquimod was applied prior to vaccination. Treatment was continued until disease progression. Clinical response was evaluated by PET-CT and immunological outcome was assessed by ELISPOT and flow cytometry. RESULTS In total, 17 patients were treated with a clinical benefit rate of 18% including one patient with partial tumor regression. Immune analyses revealed a vaccine specific response in 8 (67%) of 12 patients tested, a significant decrease in the frequency of CD4+ T-cells during treatment, a tendency towards decreasing frequencies of naïve CD4+ and CD8+ T-cells, and increasing frequencies of memory CD4+ and CD8+ T-cells. CONCLUSIONS These results demonstrate that vaccine-induced immunity towards survivin and IDO-derived peptides can be achieved in combination with TMZ in patients mainly suffering from grade M1c melanoma including patients with brain metastases. A significant clinical activity could not be proven in this small study and a larger setup is needed to properly assess clinical efficacy.
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Affiliation(s)
- Nikolaj Juul Nitschke
- Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Jon Bjoern
- Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.,Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | | | - Mads Hald Andersen
- Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Inge Marie Svane
- Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.,Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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Kim H, Seo EH, Lee SH, Kim BJ. The Telomerase-Derived Anticancer Peptide Vaccine GV1001 as an Extracellular Heat Shock Protein-Mediated Cell-Penetrating Peptide. Int J Mol Sci 2016; 17:2054. [PMID: 27941629 PMCID: PMC5187854 DOI: 10.3390/ijms17122054] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 11/28/2016] [Accepted: 12/01/2016] [Indexed: 02/08/2023] Open
Abstract
Cell-penetrating peptides (CPPs), which can facilitate the transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular delivery of macromolecules. GV1001, a peptide derived from a reverse-transcriptase subunit of telomerase (hTERT) and developed as a vaccine against various cancers, reportedly has unexpected CPP properties. Unlike typical CPPs, such as the HIV-1 TAT peptide, GV1001 enabled the cytosolic delivery of macromolecules such as proteins, DNA and siRNA via extracellular heat shock protein 90 (eHSP90) and 70 (eHSP70) complexes. The eHSP-GV1001 interaction may have biological effects in addition to its cytosolic delivery function. GV1001 was originally designed as a major histocompatibility complex (MHC) class II-binding cancer epitope, but its CPP properties may contribute to its strong anti-cancer immune response relative to other telomerase peptide-based vaccines. Cell signaling via eHSP-GV1001 binding may lead to unexpected biological effects, such as direct anticancer or antiviral effects. In this review, we focus on the CPP effects of GV1001 bound to eHSP90 and eHSP70.
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Affiliation(s)
- Hong Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea.
| | - Eun-Hye Seo
- Department of Microbiology, Konkuk University School of Medicine, Seoul 05030, Korea.
| | - Seung-Hyun Lee
- Department of Microbiology, Konkuk University School of Medicine, Seoul 05030, Korea.
| | - Bum-Joon Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea.
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Kyte JA, Gaudernack G, Faane A, Lislerud K, Inderberg EM, Brunsvig P, Aamdal S, Kvalheim G, Wälchli S, Pule M. T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy. Oncoimmunology 2016; 5:e1249090. [PMID: 28123886 DOI: 10.1080/2162402x.2016.1249090] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 09/28/2016] [Accepted: 10/12/2016] [Indexed: 12/17/2022] Open
Abstract
We herein report retargeting of T-helper (Th) cells against the universal cancer antigen telomerase for use in adoptive cell therapy. The redirected Th cells may counter tumor tolerance, transform the inflammatory milieu, and induce epitope spreading and cancer senescence. We have previously conducted a series of trials evaluating vaccination with telomerase peptides. From long-term survivors, we isolated >100 CD4+ Th-cell clones recognizing telomerase epitopes. The clones were characterized with regard to HLA restriction, functional avidity, fine specificity, proliferative capacity, cytokine profile, and recognition of naturally processed epitopes. DP4 is the most prevalent HLA molecule worldwide. Two DP4-restricted T-cell clones with different functional avidity, C13 and D71, were selected for molecular T-cell receptor (TCR) cloning. Both clones showed a high proliferative capacity, recognition of naturally processed telomerase epitopes, and a polyfunctional and Th1-weighted cytokine profile. TCR C13 and D71 were cloned into the retroviral vector MP71 together with the compact and GMP-applicable marker/suicide gene RQR8. Both TCRs were expressed well in recipient T cells after PBMC transduction. The transduced T cells co-expressed RQR8 and acquired the desired telomerase specificity, with a polyfunctional response including production of TNFa, IFNγ, and CD107a. Interestingly, the DP4-restricted TCRs were expressed and functional both in CD4+ and CD8+ T cells. The findings demonstrate that the cloned TCRs confer recipient T cells with the desired hTERT-specificity and functionality. We hypothesize that adoptive therapy with Th cells may offer a powerful novel approach for overcoming tumor tolerance and synergize with other forms of immunotherapy.
