Telomerase-based vaccines: a promising frontier in cancer immunotherapy

Abstract

Telomerase, an enzyme crucial for maintaining telomere length, plays a critical role in cellular immortality and is overexpressed in most cancers. This ubiquitous presence makes telomerase, and specifically its catalytic subunit, human telomerase reverse transcriptase (hTERT), an attractive target for cancer immunotherapy. This review explores the development and application of telomerase-based vaccines, focusing on DNA and peptide-based approaches. While DNA vaccines demonstrate promising immunogenicity, peptide vaccines, such as UV1, UCPVax, and Vx-001, have shown clinical efficacy in certain cancer types. Recent advancements in vaccine design, including multiple peptides and adjuvants, have enhanced immune responses. However, challenges remain in achieving consistent and durable anti-tumor immunity. Accordingly, we discuss the mechanisms of action, preclinical and clinical data, and the potential of these vaccines to elicit robust and durable anti-tumor immune responses. This review highlights the potential of telomerase-based vaccines as a promising strategy for cancer treatment and identifies areas for future research.

Introduction

Telomeres are a sequence of nucleotides at the ends of chromosomes that protects the chromosomal ends from damage. However, the telomeres become shorter with each cell division, leading to chromosomal instability and a limited number of cell divisions before the cell becomes senescent or undergoes apoptosis [1]. Telomerase can be activated in certain cell types, increasing their proliferation. In most somatic cells, telomerase is only active in rapidly dividing tissues like the intestine, endometrium, testes, and lymphocytes [2, 3]. Telomerase is expressed in both embryonic and adult stem cells, playing a crucial role in their proliferation. Embryonic stem cells exhibit higher telomerase activity compared to adult stem cells, which can upregulate this activity when needed. Notably, there are significant differences in telomere length and telomerase activity between these two types. Embryonic stem cells maintain their telomeres effectively, displaying robust telomerase activity, whereas adult stem cells experience progressive telomere shortening and demonstrate minimal telomerase activity. This distinction underscores the importance of telomerase in the self-renewal and longevity of stem cells [2, 4, 5].

The human telomerase reverse transcriptase (hTERT) protein is a critical component of the telomerase complex, functioning as its catalytic subunit. Telomerase activity (TA), which includes both hTERT and the telomerase RNA component (TERC), is essential for maintaining telomeres and promoting cellular immortality [6]. While hTERT contributes to preventing apoptosis, it also reduces sensitivity to apoptotic signals, reflecting both canonical and non-canonical functions of the protein [7, 8]. Overexpression of hTERT is found in 80–90% of cancer cells, which can trigger an immune response targeting hTERT, enabling the immune system to recognize and destroy tumor cells [9]. his makes hTERT an attractive target for cancer immunotherapy, as it is considered a near-universal tumor antigen [10]. Specific components of the telomerase complex, including hTERT, are utilized as tumor-specific antigens in cancer vaccines [11]. Various clinical strategies have been explored, including the use of MHC class I or II-restricted hTERT peptides, autologous antigen-presenting cells loaded with hTERT peptides, or cells transduced with stabilized hTERT mRNA for transient antigen expression. These approaches aim to harness the immune system’s ability to eliminate cancer cells expressing hTERT, while vaccinations based on universal cancer peptides (UCPs) hold potential for stimulating immune responses against tumors across different cancer types [12].

This review aims to provide a comprehensive overview of the development and clinical progress of telomerase-targeted DNA and peptide vaccines for cancer immunotherapy. We will analyze the immunological mechanisms underlying their efficacy, evaluate preclinical and clinical trial data, and discuss this promising therapeutic approach’s challenges and future directions. To ensure a comprehensive review of the literature on telomerase-based vaccines, we implemented a systematic search strategy. We utilized multiple databases, including PubMed, Scopus, and Web of Science, to identify relevant studies published up to October 2023. Our search terms included “telomerase,” “hTERT,” “cancer immunotherapy,” “DNA vaccines,” and “peptide vaccines.” We applied filters for peer-reviewed articles and clinical trials to focus on high-quality evidence. The initial search yielded over 300 articles, which we then screened based on relevance, study design, and publication date. After applying inclusion and exclusion criteria, we selected 108 references that provided a comprehensive overview of the current state of research on telomerase-based vaccines. This methodical approach ensured that our review reflects the latest advancements and challenges in the field.

Telomerase based vaccines

DNA vaccines

DNA vaccines offer significant advantages, including the flexibility to easily incorporate multiple genes encoding full-length or partial tumor antigens and molecules that stimulate the immune system. Various enhancements have been explored to improve the effectiveness of DNA vaccines, such as utilizing powerful viral promoters, optimizing the codon sequence of the genes, adding immunoglobulin sequences, and increasing the number of CpG motifs in the plasmid backbone [13–15]. These modifications are aimed at improving the immune response and the overall performance of DNA-based vaccination approaches. In addition to the advantages mentioned earlier, DNA vaccines have other favorable characteristics - they are safe, stable, and relatively easy to manufacture [16, 17]. Despite these positive attributes, early DNA vaccination studies found that the immune responses generated were generally quite weak, especially when the target antigens were self-proteins. Nonetheless, considerable advancements have been achieved in recent years. Advancements in electroporation techniques, such as using a specific sequence of high-voltage and low-voltage electrical pulses, have dramatically improved the effectiveness of DNA vaccination. As a result, numerous ongoing clinical trials are now evaluating the use of DNA vaccines for cancer immunotherapy and against infectious diseases [17–19].

TERT is a tumor-associated antigen that is highly expressed in cancer cells across mammalian species, including canine tumors, making it a promising target for cancer immunotherapy. In this context, a human telomerase DNA construct has been developed for clinical trials, while a canine-specific telomerase DNA vaccine, pDUV5, has been designed to target cTERT. When administered intradermally to mice, pDUV5 induced cTERT-specific cytotoxic T-cells, generating strong, broad, and long-lasting immune responses. Additionally, in vitro immunization with cTERT peptides demonstrated the maintenance of cTERT-specific T-cells in tumor-bearing dogs, highlighting the potential of pDUV5 as a cancer vaccine [20].

