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hTERT Universal Cancer Peptide Vaccines

hTERT peptide vaccines 

Human telomerase reverse transcriptase (hTERT) is an overexpressed tumor-associated antigen (TAA) in over 85% of tumors, including tumors of hematopoietic tissue and solid tumors [1]. hTERT expression is required for tumor immortality, especially in cancer stem cells, and is one of the crucial targets for cancer immunotherapy [2] . Its expression is absent in most normal tissues and only present at low levels in hematopoietic stem cells, basal keratinocytes, and human germline cells. Up to date, several trials with hTERT-based peptide vaccines have been conducted and showed no toxicity to normal tissues after vaccination. Furthermore, confirmation of typical bone marrow functionality was obtained. 

 

  1. GV1001 

GV1001, a 16-amino acid peptide of hTERT, residues 611–626 fragment (EAR PAL LTS RLR FIP K) [3],has emerged as a promising immunotherapeutic agent with potential applications across various cancer types, stimulating robust CD4+ T cell responses in up to 80% of vaccinated patients [4]. Moreover, GV1001 harbors putative HLA-Class I epitopes, suggesting the possibility of eliciting combined CD4+ and CD8+ T-cell responses, crucial for tumor eradication and long-term immune memory [3]. 

 

Clinical trials in pancreatic adenocarcinoma [5], non-small cell lung cancer (NSCLC) [6, 7] and malignant melanoma [4, 8] cancers have demonstrated the safety and efficacy of the GV1001 vaccination. In pancreatic cancer, intradermal administration of GV1001 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) induced immune responses in a significant proportion of patients, correlating with improved survival rates [5]. Similarly, in NSCLC patients, GV1001 vaccination elicited durable T cell responses, with some patients achieving complete remissions and prolonged survival, supporting the combination of chemoradiotherapy with vaccination for further exploration. 

 

However, not all trials yield positive outcomes. In a phase III trial for pancreatic cancer (TeloVac), GV1001 vaccination in combination with chemotherapy did not improve overall survival compared to chemotherapy alone, highlighting the need for new strategies to enhance immune response during chemotherapy [9]. Additionally, GV1001 vaccination in cutaneous T cell lymphoma (CTCL) patients failed to induce objective clinical responses, emphasizing the importance of refining vaccine strategies for specific cancer types [10]. 


Despite these challenges, GV1001 has shown promise in various settings. In metastatic breast cancer, GV1001 combined with cytotoxic chemotherapy demonstrated disease control and overall response rates, suggesting potential benefit across different breast cancer subtypes [11].  In benign prostatic hyperplasia (BPH) patients, GV1001 showed efficacy in improving symptoms and reducing prostate volume, indicating potential as an alternative therapy [12] 

 

GV1001 represents a versatile immunotherapeutic approach with the ability to induce robust immune responses and improve clinical outcomes in certain cancer types. Further research is warranted to optimize its efficacy, refine vaccination strategies, and explore its potential in combination with other treatment modalities to maximize therapeutic benefits across a broader spectrum of cancers. 

 

 

GV1001 CPP functions 

Cell-penetrating peptides (CPPs) are instrumental in facilitating the transport of molecular cargo across cell membranes. GV1001, initially devised as a cancer vaccine, exhibits unique CPP properties, facilitating the intracellular delivery of large molecules via extracellular heat shock proteins 90 and 70 (eHSP90 and eHSP70). The interactions between eHSPs and GV1001 suggest broader biological implications beyond its initial anticancer purpose [13] 

 

Examination of GV1001 uncovers its diverse functions, including its role as a ligand for the gonadotropin-releasing hormone receptor (GnRHR), which triggers specific activation of the Gαs/cAMP pathway in prostate cancer (PCa) cells, ultimately hindering metastasis. Moreover, GV1001 demonstrates potential therapeutic effects in benign prostatic hyperplasia and castration-resistant prostate cancer by modulating various pathways, including AKT/NF-kB/VEGF and VEGF-A/VEGFR-2, thereby suppressing tumor growth and angiogenesis [14-18]. 