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Affiliation(s)
- Jon Amund Kyte
- Department for Cell Therapy, Oslo University Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway; Department of Haematology, UCL Cancer Institute, University College London, London, UK
| | - Gustav Gaudernack
- Department for Immunology, Cancer Research Institute, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Anne Faane
- Department for Cell Therapy, Oslo University Hospital , Oslo, Norway
| | - Kari Lislerud
- Department for Cell Therapy, Oslo University Hospital , Oslo, Norway
| | | | - Paal Brunsvig
- Clinical Trial Unit, Department of Oncology, Oslo University Hospital , Oslo, Norway
| | - Steinar Aamdal
- Faculty of Medicine, University of Oslo, Oslo, Norway; Clinical Trial Unit, Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Gunnar Kvalheim
- Department for Cell Therapy, Oslo University Hospital , Oslo, Norway
| | - Sébastien Wälchli
- Department for Cell Therapy, Oslo University Hospital, Oslo, Norway; Department for Immunology, Cancer Research Institute, Oslo University Hospital, Oslo, Norway
| | - Martin Pule
- Department of Haematology, UCL Cancer Institute, University College London , London, UK
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Jäger K, Walter M. Therapeutic Targeting of Telomerase. Genes (Basel) 2016; 7:genes7070039. [PMID: 27455328 PMCID: PMC4962009 DOI: 10.3390/genes7070039] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 06/16/2016] [Accepted: 06/24/2016] [Indexed: 12/20/2022] Open
Abstract
Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer. Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies. Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and personalized approaches. Telomerase activation and cell rejuvenation is successfully used in regenerative medicine for tissue engineering and reconstructive surgery. However, there are also a number of pitfalls in the treatment with telomerase activating procedures for the whole organism and for longer periods of time. Extended cell lifespan may accumulate rare genetic and epigenetic aberrations that can contribute to malignant transformation. Therefore, novel vector systems have been developed for a 'mild' integration of telomerase into the host genome and loss of the vector in rapidly-proliferating cells. It is currently unclear if this technique can also be used in human beings to treat chronic diseases, such as atherosclerosis.
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Affiliation(s)
- Kathrin Jäger
- Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, Germany.
| | - Michael Walter
- Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, Germany.
- Labor Berlin-Charité Vivantes Services GmbH, Sylter Str. 2, Berlin 13353, Germany.
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30
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Zanetti M. A second chance for telomerase reverse transcriptase in anticancer immunotherapy. Nat Rev Clin Oncol 2016; 14:115-128. [DOI: 10.1038/nrclinonc.2016.67] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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31
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Chang JE, Kim HJ, Yi E, Jheon S, Kim K. Reduction of ischaemia-reperfusion injury in a rat lung transplantation model by low-concentration GV1001. Eur J Cardiothorac Surg 2016; 50:972-979. [PMID: 27122609 DOI: 10.1093/ejcts/ezw135] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 03/18/2016] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Lung ischaemia-reperfusion (IR) injury is one of the major complications following lung transplantation. The novel peptide GV1001, which is derived from human telomerase reverse transcriptase, has been reported to possess both antitumour and anti-inflammatory effects. In this study, we focused on the anti-inflammatory effects of GV1001 to investigate the IR injury prevention effect of GV1001 in a rat lung transplantation model. METHODS An orthotopic left lung transplantation rat model was established using the modified cuff technique. We applied 50 ml of normal saline (control), Perfadex (low-potassium standard dextran containing perfusion solution), Perfadex with 5 mg GV1001 (5-mg GV, low concentration) and Perfadex with 50 mg GV1001 (50-mg GV, high concentration) as both flushing and preservation solutions. The left lung was stored in the same solution as the flushing solution at 4°C for 3 h. After transplantation, the recipient rats were monitored for 3 h. Arterial blood gas analysis (ABGA), bronchoalveolar lavage (BAL) analysis, wet/dry ratio, histological analysis, apoptotic cell analysis and cytokine [tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6)] analysis were performed to determine the reduction or prevention effect of GV1001 regarding lung IR injury. RESULTS Compared with the control group, the neutrophil count in BAL, reperfusion oedema and cytokine (TNF-α, IL-6) levels of the transplanted lung were significantly decreased in the 5-mg GV group. Compared with the Perfadex group (16.85 ± 2.43), the neutrophil count in BAL was also significantly decreased in the 5-mg GV group (5.39 ± 0.81) (P< 0.001). In addition, the cytokine (TNF-α, IL-6) levels of the transplanted lung were also significantly decreased in the 5-mg GV group (41.99 ± 12.79, 1069.74 ± 98.48 pg/ml) compared with the Perfadex group (90.73 ± 23.87, 2051.92 ± 243.57 pg/ml) (P < 0.05 and P < 0.001, respectively). However, the 50-mg GV group showed less effect than the 5-mg GV group. CONCLUSIONS Adding a low concentration of GV1001 to the lung preservation solution (Perfadex) provided potential protective effects against IR injury after lung transplantation in rats. Therefore, GV1001 should be considered as a promising anti-inflammatory agent for IR injury.