Moreover, hTERT is a highly promising target recognized by T-cells, making it a potentially valuable target for broad cancer immunotherapy or protection against tumor recurrence [21]. Researchers have designed and tested a synthetic, highly optimized full-length hTERT DNA vaccine (phTERT) in both mouse and non-human primate models [22]. The immunity induced by this vaccine was found to be robust, eliciting broad hTERT-specific CD8 + T-cell responses. In the non-human primate study, the phTERT vaccine was able to break immune tolerance and induce potent cytotoxic responses [23]. Furthermore, in an HPV16-associated tumor model, vaccination with phTERT slowed tumor growth and improved survival rates. In vivo cytotoxicity tests demonstrated that the phTERT-stimulated CD8 + T-cells displayed specific activity as cytotoxic T lymphocytes [24]. As well as BALB/c mice immunized with plasmids encoding optimized rat TERT generated a strong cellular and humoral immune response targeting specific epitopes within the N-terminus and reverse transcriptase domain of the TERT protein [25]. The TERT-specific immune response in the immunized mice was linked to significant tumor formation and metastasis inhibition by inhibiting Interferon-gamma (IFN-γ) / Interleukin (IL-2) / Tumor necrosis factor-alpha (TNF-α) producing CD8 + and CD4 + T-cells. These results indicate that TERT-DNA vaccine-based immunotherapies hold considerable promise as a versatile candidate for therapeutic cancer vaccines [26, 27].

A DNA vaccine consisting of hepatitis C virus (HCV) and TERT core proteins was created to target both HCV-infected and malignant T-cells. This vaccine showed strong immunogenicity in BALB/c mice, stimulating a robust T-cellular immune response characterized by the production of IFN-γ, IL-2, and TNF-α [25]. Additionally, it enhanced the immune response against luciferase, which was delivered alongside the vaccine as a co-encoded plasmid (Luc DNA). However, when the HCV core aa 1-152 (Core152opt) was combined with TERT during the DNA immunization process, the immune response to both elements was entirely inhibited. The findings revealed that the suppression of immune response depended on the presence of full-length or nearly full-length TERT, rather than its enzymatic activity [20, 25].

Another study utilized the chemokine ligand 21 (CCL21) as an adjuvant, alongside a xenogeneic TERT DNA vaccine, to trigger an immune response against breast cancer cells that express TERT [28]. The finding was that administering CCL21 before the cTERT DNA vaccine significantly enhanced the development of TERT-specific cell-mediated immunity. This demonstrated the effectiveness of this approach in both preventive (prophylactic) and treatment regimens for TERT-expressing breast cancer.

An optimized DNA plasmid known as INVAC-1 encodes an inactivated form of the hTERT protein, which lacks functional telomerase activity, positioning it as a potentially effective candidate for cancer immunotherapy. This approach aims to stimulate cellular immune responses against tumor cells that express hTERT. When administered intradermally, INVAC-1 was found to elicit broad hTERT-specific immune responses in mouse models [29]. This involved the production of a large quantity of CD4 + T helper 1 (Th1) effector cells as well as memory CD8 + cytotoxic T-cells. In a preclinical mouse model of an aggressive, spontaneous HLA-A2 + sarcoma, therapeutic immunization with INVAC-1 was able to slow tumor growth and improve survival rates [30]. In addition, INVAC-1 induced both CD8 + and CD4 + T-cell responses and reduced the number of circulating regulatory T-cells. Thus, INVAC-1 has the potential for further development as a vaccine adjuvant or therapeutic agent. By modulating the immune response in this way, INVAC-1 may increase the infiltration of immune cells into solid tumor metastases, serving as an effective cancer immunotherapy candidate to enhance the efficacy of cancer treatments [29].

Telomerase-based DNA vaccines show significant promise as a cancer immunotherapy approach. While early DNA vaccines faced challenges, advancements have led to the development of effective TERT-targeted vaccines. These vaccines have demonstrated the ability to induce strong immune responses, including cytotoxic T-cells, in animal models [31]. Additionally, Combination therapies with adjuvants and inactivated TERT protein, which requires the telomerase RNA component (TERC) for enzymatic activity, have shown potential for enhancing vaccine efficacy. Overall, TERT-based DNA vaccines represent a promising avenue for cancer treatment and prevention (Fig. 1).

Fig. 1.

Overview of TERT-based DNA vaccine development and its potential as a cancer immunotherapy. The figure illustrates the evolution of TERT-based DNA vaccines, highlighting key advancements, including the incorporation of adjuvants and inactivated TERT proteins to enhance immune responses. One significant approach involves using the CCL21 adjuvant with the pDUV5 DNA vaccine in an electro-gene-transfer method. This combination is designed to enhance the immune response by inducing cytotoxic T-cells. Furthermore, the TERT antigen is combined with the HCV core protein. Although the HCV core protein is associated with liver cancer, it is leveraged for its immunogenic properties to stimulate robust immune responses. Additionally, phTERT and INVAC-1 illustrate their roles in promoting CD8 + T-cell activation and improving survival rates

Peptide vaccines

UV1

UV1 is a promising second-generation telomerase-targeting vaccine currently under investigation for treating various cancers. The vaccine contains three carefully selected peptides derived from a critical region of the telomerase enzyme, which is essential for cancer cell growth in melanoma, prostate, and non-small cell lung cancer (NSCLC) [32–34]. It stimulates a strong and persistent immune response against cancer cells. Previous studies indicate that this specific type of immune response, which is characterized by CD4 + Th1 cells, is associated with improved overall survival in cancer patients [35, 36]. Early phase I trials have demonstrated that the UV1 vaccine is safe and well-tolerated, with manageable side effects [37]. These trials have shown that the vaccine induces a robust immune response, particularly the activation of effector CD4 + T-cells, which are crucial for anti-tumor activity [32]. To further understand the effects of therapeutic cancer vaccines like UV1, researchers developed a mechanistic predictive model based on data from these phase I clinical trials across different cancer types. The comprehensive model consisted of a mechanistic framework for tumor growth dynamics, assessed the likelihood of a UV1-specific immune response, and utilized a time-to-event analysis to estimate overall survival outcomes. The model’s predictions suggested that the UV1 vaccine induces effector CD4 + T-cells that can lead to tumor shrinkage with distinct half-lives in NSCLC and melanoma. Additionally, the model indicated that providing additional maintenance doses of the vaccine may help sustain the reduction in tumor size over time. Overall, this predictive model captures the complex interplay between the tumor, immune system, and patient outcomes in the context of the UV1 cancer vaccine in early-stage clinical trials across multiple cancer indications [38]. Advances in melanoma vaccine research have led to using longer peptides, known as synthetic long peptides (SLPs), which are preferred over shorter peptides. SLPs can induce CD4 and CD8 + T-cell responses in a manner that is not restricted by HLA type. While bioinformatics tools can be used to identify potential peptide candidates, in-vitro validation is still necessary. Specifically, three peptides - one 30-amino acid peptide and two 15-amino acid peptides - have been identified for the UV1 melanoma vaccine, and evaluated in clinical trials [39].