 

GV1001 also exhibits promising outcomes in pancreatic cancer, renal cell carcinoma (RCC) [19], and mitigating ototoxicity while protecting against hearing loss [20, 21]. Additionally, GV1001 shows anti-inflammatory effects by reducing pro-inflammatory cytokine production and presents multifaceted benefits in periodontitis, rheumatoid arthritis, and myocardial ischemia-reperfusion injury [22-25]. Its potential cardioprotective, neuroprotective, and anticancer properties highlight GV1001 as a versatile peptide with therapeutic potential across various diseases. [26-31] 

 

  1. Vx-001 

 Vx-001, an anti-tumor vaccine containing the 9-mer cryptic TERT (572) peptide and its optimized variant TERT (572Y), has shown promising results in various studies evaluating its safety, efficacy, and immunogenicity in advanced cancer patients. Initial phase I trials demonstrated the safety and efficacy of the optimized cryptic peptide TERT (572Y) in refractory tumor patients [32]. Further optimization studies comparing TERT (572Y) and TERT572 peptides suggested an effective immunotherapy schedule, eliciting higher T cell responses with optimal results achieved by administering TERT (572Y) followed by TERT572 peptides. [33] 

 

In subsequent studies, Vx-001 demonstrated non-toxicity and high immunogenicity in chemo-resistant solid tumor patients, leading to specific T-cell responses and significant survival benefits, even in patients with disease progression at entry [34]. Expanded phase II trials in patients with advanced solid tumors, particularly in HLA-A*0201-positive patients, revealed a correlation between TERT-specific immune response and improved clinical outcomes, including disease control rate, progression-free survival, and overall survival [35]. 

 

 

Specifically in HLA-A*0201-positive NSCLC patients, Vx-001 showed promising results with a disease control rate of 28%, significantly higher rates in non-squamous histology, and median progression-free survival and overall survival of 3.8 and 19.8 months, respectively. Patients exhibiting immune responses had significantly prolonged overall survival, indicating the potential clinical benefits of Vx-001 in this subgroup [36]. 

 

While a phase 2b trial with HLA-A*201-positive NSCLC patients did not meet its primary endpoint of overall survival improvement, patients with a lasting TERT-specific immune response showed significantly longer overall survival, suggesting potential benefits for specific subgroups warranting further investigation [37]. Additionally, other strategies targeting hTERT have been explored, such as the construction of a recombinant human telomerase reverse transcriptase (hTERT)-human IL-18 (hIL18) fusion protein, demonstrating strong telomerase activity and enhanced anti-apoptotic effects, as well as the assessment of hTERT-derived peptide vaccines in hepatocellular carcinoma patients, which induced hTERT-specific immunity and prevented HCC recurrence in a significant proportion of patients [38, 39]. 

 

These findings collectively underscore the potential of TERT-targeting immunotherapies, including Vx-001 and related approaches, in the treatment of advanced cancers, with implications for improving clinical outcomes and addressing unmet medical needs in various patient populations. 

 

  1. UV1 vaccine 

The UV1 vaccine, developed by Ultimovacs ASA, is designed to achieve broad population coverage in cancer immunotherapy. It comprises three synthetic long peptides containing multiple epitopes, including a 30-mer and two 15-mers, selected based on immunological analyses of blood from long-term cancer survivors treated with a first-generation hTERT vaccine (GV1001). The UV1 peptides incorporate hTERT epitopes most frequently recognized in GV1001-vaccinated patients, indicating epitope spreading from previous vaccination [3] 

 

Administration of the UV1 vaccine involves intradermal injection into the patient, with GM-CSF used as an adjuvant to enhance the immune response. The treatment regimen consists of three injections during the first week, followed by booster vaccinations at specific intervals up to 4 years, aimed at mimicking an acute infection or inflammation, followed by maintenance doses [40] 

 