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Affiliation(s)
- Ji-Eun Chang
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea
| | - Hyun Jun Kim
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea
| | - Eunjue Yi
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea
| | - Sanghoon Jheon
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea.,Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kwhanmien Kim
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea .,Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
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32
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Fenoglio D, Parodi A, Lavieri R, Kalli F, Ferrera F, Tagliamacco A, Guastalla A, Lamperti MG, Giacomini M, Filaci G. Immunogenicity of GX301 cancer vaccine: Four (telomerase peptides) are better than one. Hum Vaccin Immunother 2016; 11:838-50. [PMID: 25714118 PMCID: PMC4514186 DOI: 10.1080/21645515.2015.1012032] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Peptide540–548, peptide611–626, peptide672–686 and peptide766–780, which are derived from human telomerase, constitute the immunogenic component of the GX301 cancer vaccine. The relative immunogenicity of these peptides is unknown, thus it is unsure whether their combined use offers real advantages over single peptide stimulation. Hence, this study compared the number of specific immune responses and responders to each peptide, as well as to their mixture (meaning the co-presence of the 4 peptides in the same culture well), achieved after ex vivo stimulation of PBMC from 21, HLA-A2+ (n.11) or HLA-A2- (n.10), healthy donors. The study was performed on freshly collected PBMC (T0) and on PBMC stimulated for 10 d with single peptides or their mixture (T1). Peptide-specific immune responses were analyzed by Elispot and cytokine intracellular staining by flow cytometry. The results showed that each peptide induced specific immune responses in some subjects, with different panels of responders among the peptides. Moreover, the numbers of responses and responders to the single peptides or their mixture were comparable. Importantly, the overall number of responders to the 4 peptides was higher than to each single peptide, or to their mixture, both at T0 and T1. These data demonstrate the immunogenicity of each of the 4 GX301 telomerase peptides. Moreover, they show the advantage of multi-peptide over single peptide stimulation, providing a clear support to their combined administration in vaccination protocols. However, the data pose a warning against peptide administration as a mixture due to possible interference phenomena during antigen presentation processes.
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Affiliation(s)
- Daniela Fenoglio
- a Centre of Excellence for Biomedical Research ; University of Genoa ; Genoa , Italy
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Choi J, Kim H, Kim Y, Jang M, Jeon J, Hwang YI, Shon WJ, Song YW, Kang JS, Lee WJ. The Anti-inflammatory Effect of GV1001 Mediated by the Downregulation of ENO1-induced Pro-inflammatory Cytokine Production. Immune Netw 2015; 15:291-303. [PMID: 26770183 PMCID: PMC4700405 DOI: 10.4110/in.2015.15.6.291] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 11/04/2015] [Accepted: 11/10/2015] [Indexed: 12/11/2022] Open
Abstract
GV1001 is a peptide derived from the human telomerase reverse transcriptase (hTERT) sequence that is reported to have anti-cancer and anti-inflammatory effects. Enolase1 (ENO1) is a glycolytic enzyme, and stimulation of this enzyme induces high levels of pro-inflammatory cytokines from concanavalin A (Con A)-activated peripheral blood mononuclear cells (PBMCs) and ENO1-expressing monocytes in healthy subjects, as well as from macrophages in rheumatoid arthritis (RA) patients. Therefore, this study investigated whether GV1001 downregulates ENO1-induced pro-inflammatory cytokines as an anti-inflammatory peptide. The results showed that GV1001 does not affect the expression of ENO1 in either Con A-activated PBMCs or RA PBMCs. However, ENO1 stimulation increased the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, and these cytokines were downregulated by pretreatment with GV1001. Moreover, p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB were activated when ENO1, on the surface of Con A-activated PBMCs and RA PBMCs, was stimulated, and they were successfully suppressed by pre-treatment with GV1001. These results suggest that GV1001 may be an effective anti-inflammatory peptide that downregulates the production of pro-inflammatory cytokines through the suppression of p38 MAPK and NF-κB activation following ENO1 stimulation.