UCPVax

The universal cancer peptide-based vaccine (UCPVax) is an experimental therapeutic cancer vaccine that holds promise for the treatment of cancers. The vaccine is composed of two distinct peptides, UCP2 and UCP4, derived from the TERT/telomerase protein. The mechanism of action for UCPVax involves stimulating a specific type of immune cell, the CD4 + Th1 cell. These helper T-cells play a crucial role in orchestrating a broader immune response, recruiting and activating other powerful immune cells to attack tumor cells [26, 40]. Early clinical studies have yielded encouraging results, suggesting that UCPVax is safe, well-tolerated, and capable of eliciting an immune response in NSCLC patients [41]. These findings make UCPVax a valuable candidate for further investigation, particularly in combination with other cancer treatment modalities. The potential of UCPVax to harness the body’s immune defenses against cancer cells represents an exciting avenue of cancer immunotherapy research. As researchers continue to explore the vaccine’s efficacy and optimal integration with existing therapies, UCPVax may emerge as a promising new tool in the fight against malignancies [40, 42, 43].

Vx-001

Vx-001, a new vaccine targeting a common cancer protein; TERT, which is non-toxic and highly immunogenic, is linked to extended survival in tumors and could be effective. It triggered a strong immune response in some patients, especially those with existing immunity to TERT [44]. However, a large-scale clinical trial didn’t show a clear survival advantage for lung cancer patients receiving Vx-001 compared to a placebo. Encouragingly, patients who developed a specific immune response after vaccination lived longer and had better treatment outcomes [44, 45]. This benefit was even stronger in a group with specific blood marker such as tumor-infiltrating lymphocytes (TILs) and PD-L1 expression levels, potentially helping to identify who might respond best to Vx-001 [44, 45]. While the overall results are unclear, Vx-001 could be effective for certain patient groups. More research is needed to pinpoint these groups and design focused studies to confirm the vaccine’s benefit for these patients [46, 47]. The Vx-001 vaccine has demonstrated promise for cancer immunotherapy by triggering a TERT-specific T-cell immune response linked to extended survival. Therefore, Vx-001 appears to be a hopeful option for cancer immunotherapy [48].

GX301

GX301 is a novel vaccine in development for men with advanced prostate cancer (metastatic castration-resistant prostate cancer, mCRPC) and also higher-stage renal cancer [49]. Early studies suggest promise, with the vaccine demonstrating safety and the ability to activate the immune system against cancer cells. Researchers are currently conducting further studies to determine the most effective dosing schedule and long-term impact of GX301 on mCRPC treatment [50]. The GX301 cancer vaccine uses four peptides (540–548, 611–626, 672–686, and 766–780) derived from telomeras. While each peptide can trigger an immune response, the researchers weren’t sure if using all four together was the best approach. To investigate, they studied immune system reactions in healthy individuals after exposure to each peptide alone and all four combined. The results showed that each peptide could trigger a response in some people, but the specific individuals varied between peptides. Importantly, the overall number of responders was higher when all four peptides were used compared to single peptides or a mixture. This suggests that each peptide contributes to the immune response, and using multiple peptides is better than just one. However, combining all four peptides into a single mixture might not be ideal, as it could interfere with how the immune system recognizes the individual peptides [1, 49, 51].

GV1001

GV1001, a 16-amino acid telomerase peptide vaccine derived from hTERT involved in cell replication also functions as a cell-penetrating peptide (CPP). This means it can facilitate the delivery of large biomolecules, such as proteins, DNA, and small interfering RNA (siRNA), into cells. The protein GV1001 was observed to be primarily located within the cytoplasm, or fluid-filled region, of cells. In contrast, a higher proportion of the trans-activator of transcription (TAT) peptide which is derived from the HIV-1 protein was found in the nucleus. GV1001 has a promising potential as a delivery vehicle, transporting large macromolecules into cells. Furthermore, Heat Shock Protein 90 and Heat Shock Protein 70 as critical interacting partners of GV1001, indicate that this interaction is crucial for enabling the efficienT-cellular internalization and uptake of GV1001 and any cargo it may be carrying [52]. This therapy also resulted in decreased cancer cell growth and VEGF production. These findings indicate that GV1001 has the potential to be a treatment, as it can stimulate anti-cancer immune responses by suppressing both HSP70 and HSP90 [53]. In a mouse xenograft model, GV1001 exhibited a tumor-inhibiting effect, causing more cell death through apoptosis, reduced cell growth, and fewer blood vessels in the treated tumors [54]. Notably, GV1001 is a telomerase-specific vaccine currently undergoing advanced clinical development for various cancer treatments, highlighting its potential to target multiple diseases [55].

Additionally, GV1001 is a novel ligand that interacts with the gonadotropin-releasing hormone receptor (GnRHR) [56]. It stimulates the Gas-coupled cAMP signaling pathway and inhibits the G protein Gaq-coupled Ca2 + release pathway activated by leuprolide acetate (LA). It also inhibits tumor growth in LNCaP and other prostate cancer cells by suppressing the levels of matrix metalloproteinase 2 and 9 mRNAs, as well as inhibiting cell proliferation and migration [57] (Fig. 2). Meanwhile, GV1001 is effective at suppressing the proliferation of prostate cells, including both stromal myofibroblasts and epithelial cells, when treated with dihydrotestosterone. Furthermore, GV1001 was observed to bind to the androgen receptors present in the cytoplasm of these prostate cells. In an animal model experiment, GV1001 was shown to reduce prostate hypertrophy. In addition, GV1001 prevented prostate fibrosis by decreasing the level of proteins associated with epithelial-mesenchymal transition (EMT) in the prostate, while increasing the levels of the cell-cell adhesion protein E-cadherin [58].

Fig. 2.

The representation of the multifunctional peptide GV1001 and its potential mechanisms of action. HSP70 and HSP90: Heat shock proteins, GnRHR: Gonadotropin-releasing hormone receptor, cAMP: Cyclic adenosine monophosphate, Ca2+: Calcium ions, HIF1-α: Hypoxia-inducible factor 1-alpha, MMP-2 and MMP9: Matrix metalloproteinases

GV1001 blocks multiple processes crucial for tumor growth. It hinders blood vessel formation triggered by lung and pancreatic cancer cells and directly stops these cancer cells from multiplying and spreading [59].