In clinical trials, UV-11 has shown promising results across various cancer types. In a phase I/IIa trial involving men with metastatic hormone-naïve prostate cancer, UV1 combined with GM-CSF induced specific immune responses in a large proportion of patients, resulting in PSA decline and stable disease in a significant number of participants [41]. Similarly, in patients with advanced non-small cell lung cancer (NSCLC), UV1 vaccination demonstrated safety, immune response induction, and favorable long-term clinical outcomes, with median progression-free survival (PFS) and overall survival (OS) reaching notable durations. Notably, higher UV1 dosages correlated with stronger immune responses and improved OS, indicating dose-dependent effects [40]

 

In metastatic malignant melanoma, UV1 vaccination in combination with ipilimumab, an immune checkpoint inhibitor, showed synergistic effects, with patients exhibiting Th1 immune responses and favorable clinical outcomes, including partial or complete responses and prolonged overall survival. The combination therapy was well-tolerated, suggesting potential benefits of integrating UV1 vaccination with standard treatment regimens containing immune checkpoint inhibitors [42]. 

 

Overall, UV1 vaccination has demonstrated safety, efficacy, and immune response induction across multiple cancer types, providing a promising avenue for cancer immunotherapy. The findings from these trials support further investigation of UV1 in combination with existing treatments and its potential integration into standard care protocols for cancer patients. Further research is warranted to explore its utility in larger patient populations and optimize dosing regimens for maximal therapeutic benefit. 

 

Written By: Feng Lin, M.D., Ph.D. 

 

 

References 

 

1. Liu JP, Chen W, Schwarer AP, Li H: Telomerase in cancer immunotherapy. Biochim Biophys Acta 2010, 1805:35-42. 

2. Terashima T, Mizukoshi E, Arai K, Yamashita T, Yoshida M, Ota H, Onishi I, Kayahara M, Ohtsubo K, Kagaya T, et al: P53, hTERT, WT-1, and VEGFR2 are the most suitable targets for cancer vaccine therapy in HLA-A24 positive pancreatic adenocarcinoma. Cancer Immunol Immunother 2014, 63:479-489. 

3. 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 2012, 1:670-686. 

4. Kyte JA, Gaudernack G, Dueland S, Trachsel S, Julsrud L, Aamdal S: Telomerase peptide vaccination combined with temozolomide: a clinical trial in stage IV melanoma patients. Clin Cancer Res 2011, 17:4568-4580. 

5. Bernhardt SL, Gjertsen MK, Trachsel S, Moller M, Eriksen JA, Meo M, Buanes T, Gaudernack G: Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: A dose escalating phase I/II study. Br J Cancer 2006, 95:1474-1482. 

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7. Brunsvig PF, Kyte JA, Kersten C, Sundstrom S, Moller M, Nyakas M, Hansen GL, Gaudernack G, Aamdal S: Telomerase peptide vaccination in NSCLC: a phase II trial in stage III patients vaccinated after chemoradiotherapy and an 8-year update on a phase I/II trial. Clin Cancer Res 2011, 17:6847-6857. 

8. Hunger RE, Kernland Lang K, Markowski CJ, Trachsel S, Moller M, Eriksen JA, Rasmussen AM, Braathen LR, Gaudernack G: Vaccination of patients with cutaneous melanoma with telomerase-specific peptides. Cancer Immunol Immunother 2011, 60:1553-1564. 

9. Middleton G, Silcocks P, Cox T, Valle J, Wadsley J, Propper D, Coxon F, Ross P, Madhusudan S, Roques T, et al: Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol 2014, 15:829-840. 

10. Schlapbach C, Yerly D, Daubner B, Yawalkar N, Hunger RE: Telomerase-specific GV1001 peptide vaccination fails to induce objective tumor response in patients with cutaneous T cell lymphoma. J Dermatol Sci 2011, 62:75-83. 

11. 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 Med Press) 2023, 15:955-966. 

12. Moon KT, Yoo TK, Kwon SY, Ha JY, Byun SS, Kim JH, Chung JI, Kim TH, Moon HS, Kim SJ, Lee KS: A randomised, placebo-controlled, multicentre, Phase 2 clinical trial to evaluate the efficacy and safety of GV1001 in patients with benign prostatic hyperplasia. BJU Int 2018, 122:283-292. 