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Affiliation(s)
- Jiyea Choi
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Hyemin Kim
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy, Seoul National University College of Medicine, Seoul 03080, Korea.; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Korea
| | - Yejin Kim
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Mirim Jang
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jane Jeon
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Young-Il Hwang
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Won Jun Shon
- Department of Endodontics, Seoul National University School of Dentistry, Seoul 03080, Korea
| | - Yeong Wook Song
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Medical Research Center, Seoul National University, Seoul 03080, Korea.; Division of Rheumatology, Department of Internal Medicine, College of Medicine, Seoul National University, Seoul 03080, Korea
| | - Jae Seung Kang
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy, Seoul National University College of Medicine, Seoul 03080, Korea.; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Korea
| | - Wang Jae Lee
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy, Seoul National University College of Medicine, Seoul 03080, Korea
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Abstract
Overexpressed tumor-self antigens represent the largest group of candidate vaccine targets. Those exhibiting a role in oncogenesis may be some of the least studied but perhaps most promising. This review considers this subset of self antigens by highlighting vaccine efforts for some of the better known members and focusing on TPD52, a new promising vaccine target. We shed light on the importance of both preclinical and clinical vaccine studies demonstrating that tolerance and autoimmunity (presumed to preclude this class of antigens from vaccine development) can be overcome and do not present the obstacle that might have been expected. The potential of this class of antigens for broad application is considered, possibly in the context of low tumor burden or adjuvant therapy, as is the need to understand mechanisms of tolerance that are relatively understudied.
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Key Words
- ALK, Anaplastic lymphoma kinase
- AR, androgen receptor
- CTL, cytotoxic T lymphocyte
- CTLA-4, cytotoxic T lymphocyte-associated antigen 4
- HLA, human leukocyte antigen
- Her-2/neu, human epithelial growth factor receptor 2
- ODN, oligodeoxynucleotide
- Overexpressed tumor-self antigen
- TAA, tumor associated antigen
- TPD52
- TRAMP, Transgenic adenocarcinoma of the mouse prostate
- Treg, T regulatory cell
- VEGFR2, vascular endothelial growth factor receptor 2
- WT-1, Wilms tumor-1
- hD52
- hD52, human TPD52
- mD52
- mD52, murine TPD52
- oncogenic
- shared
- tumor protein D52
- universal
- vaccine
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Affiliation(s)
- Robert K Bright
- a Department of Immunology and Molecular Microbiology and the TTUHSC Cancer Center ; Texas Tech University Health Sciences Center ; Lubbock , TX USA
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35
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Teulings HE, Limpens J, Jansen SN, Zwinderman AH, Reitsma JB, Spuls PI, Luiten RM. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol 2015; 33:773-81. [PMID: 25605840 DOI: 10.1200/jco.2014.57.4756] [Citation(s) in RCA: 455] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Vitiligo-like depigmentation in patients with melanoma may be associated with more favorable clinical outcome. We conducted a systematic review of patients with stage III to IV melanoma treated with immunotherapy to determine the cumulative incidence of vitiligo-like depigmentation and the prognostic value of vitiligo development on survival. METHODS We systemically searched and selected all studies on melanoma immunotherapy that reported on autoimmune toxicity and/or vitiligo between 1995 and 2013. Methodologic quality of each study was appraised using adapted criteria for systematic reviews in prognostic studies. Random-effect models were used to calculate summary estimates of the cumulative incidence of vitiligo-like depigmentation across studies. The prognostic value of vitiligo-like depigmentation on survival outcome was assessed using random-effects Cox regression survival analyses. RESULTS One hundred thirty-seven studies were identified comprising 139 treatment arms (11 general immune stimulation, 84 vaccine, 28 antibody-based, and 16 adoptive transfer) including a total of 5,737 patients. The overall cumulative incidence of vitiligo was 3.4% (95% CI, 2.5% to 4.5%). In 27 studies reporting individual patient data, vitiligo development was significantly associated with both progression-free-survival (hazard ratio [HR], 0.51; 95% CI, 0.32 to 0.82; P < .005) and overall survival (HR, 0.25; 95% CI, 0.10 to 0.61; P < .003), indicating that these patients have two to four times less risk of disease progression and death, respectively, compared with patients without vitiligo development. CONCLUSION Although vitiligo occurs only in a low percentage of patients with melanoma treated with immunotherapy, our findings suggest clear survival benefit in these patients. Awareness of vitiligo induction in patients with melanoma is important as an indicator of robust antimelanoma immunity and associated improved survival.