The effectiveness of the GV1001 vaccine in NSCLC found that patients with high levels of regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) had a cytokine profile indicative of a strong immune response, with high ratios of IFN-gamma to IL-4 and IFN-gamma to IL-10 [60]. Regardless, Tregs and MDSCs are generally associated with an immunosuppressive, tolerogenic cytokine environment linked to impaired clinical efficacy of cancer vaccine responses.

Schlapbach et al. explored the potential of the GV1001 vaccine in treating cutaneous T-cell lymphoma (CTCL) and unfortunately revealed that the vaccine was ineffective and failed to demonstrate any objective clinical response such as tumor size reduction or complete remission. Furthermore, among the six patients treated in the trial, one experienced disease progression. While one patient did develop a GV1001-specific T-cell response characterized by a Th1 cytokine profile and skin-homing receptor expression, this immune response did not lead to beneficial changes in tumor-infiltrating leukocytes. These findings suggest that the GV1001 vaccine, as administered in this trial, may not be a viable treatment option for CTCL [61].

PNDV

Guo et al. initially reported the strategy of co-locating a low-affinity epitope variant together with the hTERT gene for the design of a novel virus-like particulate peptide-nucleotide dual vaccine (PNDV). PNDV, which consists of a low-affinity epitope variant coupled with the full-length hTERT gene, has been verified for its ability to induce an immune response and its capacity for transfection into mammalian cells [62]. In vivo experiments involving the immunization of HLA-A2.1 transgenic mice generated robust IFN-gamma secretion and the induction of hTERT-specific cytotoxic T lymphocytes (CTLs). Importantly, these hTERT-specific CTLs were able to selectively cause cell death in telomerase-positive gastrointestinal cancer cells [62].

A study involving fourteen hepatocellular carcinoma (HCC) patients investigated the safety and immunogenicity of an hTERT-derived peptide called hTERT461 as a vaccine. The peptide was administered three times biweekly via subcutaneous injection and induced hTERT-specific immunity. Moreover, 57% of 14 patients administered with hTERT461 peptide-specific T-cells were able to prevent HCC recurrence after vaccination. The vaccination led to an increase in hTERT-specific T-cells with the effector memory phenotype, capable of producing multiple cytokines. Moreover, seven hTERT-specific T-cell receptors isolated from vaccinated patients demonstrated cytotoxic activity against cells presenting hTERT-derived peptides [63].

Telomerase-targeting peptide vaccines represent a promising avenue for cancer immunotherapy. While challenges remain in optimizing their efficacy, particularly in overcoming tumor-mediated immunosuppression, these vaccines demonstrate the potential to induce targeted anti-tumor immunity. Further research is crucial to identify optimal vaccine formulations, combination strategies, and predictive biomarkers for patient selection to translate these promising findings into effective clinical therapies.

Protein/recombinant vaccines

Protein and recombinant vaccines represent a significant advancement in immunization technology. These vaccines utilize purified proteins or genetically engineered components derived from pathogens to stimulate an immune response without using the live virus or bacteria [64, 65]. Recombinant vaccines are created by inserting the DNA encoding a pathogen’s protein into yeast, bacteria, or other cells. This process allows for the mass production of the target protein, which can then be purified and used in the vaccine formulation [66]. The primary advantages of protein and recombinant vaccines include safety, as they do not contain live pathogens, which reduces the risk of disease; specificity, since they can be designed to target specific components of a pathogen, thereby enhancing the immune response; and stability, with many recombinant vaccines being more stable and easier to store than traditional vaccines [66, 67]. Protein and recombinant vaccines are emerging as innovative strategies in cancer immunotherapy, leveraging the body’s immune system to target and eliminate cancer cells. These vaccines work by introducing specific tumor-associated antigens or tumor-specific antigens into the body, prompting an immune response that can recognize and destroy cancer cells [68]. Moreover, ongoing research is focusing on personalized cancer vaccines that target neoantigens, specific mutations found in individual tumors, demonstrating improved efficacy in clinical trials [67]. These innovations underscore the growing importance of protein and recombinant vaccines in the fight against cancer, offering new avenues for prevention and treatment.

In the field of cancer immunotherapy, recombinant adenoviruses have emerged as promising vectors for delivering therapeutic genes [69]. These viruses are modified to be non-pathogenic and can effectively deliver genetic material to target cells, thereby enhancing immune responses. It has been observed that most cytotoxic T lymphocytes (CTLs) target antigens derived from the telomerase enzyme, a marker often overexpressed in cancer cells [1]. Dendritic cells that have been reconstituted with the human telomerase gene have been found to induce strong cytotoxic T-cell responses in cancer patients. This indicates that the hTERT gene could be effectively utilized as a vaccine, especially when delivered through recombinant adenoviruses, to stimulate specific T-cell-mediated immune responses against tumor cell [70].

A recombinant lentiviral vector carrying the hTERT gene (lv-hTERT) was evaluated as a vaccine in mice expressing the HLA-B*0702 human leukocyte antigen. The lv-hTERT vaccine was found to induce potent and widespread HLA-B7-restricted cytotoxic T lymphocyte (CTL) responses targeting hTERT. This resulted in high and sustained production of the immune signaling molecule interferon-gamma by CD8 + T-cells. The application of a prime-boost vaccination strategy further amplifies the potency of CD8 + T-cell responses, suggesting that lentiviral delivery of the hTERT antigen could be a valuable method for enhancing immune responses in the context of cancer immunotherapy [71].

Clinical trials of different hTERT vaccines: efficacy and safety in cancer immunotherapy

As mentioned during this review, telomerase, an enzyme crucial for cellular replication, is often overexpressed in cancer cells. This characteristic has prompted the development of telomerase-based vaccines as a potential immunotherapy for various cancers. This section presents a comprehensive overview of clinical trials investigating the efficacy and safety of these vaccines in treating various cancers, including pancreatic, hepatocellular, lung, and prostate cancers. While telomerase-based vaccines offer the potential to target a cancer-specific antigen, challenges in vaccine design and delivery remain. The following sections will explore the clinical evidence supporting this therapeutic strategy, examining different vaccination approaches, combination therapies, and patient outcomes (Table 1).

Table 1.