13. 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. 

14. Kim JW, Park M, Kim S, Lim SC, Kim HS, Kang KW: Anti-metastatic effect of GV1001 on prostate cancer cells; roles of GnRHR-mediated Galphas-cAMP pathway and AR-YAP1 axis. Cell Biosci 2021, 11:191. 

15. Kim JW, Yadav DK, Kim SJ, Lee MY, Park JM, Kim BS, Kim MH, Park HG, Kang KW: Anti-cancer effect of GV1001 for prostate cancer: function as a ligand of GnRHR. Endocr Relat Cancer 2019, 26:147-162. 

16. Kim Y, Lee D, Jo H, Go C, Yang J, Kang D, Kang JS: GV1001 interacts with androgen receptor to inhibit prostate cell proliferation in benign prostatic hyperplasia by regulating expression of molecules related to epithelial-mesenchymal transition. Aging (Albany NY) 2021, 13:3202-3217. 

17. Park YH, Jung AR, Kim GE, Kim MY, Sung JW, Shin D, Cho HJ, Ha US, Hong SH, Kim SW, Lee JY: GV1001 inhibits cell viability and induces apoptosis in castration-resistant prostate cancer cells through the AKT/NF-kappaB/VEGF pathway. J Cancer 2019, 10:6269-6277. 

18. 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. 

19. Kim GE, Jung AR, Kim MY, Lee JB, Im JH, Lee KW, Park YH, Lee JY: GV1001 Induces Apoptosis by Reducing Angiogenesis in Renal Cell Carcinoma Cells Both In Vitro and In Vivo. Urology 2018, 113:129-137. 

20. Kim SY, Jung G, Shim YJ, Koo JW: The Novel Peptide Vaccine GV1001 Protects Hearing in a Kanamycin-induced Ototoxicity Mouse Model. Otol Neurotol 2018, 39:e731-e737. 

21. Kim SH, Jung G, Kim S, Koo JW: Novel Peptide Vaccine GV1001 Rescues Hearing in Kanamycin/Furosemide-Treated Mice. Front Cell Neurosci 2018, 12:3. 

22. 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. 

23. Kim SY, Kim YJ, Kim S, Momeni M, Lee A, Treanor A, Kim S, Kim RH, Park NH: GV1001 Inhibits the Severity of the Ligature-Induced Periodontitis and the Vascular Lipid Deposition Associated with the Periodontitis in Mice. Int J Mol Sci 2023, 24. 

24. Choi IA, Choi JY, Jung S, Basri F, Park S, Lee EY: GV1001 immunotherapy ameliorates joint inflammation in a murine model of rheumatoid arthritis by modifying collagen-specific T-cell responses and downregulating antigen-presenting cells. Int Immunopharmacol 2017, 46:186-193. 

25. Chang JE, Kim HJ, Jheon S, Lim C: Protective effects of GV1001 on myocardial ischemia‑reperfusion injury. Mol Med Rep 2017, 16:7315-7320. 

26. Lee SY, Han JJ, Lee SY, Jung G, Min HJ, Song JJ, Koo JW: Outcomes of Peptide Vaccine GV1001 Treatment in a Murine Model of Acute Noise-Induced Hearing Loss. Antioxidants (Basel) 2020, 9. 

27. Koh SH, Kwon HS, Choi SH, Jeong JH, Na HR, Lee CN, Yang Y, Lee AY, Lee JH, Park KW, et al: Efficacy and safety of GV1001 in patients with moderate-to-severe Alzheimer's disease already receiving donepezil: a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. Alzheimers Res Ther 2021, 13:66. 

28. Kwon HS, Kim YE, Park HH, Son JW, Choi H, Lee YJ, Kim HY, Lee KY, Koh SH: Neuroprotective Effects of GV1001 in Animal Stroke Model and Neural Cells Subject to Oxygen-Glucose Deprivation/Reperfusion Injury. J Stroke 2021, 23:420-436. 