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Affiliation(s)
- Hansje-Eva Teulings
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
| | - Jacqueline Limpens
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Sophia N Jansen
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Aeilko H Zwinderman
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Johannes B Reitsma
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Phyllis I Spuls
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Rosalie M Luiten
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
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Picariello L, Grappone C, Polvani S, Galli A. Telomerase activity: An attractive target for cancer therapeutics. World J Pharmacol 2014; 3:86-96. [DOI: 10.5497/wjp.v3.i4.86] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 10/01/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
Telomeres are non-coding tandem repeats of 1000-2000 TTAGGG nucleotide DNA sequences on the 3’ termini of human chromosomes where they serve as protective “caps” from degradation and loss of genes. The “cap” at the end of chromosome required to protect its integrity is a 150-200 nucleotide-long single stranded G-rich 3’ overhang that forms two higher order structures, a T-loop with Sheltering complex, or a G-quadruplex complex. Telomerase is a human ribonucleoprotein reverse transcriptase that continually added single stranded TTAGGG DNA sequences onto the single strand 3’ of telomere in the 5’ to 3’ direction. Telomerase activity is detected in male germ line cells, proliferative cells of renewal tissues, some adult pluripotent stem cells, embryonic cells, but in most somatic cells is not detected. Re-expression or up-regulation of telomerase in tumours cells is considered as a critical step in cell tumorigenesis and telomerase is widely considered as a tumour marker and a target for anticancer drugs. Different approaches have been used in anticancer therapeutics targeting telomerase. Telomerase inhibitors can block directly Human TElomerase Reverse Transcriptase (hTERT) or Human TElomerase RNA telomerase subunits activity, or G-quadruplex and Sheltering complex components, shortening telomeres and inhibiting cell proliferation. Telomerase can become an immune target and GV1001, Vx-001, I540 are the most widespread vaccines used with encouraging results. Another method is to use hTERT promoter to drive suicide gene expression or to control a lytic virus replication. Recently telomerase activity was used to activate pro-drugs such as Acycloguanosyl 5’-thymidyltriphosphate, a synthetic ACV-derived molecule when it is activated by telomerase it does not require any virus or host active immune response to induce suicide gene therapy. Advantage of all these therapies is that target only neoplastic cells without any effects in normal cells, avoiding toxicity and adverse effects of the current chemotherapy. However, as not all the approaches are equally efficient, further studies will be necessary.
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Park HH, Lee KY, Kim S, Lee JW, Choi NY, Lee EH, Lee YJ, Lee SH, Koh SH. Novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. Neurobiol Aging 2013; 35:1255-74. [PMID: 24439482 DOI: 10.1016/j.neurobiolaging.2013.12.015] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Revised: 11/21/2013] [Accepted: 12/19/2013] [Indexed: 12/17/2022]
Abstract
GV1001 is a 16-amino-acid vaccine peptide derived from the human telomerase reverse transcriptase sequence. We investigated the effects of GV1001 against β-amyloid (Aβ) oligomer-induced neurotoxicity in rat neural stem cells (NSCs). Primary culture NSCs were treated with several concentrations of GV1001 and/or Aβ₂₅₋₃₅ oligomer for 48 hours. GV1001 protected NSCs against the Aβ₂₅₋₃₅ oligomer in a concentration-dependent manner. Aβ₂₅₋₃₅ concentration dependently decreased viability, proliferation, and mobilization of NSCs and GV1001 treatment restored the cells to wild-type levels. Aβ₂₅₋₃₅ increased free radical levels in rat NSCs while combined treatment with GV1001 significantly reduced these levels. In addition, GV1001 treatment of Aβ₂₅₋₃₅-injured NSCs increased the expression level of survival-related proteins, including mitochondria-associated survival proteins, and decreased the levels of death and inflammation-related proteins, including mitochondria-associated death proteins. Together, these results suggest that GV1001 possesses neuroprotective effects against Aβ₂₅₋₃₅ oligomer in NSCs and that these effects are mediated through mimicking the extra-telomeric functions of human telomerase reverse transcriptase, including the induction of cellular proliferation, anti-apoptotic effects, mitochondrial stabilization, and anti-aging and anti-oxidant effects.
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Affiliation(s)
- Hyun-Hee Park
- Department of Neurology, Hanyang University College of Medicine, Guri, Gyeonggi, Korea
| | - Kyu-Yong Lee
- Department of Neurology, Hanyang University College of Medicine, Guri, Gyeonggi, Korea
| | - Sangjae Kim
- Department of Neuroscience, KAEL-Gemvax Co, Ltd, Seoul, Korea
| | | | - Na-Young Choi
- Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Korea
| | - Eun-Hye Lee
- Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Korea
| | - Young Joo Lee
- Department of Neurology, Hanyang University College of Medicine, Guri, Gyeonggi, Korea
| | - Sang-Hun Lee
- Department of Biochemistry and Molecular Biology, Hanyang University College of Medicine, Seoul, Korea
| | - Seong-Ho Koh
- Department of Neurology, Hanyang University College of Medicine, Guri, Gyeonggi, Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Korea.