Overview of clinical trials assessing the effectiveness and safety of telomerase-based vaccines across different cancer types

Cancer type	Intervention	Outcome	Ref
Pancreatic	Chemotherapy + Telomerase Vaccination (sequential or concurrent)	No improvement in overall survival	[72]
Hepatocellular Carcinoma	Anti-PD-1/PD-L1 + UCPVax vaccine	Evaluating clinical and immunological efficacy	[73]
HPV + Cancers	Anti-PD-1/PD-L1 + UCPVax vaccine	Evaluating safety and effectiveness	[74]
Non-Small Cell Lung Cancer	UCPVax vaccine (3-dose)	Safe, triggered immune response, improved survival	[41, 44]
	Vx-001 vaccine	Triggered immune response, no significant improvement in overall survival
Pleural Mesothelioma	Standard treatment + UV1 vaccine	No significant difference in progression-free survival, trend favoring the vaccine group	[75]
Melanoma	UV1 vaccine + Pembrolizumab	Safe, well-tolerated, positive outcomes, immune system stimulation	[32, 37, 76]
	UV1 vaccine + Ipilimumab	Immune response
	UV1 vaccine + GM-CSF + Ipilimumab	Improved survival rates, enhanced Th1 cell response
Prostate	UV1 vaccine + Standard treatment	Immune response in some patients, the potential benefit for some	[77, 78]
	GX301 vaccine	Safe, immune response increased with dose, no impact on overall survival
	V935 (adenoviral) + V934 (DNA plasmid)	Safe, increased immune response
Breast/Prostate	HLA-A2-restricted hTERT I540 peptide	Induced hTERT-specific T lymphocytes, partial tumor regression	[81]
Colorectal	GV1001 vaccine + Chemotherapy	Evaluating efficacy and safety, no significant immune response	[79]
Renal Cell Carcinoma	mRNA-based vaccine	Immune response associated with longer survival, long-term safety and efficacy	[82, 83]

The TeloVac trial assessed the effectiveness and safety of telomerase vaccination (GV1001) administered sequentially or concurrently with chemotherapy in patients with advanced pancreatic cancer. A total of 1,110 patients were enrolled and divided into three groups: 358 received chemotherapy alone, 350 received sequential telomerase vaccination alongside chemotherapy, and 354 received concurrent telomerase vaccination with chemotherapy. The results indicated that the addition of telomerase vaccination did not improve overall survival compared to chemotherapy alone [72].

In a recent study, researchers explored a novel approach to treating unresectable HCC. They investigated the potential of combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine (CD4 + Th1-inducer cancer vaccine derived from telomerase), UCPVax. The TERTIO study, a multi-center randomized phase II trial, aimed to evaluate this combination therapy’s clinical and immunological efficacy. A total of 105 eligible participants were enrolled, including patients with locally advanced, metastatic, or unresectable HCC who had not undergone any previous systemic anti-cancer therapy. The primary endpoint of the study was the objective response rate at 6 months. Patients were randomly assigned in a 2:1 ratio to receive either the combination of atezolizumab, bevacizumab, and UCPVax, or atezolizumab and bevacizumab alone. The researchers hypothesized that the addition of the anti-telomerase vaccine could enhance the efficacy of the anti-PD-1/PD-L1 therapy by activating tumor-specific T-cell immunity and overcoming the immunosuppressive tumor microenvironment in HCC [73].

While drugs blocking programmed cell death protein/programmed cell death ligand 1 (PD-1/PD-L1) proteins show promise in treating human papillomavirus (HPV)-caused cancers, they often don’t lead to significant tumor shrinkage alone. Researchers combined these drugs with anti-tumor vaccines like UCPVax. The VolATIL study tested this combination in patients with HPV + cancers. It involves giving patients the anti-PD-L1 drug atezolizumab every 3 weeks along with UCPVax vaccine injections [74]. They aimed to test the safety and effectiveness of combining UCPVax and anti-PD-L1 therapy for treating HPV + cancers. The vaccines train the immune system to recognize and attack cancer cells, particularly in patients with tumors that may not elicit a strong immune response due to immune evasion mechanisms. This combination therapy represents an important advancement in the development of innovative strategies for HPV + cancer management.

Another study investigated a three-dose schedule of UCPVax for patients with advanced non-small cell lung cancer who had already received multiple prior treatments. The main goals were to explore if the vaccine was safe and caused an immune response. The researchers also evaluated how long patients lived overall and how long their cancer didn’t progress. The results were promising: the vaccine seemed to be safe and triggered an immune response in most patients. Interestingly, patients experienced a relatively long survival period after receiving the vaccine, despite having previously undergone treatment. This suggests that the vaccine may have contributed positively to their overall prognosis [41].

A clinical trial called NIPU (Nivolumab and Ipilimumab +/- UV1 Vaccination as Second Line Treatment in Patients with Malignant Mesothelioma) aimed to investigate the effectiveness of adding UV1 telomerase vaccine to standard treatment for pleural mesothelioma (PM). The trial involved 118 patients divided into two groups: one received standard treatment alone and the other received the vaccine and treatment. The main goal was to determine if the vaccine improved progression-free survival (PFS). The results indicated no notable difference in PFS between the two groups. However, doctors observed a trend favoring the vaccine group, and predefined analyses of response rates suggest that adding the vaccine might be beneficial [75].

Early trials involving patients with advanced melanoma have shown that the UV1 vaccine, combined with the drug pembrolizumab, is safe and well-tolerated [76]. Side effects were manageable, with no severe issues reported. Patients who received this combination of treatments experienced positive outcomes, including a significant duration of disease stabilization and improved overall survival. The vaccine also appears to stimulate the immune system to fight cancer cells, and this effect is being further studied. Larger clinical trials are underway to confirm these initial findings [76]. The investigation involving the UV1 vaccine in combination with ipilimumab for patients with melanoma indicated that, on average, it took about 4 weeks for patients to show their first immune response [37]. Furthermore, combining a UV1 vaccine along with a helper molecule (GM-CSF) and ipilimumab in metastatic melanoma significantly improved survival rates. Additionally, it suggested the vaccine and ipilimumab worked well together by boosting a specific type of immune cells (Th1 cells). This combined approach might be a better treatment for advanced melanoma [32].