29. Park H, Kwon HS, Lee KY, Kim YE, Son JW, Choi NY, Lee EJ, Han MH, Park DW, Kim S, Koh SH: GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer's disease mouse model. Brain Behav Immun 2024, 115:295-307. 

30. Kwon HS, Koh SH, Choi SH, Jeong JH, Na HR, Lee CN, Yang Y, Lee AY, Lee JH, Park KW, et al: Effects of GV1001 on Language Dysfunction in Patients With Moderate-to-Severe Alzheimer's Disease: Post Hoc Analysis of Severe Impairment Battery Subscales. Dement Neurocogn Disord 2023, 22:100-108. 

31. Park HH, Lee KY, Kim S, Lee JW, Choi NY, Lee EH, Lee YJ, Lee SH, Koh SH: Novel vaccine peptide GV1001 effectively blocks beta-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. Neurobiol Aging 2014, 35:1255-1274. 

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33. Vetsika EK, Papadimitraki E, Aggouraki D, Konsolakis G, Mela ME, Kotsakis A, Christou S, Patramani S, Alefantinou M, Kaskara A, et al: Sequential administration of the native TERT572 cryptic peptide enhances the immune response initiated by its optimized variant TERT(572Y) in cancer patients. J Immunother 2011, 34:641-650. 

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36. Kotsakis A, Papadimitraki E, Vetsika EK, Aggouraki D, Dermitzaki EK, Hatzidaki D, Kentepozidis N, Mavroudis D, Georgoulias V: A phase II trial evaluating the clinical and immunologic response of HLA-A2(+) non-small cell lung cancer patients vaccinated with an hTERT cryptic peptide. Lung Cancer 2014, 86:59-66. 

37. Gridelli C, Ciuleanu T, Domine M, Szczesna A, Bover I, Cobo M, Kentepozidis N, Zarogoulidis K, Kalofonos C, Kazarnowisz A, et al: Clinical activity of a htert (vx-001) cancer vaccine as post-chemotherapy maintenance immunotherapy in patients with stage IV non-small cell lung cancer: final results of a randomised phase 2 clinical trial. Br J Cancer 2020, 122:1461-1466. 

38. Tong XM, Zheng SE, Bader A, Yao HP, Wu NP, Altmeyer P, Brockmeyer NH, Jin J: Construction of expression vector of hTERT- hIL18 fusion gene and induction of cytotoxic T lymphocyte response against hTERT. Eur J Med Res 2008, 13:7-14. 

39. Mizukoshi E, Nakagawa H, Kitahara M, Yamashita T, Arai K, Sunagozaka H, Fushimi K, Kobayashi E, Kishi H, Muraguchi A, Kaneko S: Immunological features of T cells induced by human telomerase reverse transcriptase-derived peptides in patients with hepatocellular carcinoma. Cancer Lett 2015, 364:98-105. 

40. Brunsvig PF, Guren TK, Nyakas M, Steinfeldt-Reisse CH, Rasch W, Kyte JA, Juul HV, Aamdal S, Gaudernack G, Inderberg EM: Long-Term Outcomes of a Phase I Study With UV1, a Second Generation Telomerase Based Vaccine, in Patients With Advanced Non-Small Cell Lung Cancer. Front Immunol 2020, 11:572172. 

41. Lilleby W, Gaudernack G, Brunsvig PF, Vlatkovic L, Schulz M, Mills K, Hole KH, Inderberg EM: Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer. Cancer Immunol Immunother 2017, 66:891-901. 

42. Aamdal E, Inderberg EM, Ellingsen EB, Rasch W, Brunsvig PF, Aamdal S, Heintz KM, Vodak D, Nakken S, Hovig E, et al: Combining a Universal Telomerase Based Cancer Vaccine With Ipilimumab in Patients With Metastatic Melanoma - Five-Year Follow Up of a Phase I/IIa Trial. Front Immunol 2021, 12:663865. 

 

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