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Talebian Yazdi M, Keene KR, Hiemstra PS, van der Burg SH. Recent progress in peptide vaccination in cancer with a focus on non-small-cell lung cancer. Expert Rev Vaccines 2013; 13:87-116. [PMID: 24308580 DOI: 10.1586/14760584.2014.862499] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Active immunotherapy aimed at the stimulation of tumor-specific T cells has established itself within the clinic as a therapeutic option to treat cancer. One strategy is the use of so-called peptides that mimic genuine T-cell epitopes as vaccines to activate tumor-specific T cells. In various clinical trials, different types of vaccines, adjuvants and other immunomodulatory compounds were evaluated in patients with different types of tumors. Here, we review the trials published in the last 3 years focusing on the T-cell response, the effect of immunomodulation and potential relationships with clinical outcomes. Furthermore, we would like to make a case for the development of peptide vaccines aiming to treat non-small-cell lung cancer, the most common cause of cancer mortality.
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Affiliation(s)
- Mehrdad Talebian Yazdi
- Department of Pulmonology, Leiden University Medical Center (LUMC), Leiden, the Netherlands
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Aranda F, Vacchelli E, Eggermont A, Galon J, Sautès-Fridman C, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Peptide vaccines in cancer therapy. Oncoimmunology 2013; 2:e26621. [PMID: 24498550 PMCID: PMC3902120 DOI: 10.4161/onci.26621] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 09/26/2013] [Indexed: 02/08/2023] Open
Abstract
Throughout the past 3 decades, along with the recognition that the immune system not only influences oncogenesis and tumor progression, but also determines how established neoplastic lesions respond therapy, renovated enthusiasm has gathered around the possibility of using vaccines as anticancer agents. Such an enthusiasm quickly tempered when it became clear that anticancer vaccines would have to be devised as therapeutic, rather than prophylactic, measures, and that malignant cells often fail to elicit (or actively suppress) innate and adaptive immune responses. Nonetheless, accumulating evidence indicates that a variety of anticancer vaccines, including cell-based, DNA-based, and purified component-based preparations, are capable of circumventing the poorly immunogenic and highly immunosuppressive nature of most tumors and elicit (at least under some circumstances) therapeutically relevant immune responses. Great efforts are currently being devoted to the identification of strategies that may provide anticancer vaccines with the capacity of breaking immunological tolerance and eliciting tumor-associated antigen-specific immunity in a majority of patients. In this sense, promising results have been obtained by combining anticancer vaccines with a relatively varied panels of adjuvants, including multiple immunostimulatory cytokines, Toll-like receptor agonists as well as inhibitors of immune checkpoints. One year ago, in the December issue of OncoImmunology, we discussed the biological mechanisms that underlie the antineoplastic effects of peptide-based vaccines and presented an abundant literature demonstrating the prominent clinical potential of such an approach. Here, we review the latest developments in this exciting area of research, focusing on high-profile studies that have been published during the last 13 mo and clinical trials launched in the same period to evaluate purified peptides or full-length proteins as therapeutic anticancer agents.
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Affiliation(s)
- Fernando Aranda
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre, France ; Equipe 11 labellisée par la Lique Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France
| | - Erika Vacchelli
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre, France ; Equipe 11 labellisée par la Lique Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France
| | | | - Jerome Galon
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France ; Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, U872; Paris, France ; Equipe 15, Centre de Recherche des Cordeliers; Paris, France
| | - Catherine Sautès-Fridman
- Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, U872; Paris, France ; Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | - Eric Tartour
- Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France ; INSERM, U970; Paris, France
| | - Laurence Zitvogel
- Gustave Roussy; Villejuif, France ; INSERM, U1015; CICBT507; Villejuif, France
| | - Guido Kroemer
- Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Lique Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France ; Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France ; Metabolomics and Cell Biology Platforms; Gustave Roussy; Villejuif, France
| | - Lorenzo Galluzzi
- Gustave Roussy; Villejuif, France ; Equipe 11 labellisée par la Lique Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France ; Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
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Sekaran V, Soares J, Jarstfer MB. Telomere Maintenance as a Target for Drug Discovery. J Med Chem 2013; 57:521-38. [DOI: 10.1021/jm400528t] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Vijay Sekaran
- Division of Chemical Biology
and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Joana Soares
- Division of Chemical Biology
and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Michael B. Jarstfer
- Division of Chemical Biology
and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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Fenoglio D, Traverso P, Parodi A, Kalli F, Zanetti M, Filaci G. Generation of more effective cancer vaccines. Hum Vaccin Immunother 2013; 9:2543-7. [PMID: 23978951 DOI: 10.4161/hv.26147] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Cancer vaccines represent a promising therapeutic approach for which prime time is imminent. However, clinical efficacy must be improved in order for cancer vaccines to become a valid alternative or complement to traditional cancer treatments. Considerable efforts have been undertaken so far to better understand the fundamental requirements for clinically-effective cancer vaccines. Recent data emphasize that important requirements, among others, are (1) the use of multi-epitope immunogens, possibly deriving from different tumor antigens; (2) the selection of effective adjuvants; (3) the association of cancer vaccines with agents able to counteract the regulatory milieu present in the tumor microenvironment; and (4) the need to choose the definitive formulation and regimen of a vaccine after accurate preliminary tests comparing different antigen formulations. The first requirement deals with issues related to HLA restriction of tumor antigen presentation, as well as usefulness of tumor antigen spreading and counteraction of immune escape phenomena, linked to tumor antigen down-modulation, for an effective anti-cancer immune response. The second point underscores the necessity of optimal activation of innate immunity to achieve an efficient adaptive anti-cancer immune response. The third point focuses on the importance to inhibit subsets of regulatory cells. The last requirement stresses the concept that the regimen and formulation of the vaccine impacts profoundly on cancer vaccine efficacy. A new generation of cancer vaccines, provided with both immunological and clinical efficacy, will hopefully soon address these requirements.