The UV1 vaccine was investigated to target hTERT for men with advanced prostate cancer [77]. The study included 22 men who received standard treatment (hormone therapy and radiation) along with the UV1 vaccine. The researchers monitored the immune system’s response to the vaccine over time. Interestingly, some patients showed a strong immune response later on, even though their cancer hadn’t returned. The observation that immune responses and cancer presence appear to be independent in some patients raises important considerations for the development and application of anti-TERT vaccines. According to Lilleby et al., a subset of patients treated with the hTERT peptide vaccine exhibited sustained immune responses even during long-term clinical follow-up, regardless of whether their cancer had clinically progressed or remained in remission [77]. This suggests that the vaccine-induced immune response may selectively target hTERT-expressing cells, which include not only cancer cells but potentially other normal cells such as stem cells, lymphocytes, endothelial cells, and germ cells [31]. This suggests that UV1 might have a specific benefit for some men with advanced prostate cancer who are undergoing standard treatment. They followed the men for over five years, with nine still alive at the last check-up. While more research is needed, these results are promising for the potential use of UV1 in treating this type of prostate cancer [77]. For an anti-TERT vaccine to be clinically viable, it must balance specificity and safety, ensuring robust targeting of tumor cells while minimizing potential damage to essential hTERT-expressing normal cells [1]. There is a need for future research to determine whether the immune responses observed in patients are specifically due to the selective targeting of tumor-associated hTERT, or if there is a wider, though possibly subclinical, impact on normal tissues. These findings will significantly influence the design, dosing, and safety evaluation of future hTERT-based immunotherapies.

In a pilot phase I study, researchers evaluated the safety and feasibility of a prime-boost immunization regimen based on V935, an adenoviral type 6 vector vaccine expressing a modified version of the hTERT gene. This modification was implemented to enhance immune recognition and response. The study analyzed the vaccine’s effects in patients with solid tumors, particularly those with prostate cancer, either administered independently or in combination with V934, a DNA plasmid encoding the full-length hTERT gene. The results indicated that the various vaccination regimens exhibited a robust and comparable safety profile across all treatment groups, with no severe adverse events, dose-limiting toxicities, or treatment discontinuations reported. Furthermore, a significant increase in ELISPOT (Enzyme-Linked ImmunoSpot) responses—an assay measuring antigen-specific T-cell activity—was observed against the hTERT peptide pool 2, indicating a heightened immune response in prostate cancer patients following immunization [78].

A phase II clinical trial was conducted to assess the efficacy and safety of the investigational drug GV1001 when administered in combination with chemotherapy for individuals with advanced colorectal cancer. The primary endpoint was to evaluate the disease control rate, defined as the proportion of patients experiencing stable disease or tumor reduction. Secondary objectives included examining the treatment regimen’s response rates, determined through imaging studies per RECIST criteria (response evaluation criteria in solid tumors), progression-free survival, overall survival, and safety. The study also explored baseline serum eotaxin levels, a chemokine associated with immune response, to better understand its relationship with treatment outcomes. The most frequently reported adverse events were neutropenia, nausea, neuropathy, stomatitis, and diarrhea. Furthermore, the immune response analysis indicated no positive delayed-type hypersensitivity test results, suggesting limited immune recognition, with only a small fraction of patients demonstrating antigen-specific T-cell proliferation. Notably, the findings revealed that the baseline eotaxin level did not correlate with efficacy outcomes [79].

Researchers conducted a phase I clinical trial to examine the safety and immune system impact of a new cancer vaccine called GX301, which targets telomerase. The trial involved 98 men with advanced prostate cancer who received two, four, or eight doses of the vaccine, with overall assessments of immune responses conducted at 90 and 180 days from baseline [80]. The researchers noted no serious side effects from the vaccine and found that more than 50% of patients developed an immune response to the cancer cells. The response rate increased with the number of vaccine doses, indicating that higher dose schedules could be more effective than the lowest dose. While overall survival was not influenced by the number of vaccine doses or immune response, the study did identify a connection between higher levels of a specific immune cell type (circulating CD8 + T regulatory cells) at six months and poorer survival outcomes. In conclusion, the research suggests that future studies of the GX301 vaccine should concentrate on high-dose regimens to maximize the immune system’s response against cancer [80].

A vaccine called Vx-001 which targeted TERT and induced specific CD8 + cytotoxic T-cells in a large study with nearly 200 patients who had advanced NSCLC was investigated. The goal was to determine if the vaccine could help patients live longer. The vaccine triggered a specific CD8 + immune response, and some patients who developed this response did live longer. However, overall, the vaccine did not significantly improve survival compared to a control group consisting of patients who received a placebo instead of the vaccine. The researchers are now looking for ways to identify patients who might benefit most from this vaccine [44].

A Phase I clinical trial tested a vaccine with the HLA-A2-restricted hTERT I540 peptide in advanced cancer patients. Results showed that the vaccine-induced hTERT-specific T lymphocytes in 4 out of 7 patients with advanced breast or prostate cancer. These T-cells could kill tumor cells and one patient showed partial tumor regression. No significant toxicity was observed. These findings support using hTERT as a target for cancer immunotherapy [81].

A clinical trial conducted between 2003 and 2005 evaluated an experimental mRNA-based vaccine in metastatic renal cell carcinoma (RCC). Patients who received the mRNA-based vaccine for renal cell carcinoma exhibited significantly longer survival rates compared to those without detectable immune responses, with a median survival of 24.5 months for all patients, and up to 89 months for those with favorable risk, while no patient without an immune response survived beyond 33 months. The results indicate that mRNA-based immunotherapy can stimulate both CD4 + and CD8 + T-cells, contributing to durable clinical responses in some patients [82, 83].

Combination therapy

Scientists tested two ways to deliver a vaccine targeting hTERT and both methods successfully induced a long-lasting immune response against hTERT in monkeys, with no negative side effects. To make the vaccine even more effective, they added an immune booster (IMO) alongside the vaccine and a novel Toll-like receptor 9 (TLR9) agonist. This combination increased the activity of immune cells and created specific targets for antibodies to attack. Importantly, it did not weaken the vaccine’s ability to prime T-cells to fight cancer. These results suggest that combining this vaccine with IMO is a promising approach to strengthen the body’s natural defenses against cancer [84]. The effects of a synthetic consensus TERT DNA vaccine, which targets the hTERT protein frequently overexpressed in cancer cells, were evaluated alongside immune checkpoint inhibitors. Blocking the CTLA-4 or PD-1 checkpoint pathways had a synergistic effect when combined with the TERT vaccine, leading to a more robust anti-tumor activity. However, surprisingly, neither the TERT vaccine alone nor the combination therapies were able to improve the overall TERT antigen-specific immune responses in tumor-bearing mice. Interestingly, the researchers observed that CTLA-4 blockade had a greater synergistic effect with the TERT DNA vaccine compared to depletion of regulatory T-cells (Tregs). This suggests that the immune checkpoint inhibitors function primarily by altering the broader immune regulatory environment to enhance the efficacy of the DNA vaccine, rather than directly boosting the antigen-specific immune responses generated at the vaccination site [85–87].