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Affiliation(s)
- Daniela Fenoglio
- Centre of Excellence for Biomedical Research; University of Genoa; Genoa, Italy; Department of Internal Medicine; University of Genoa; Genoa, Italy
| | - Paolo Traverso
- Centre of Excellence for Biomedical Research; University of Genoa; Genoa, Italy; Department of Surgical Sciences; University of Genoa; Genoa, Italy
| | - Alessia Parodi
- Centre of Excellence for Biomedical Research; University of Genoa; Genoa, Italy
| | - Francesca Kalli
- Centre of Excellence for Biomedical Research; University of Genoa; Genoa, Italy
| | - Maurizio Zanetti
- The Laboratory of Immunology; Department of Medicine and Cancer Center; University of California; San Diego, CA USA
| | - Gilberto Filaci
- Centre of Excellence for Biomedical Research; University of Genoa; Genoa, Italy; Department of Internal Medicine; University of Genoa; Genoa, Italy
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Fenoglio D, Traverso P, Parodi A, Tomasello L, Negrini S, Kalli F, Battaglia F, Ferrera F, Sciallero S, Murdaca G, Setti M, Sobrero A, Boccardo F, Cittadini G, Puppo F, Criscuolo D, Carmignani G, Indiveri F, Filaci G. A multi-peptide, dual-adjuvant telomerase vaccine (GX301) is highly immunogenic in patients with prostate and renal cancer. Cancer Immunol Immunother 2013; 62:1041-1052. [PMID: 23591981 PMCID: PMC11029691 DOI: 10.1007/s00262-013-1415-9] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Accepted: 03/07/2013] [Indexed: 11/30/2022]
Abstract
BACKGROUND Anti-tumor vaccination is a new frontier in cancer treatment applicable to immunogenic neoplasms such as prostate and renal cancers. GX301 is a vaccine constituted by four telomerase peptides and two adjuvants, Montanide ISA-51 and Imiquimod. OBJECTIVE The aim of this study was to analyze safety and tolerability of GX301 in an open-label, phase I/II trial. Immunological and clinical responses were also evaluated as secondary endpoints. EXPERIMENTAL DESIGN GX301 was administered by intradermally injecting 500 μg of each peptide (dissolved in Montanide ISA-51) in the skin of the abdomen. Imiquimod was applied as a cream at the injection sites. The protocol included 8 administrations at days 1, 3, 5, 7, 14, 21, 35, 63. Eligible patients were affected with stage IV prostate or renal cancer resistant to conventional treatments. Patients were clinically and immunologically monitored up to 6 months from the first immunization. RESULTS No grade 3-4 adverse events were observed. Evidence of vaccine-specific immunological responses was detected in 100 % of patients. Disease stabilization occurred in 4 patients. Prolonged progression-free survival and overall survival were observed in patients showing a full pattern of vaccine-specific immunological responses. CONCLUSION GX301 demonstrated to be safe and highly immunogenic. Further studies are needed to determine its clinical efficacy.