New drugs, such as atezolizumab, are promising in fighting HCC by blocking the PD-L1 protein, allowing immune system T-cells to recognize and kill cancer cells. When combined with bevacizumab, it shrinks tumors and has been approved for first-line treatment [88, 89]. However, other combinations can cause side effects in patients with other health conditions. Anti-PD-1/PD-L1 treatments could be more effective if they boost Th1 lymphocytes targeting tumors. Researchers are testing a vaccine to help Th1 cells recognize tumors alongside atezolizumab treatment and combining anti-PD-1/PD-L1 therapy with a vaccine targeting telomerase for improved treatment outcomes [90, 91].

Recent research assessed the efficacy of using both temozolomide and a telomerase peptide vaccine in treating advanced stage IV melanoma. The findings showed that the treatment was well tolerated and led to a significant immune response in approximately 80% of the participants. Patients who developed long-term T-cell memory exhibited improved survival rates. Clinical responses, such as partial tumor regression and stable disease, were observed to emerge gradually over several years, which differed from the expected response to chemotherapy. Consequently, combining cancer vaccination with chemotherapy demonstrates a substantial immunological response rate with minimal toxicity [92].

UV1 was investigated in combination with the immunotherapy drug ipilimumab in patients with advanced melanoma. It was found that the vaccine was able to stimulate an immune response in most of the evaluable patients. Tumor samples confirmed the presence of the target protein telomerase, and the vaccine was associated with increased numbers of specific T-cell clones in the blood and tumor samples. The clinical responses were observed regardless of established biomarkers for checkpoint inhibitor efficacy, suggesting an added benefit from the vaccine-induced T-cells [93]. Furthermore, it suggests that UV1 vaccination may be particularly effective when used in combination with other immunotherapy drugs, such as pembrolizumab, and has the potential to enhance treatment outcomes for patients with advanced cancers [94, 95].

GV1001 along with cytotoxic chemotherapy revealed encouraging rates of disease control, overall response, and improved quality of life without any additional adverse effects, implying that GV1001 might offer a safe and beneficial option for patients with advanced breast cancer [96]. The combination of GV1001 and gemcitabine in pancreatic ductal adenocarcinoma demonstrated that GV1001 treatment alone had no impact on cell proliferation or apoptosis. Gemcitabine, alone and in combination with GV1001, reduced tumor size and increased apoptosis. The combination also significantly decreased tumor tissue fibrosis and enhanced cell death [97]. Alternatively, administration of the GV1001 vaccine sequentially or concurrently with combination chemotherapy showed no difference at baseline compared to post-treatment levels of biomarkers CRP, IL-6 and GM-CSF. A positive correlation was found between post-chemotherapy levels of CRP and IL-6, as well as between CRP and carbohydrate antigen-19-9. Thus, the chemotherapy-induced cell death was not linked to the immune response generated by the GV1001 vaccine in patients with advanced pancreatic cancer [98]. The GV1001 cancer vaccine was given along with the immune-stimulating drug GM-CSF and the chemotherapy drug gemcitabine as an initial treatment for pancreatic cancer. Three different vaccination schedules were tested, and the side effects were generally mild, with some temporary more severe reactions. The patients developed some immune responses targeting the cancer-related proteins telomerase and Ras, but these responses were weak and short-lived. Furthermore, there was a significant reduction in regulatory T-cells, which typically inhibits the immune response. Overall, the combination of the telomerase vaccine and chemotherapy appeared to be safe, but the immune responses generated were not very strong or long-lasting [99].

In addition, NIPU research aims to assess the effectiveness and safety of a combination therapy for inoperable malignant pleural mesothelioma (MPM) following first-line chemotherapy. This research focuses on the utilization of nivolumab and ipilimumab, with or without a telomerase vaccine. The objective is to enhance treatment response by combining checkpoint inhibition with a telomerase vaccine and investigate the mechanisms behind treatment response and resistance. This investigation offers valuable insights for enhancing immunotherapy in mesothelioma and other cancers that have a limited response to immunotherapy [100].

A therapeutic cancer vaccine uses a combination of herpes simplex virus-thymidine kinase gene (HSV-TK) and IL-18, driven by an hTERT promoter. The vaccine eliminated large tumors in mice and led to high levels of T lymphocyte infiltration into the tumors. This combination therapy shows promise for cancer vaccination and immunotherapy by inducing a potent antitumor immune response [101].

A novel combinatorial approach for treating HCC was investigated in a mouse model involving metronomic chemotherapy (a low-dose, frequent administration regimen) in combination with a multi-peptide vaccine. The chemotherapy regimen featured taxanes and alkylating agents, whereas the vaccine was composed of peptides derived from HCV along with the universal tumor antigen TERT. The results showed that this combinatorial approach induced an enhanced, specific T-cell immune response compared to the vaccine alone. This correlated with a reduced frequency of immunosuppressive Tregs [102]. Accordingly, Table 2 summarizes various investigations examining the efficacy of combination therapies designed to enhance cancer treatment outcomes. It highlights different approaches, including the use of the hTERT vaccine in conjunction with immune boosters and checkpoint inhibitors, as well as novel immunotherapeutic strategies involving T-cell activation and chemotherapy. Key findings from each analysis are presented, demonstrating the potential benefits and mechanisms of action of these combination therapies in promoting antitumor immune responses and improving patients’ overall health outcomes.

Table 2.