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Affiliation(s)
- Daniela Fenoglio
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV n. 7, 16132 Genoa, Italy
- Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Paolo Traverso
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV n. 7, 16132 Genoa, Italy
- Department of Surgical Sciences, University of Genoa, Genoa, Italy
| | - Alessia Parodi
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV n. 7, 16132 Genoa, Italy
| | - Laura Tomasello
- Istituto Nazionale per la Ricerca sul Cancro, IRCCS Azienda Ospedaliero Universitaria San Martino—IST, Genoa, Italy
| | - Simone Negrini
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV n. 7, 16132 Genoa, Italy
| | - Francesca Kalli
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV n. 7, 16132 Genoa, Italy
| | - Florinda Battaglia
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV n. 7, 16132 Genoa, Italy
| | - Francesca Ferrera
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV n. 7, 16132 Genoa, Italy
| | - Stefania Sciallero
- Istituto Nazionale per la Ricerca sul Cancro, IRCCS Azienda Ospedaliero Universitaria San Martino—IST, Genoa, Italy
| | - Giuseppe Murdaca
- Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Maurizio Setti
- Istituto Nazionale per la Ricerca sul Cancro, IRCCS Azienda Ospedaliero Universitaria San Martino—IST, Genoa, Italy
| | - Alberto Sobrero
- Istituto Nazionale per la Ricerca sul Cancro, IRCCS Azienda Ospedaliero Universitaria San Martino—IST, Genoa, Italy
| | - Francesco Boccardo
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- Istituto Nazionale per la Ricerca sul Cancro, IRCCS Azienda Ospedaliero Universitaria San Martino—IST, Genoa, Italy
| | - Giuseppe Cittadini
- Istituto Nazionale per la Ricerca sul Cancro, IRCCS Azienda Ospedaliero Universitaria San Martino—IST, Genoa, Italy
| | - Francesco Puppo
- Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Domenico Criscuolo
- Genovax srl, Colleretto Giacosa, Italy
- Present Address: Mediolanum Farmaceutici Spa, Milan, Italy
| | | | - Francesco Indiveri
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV n. 7, 16132 Genoa, Italy
- Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Gilberto Filaci
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV n. 7, 16132 Genoa, Italy
- Department of Internal Medicine, University of Genoa, Genoa, Italy
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Vaccination for the prevention and treatment of breast cancer with special focus on Her-2/neu peptide vaccines. Breast Cancer Res Treat 2013; 138:1-12. [PMID: 23340862 DOI: 10.1007/s10549-013-2410-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 01/07/2013] [Indexed: 01/18/2023]
Abstract
Immunologic interventions in a subset of breast cancer patients represent a well-established therapeutic approach reflecting individualized treatment modalities. Thus, the therapeutic administration of monoclonal antibodies targeting tumor-associated antigens (TAA), such as Her-2/neu, represents a milestone in cancer treatment. However, passive antibody administration suffers from several drawbacks, including frequency and long duration of treatment. These undesirables may be avoidable in an approach based on generating active immune responses against these same targets. Only recently has the significance of tumors in relation to their microenvironments been understood as essential for creating an effective cancer vaccine. In particular, the immune system plays an important role in suppressing or promoting tumor formation and growth. Therefore, activation of appropriate triggers (such as induction of Th1 cells, CD8+ T cells, and suppression of regulatory cells in combination with generation of antibodies with anti-tumor activity) is a desirable goal. Current vaccination approaches have concentrated on therapeutic vaccines using certain TAA. Many cancer antigens, including breast cancer antigens, have been described and also given priority ranking for use as vaccine antigens by the US National Cancer Institute. One of the TAA antigens which has been thoroughly examined in numerous trials is Her-2/neu. This review will discuss delivery systems for this antigen with special focus on T and B cell peptide vaccines. Attention will be given to their advantages and limitations, as well as the use of certain adjuvants to improve anti-cancer responses.
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Characterization of CD8+ T-cell responses in the peripheral blood and skin injection sites of melanoma patients treated with mRNA electroporated autologous dendritic cells (TriMixDC-MEL). BIOMED RESEARCH INTERNATIONAL 2013; 2013:976383. [PMID: 23509826 PMCID: PMC3581259 DOI: 10.1155/2013/976383] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Accepted: 07/21/2012] [Indexed: 12/22/2022]
Abstract
Treatment of melanoma patients with mRNA electroporated dendritic cells (TriMixDC-MEL) stimulates T-cell responses against the presented tumor-associated antigens (TAAs). In the current clinical trials, melanoma patients with systemic metastases are treated, requiring priming and/or expansion of preexisting TAA-specific T cells that are able to migrate to both the skin and internal organs. We monitored the presence of TAA-specific CD8+ T cells infiltrating the skin at sites of intradermal TriMixDC-MEL injection (SKILs) and within the circulation of melanoma patients treated in two clinical trials.
In 10 out of fourteen (71%) patients screened, CD8+ T cells recognizing any of the four TAA presented by TriMixDC-MEL cellular vaccine were found in both compartments. In total, 30 TAA-specific T-cell responses were detected among the SKILs and 29 among peripheral blood T cells, of which 24 in common. A detailed characterization of the antigen specificity of CD8+ T-cell populations in four patients indicates that the majority of the epitopes detected were only recognized by CD8+ T cells derived from either skin biopsies or peripheral blood, indicating that some compartmentalization occurs after TriMix-DC therapy. To conclude, functional TAA-specific CD8+ T cells distribute both to the skin and peripheral blood of patients after TriMixDC-MEL therapy.
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