Overview of cancer treatment combinations against telomerase and boosting immune response

Cancer	Vaccines	Combination Therapy	Outcome	Ref
-	hTERT vaccine	IMO + TLR9 agonist	Strong immune response, no side effects	[84]
-	DNA	Immune checkpoint inhibitors (CTLA-4 or PD-1)	Synergistic effect, increased anti-tumor activity, no improvement in TERT antigen-specific immune responses	[85]
Melanoma	Peptide	Temozolomide	Well-tolerated, significant immune response, improved survival rates	[92]
Melanoma	UV1	Ipilimumab	Stimulated immune response, increased T-cell clones	[93–95]
Breast	GV1001	cytotoxic chemotherapy	Improved disease control, quality of life, no additional adverse effects	[96]
Pancreatic	GV1001	Gemcitabine	Reduced tumor size, increased apoptosis, decreased fibrosis	[99]
Malignant Pleural Mesothelioma	Telomerase	Nivolumab + Ipilimumab	Aim to enhance treatment response, investigate resistance mechanisms	[100]
Colorectal	Telomerase	Suicide gene (HSV-TK) + IL-18	Eliminated large tumors in mice, high T lymphocyte infiltration	[101]
Hepatocellular	multi-peptide vaccine	Metronomic chemotherapy	Enhanced T-cell immune response, reduced Tregs	[102]

mRNA-based telomerase-specific T-cell therapy for cancer

Adoptive cell therapy (ACT) using engineered T-cells holds promise for cancer treatment but carries significant safety risks. To address this, researchers have developed a novel approach using mRNA-based T-cell receptors (TCRs) targeting telomerase. Transiently expressing these TCRs in T-cells offers a potentially safer way to redirect the immune system against cancer. The researchers successfully cloned and produced telomerase-specific TCRs in more T-cells, demonstrating their functionality in both CD4 + and CD8 + T-cell subsets. These findings lay the groundwork for a first-in-human clinical trial to evaluate the safety and efficacy of this mRNA-based ACT strategy [103, 104]. Redirecting T helper (Th) cells to target telomerase is also being explored as a complementary approach to enhance anti-tumor immunity. By combining these strategies, researchers aim to create a more robust and effective immunotherapy, overcoming tumor immune evasion and promoting a sustained anti-cancer response [105, 106]. Researchers isolated a TCR sequence called Radium-4 from a pancreatic cancer patient who was vaccinated with the hTERT peptide 611–626. T-cells redirected to express the Radium-4 TCR were able to effectively kill melanoma cells and patient-derived ascites cells that expressed hTERT, without harming healthy cells. In a mouse xenograft model, T-cells expressing the Radium-4 TCR reduced tumor growth and improved survival, suggesting this TCR is a promising candidate for solid tumor immunotherapy [107]. A first-in-human clinical trial has investigated the safety and tolerability of Radium-4-based T-cell therapy in patients with metastatic NSCLC. This innovative approach utilizes mRNA electroporation for transfection TCR bound by a widely expressed MHC class II allele and aims to minimize toxicity while exploring the therapeutic potential of TCR immunotherapy for solid tumors [108] (Fig. 3).

Fig. 3.

Overview of mRNA-Based Telomerase-Specific T Cell Therapy for Cancer Treatment. This figure illustrates the novel approach of using mRNA to engineer TCRs that target telomerase. It highlights the role of CD4 + and CD8 + T cell subsets in redirecting the immune response against cancer cells. It also depicts successfully targeting melanoma and pancreatic cells using the Radium-4 TCR. It outlines the pathway toward first-in-human clinical trials in NSCLC to evaluate the safety and efficacy of this promising immunotherapeutic strategy

Conclusion

In conclusion, the research on telomerase-based vaccines for cancer immunotherapy shows promising results and potential for significant advancements in cancer treatment. Various investigations have explored the efficacy of combining telomerase vaccines with different immunotherapy approaches to enhance anti-tumor activity and improve treatment outcomes.

We have comprehensively explored the landscape of telomerase-based vaccines, encompassing DNA, peptide, and protein/recombinant approaches. While early-stage studies encountered challenges in achieving robust immune responses, advancements in vaccine design, including incorporating multiple peptides, adjuvants, and optimization of delivery methods, have yielded encouraging results.

Combination therapies involving telomerase vaccines, immune boosters, and immune checkpoint inhibitors have demonstrated synergistic effects in activating immune responses against cancer cells. These combinations have been shown to increase the activity of immune cells, create specific targets for antibodies, and enhance the body’s natural defenses against cancer.

Furthermore, novel approaches such as mRNA-based telomerase-specific T-cell therapy offer a safer and potentially more effective way to target telomerase in cancer cells. Adoptive cell therapy using engineered T-cells, in combination with targeting telomerase, shows promise in redirecting the immune system against cancer while minimizing safety risks. The development of innovative strategies, such as redirecting T helper cells to target telomerase and isolating novel T-cell receptor sequences, indicates a continuous effort to enhance anti-tumor immunity and overcome immune evasion by cancer cells.

Overall, the comprehensive review of telomerase-based vaccines and combination therapies presented in this review highlights the significant progress in cancer immunotherapy research. These findings provide valuable insights into the potential of telomerase vaccines as a critical component in the future of cancer treatment, offering new hope for patients with various types of cancers. Continued research and clinical trials are essential to further optimize these approaches and bring them closer to mainstream clinical practice for improved patient outcomes in the fight against cancer.

Limitations and future perspective

Despite the promising developments in telomerase-based vaccines for cancer immunotherapy, several limitations must be acknowledged. The clinical trials reviewed exhibit significant variability in design, including differences in sample sizes, patient populations, and endpoints. This heterogeneity may impact the comparability of results and the generalizability of conclusions drawn. While some studies report short-term efficacy and safety, there is a lack of long-term follow-up data to assess the durability of immune responses and the sustainability of therapeutic benefits. This gap makes it challenging to evaluate the long-term impact of these vaccines on patient outcomes. Furthermore, individual patient differences, such as genetic background, pre-existing immunity, and the tumor microenvironment, can lead to variable immune responses to telomerase-based vaccines. This variability complicates the interpretation of clinical efficacy and may necessitate personalized approaches to vaccination. Likewise, cancer cells may develop mechanisms to evade immune detection and destruction, limiting the effectiveness of telomerase-targeted immunotherapies. The potential for tumors to adapt and resist the immune response remains a significant concern.

While initial safety profiles of telomerase-based vaccines appear favorable, the potential for adverse effects, including autoimmune responses or cytokine release syndromes, needs further investigation. Comprehensive safety assessments in diverse patient populations are essential.

In addition, telomerase-based vaccines may be more effective when used in conjunction with other therapeutic modalities (e.g., checkpoint inhibitors, and chemotherapy). However, optimal combination strategies are still under investigation and require further elucidation.

These limitations highlight the need for ongoing research to address these challenges and to optimize the development and application of telomerase-based vaccines in cancer treatment. Future studies should focus on overcoming these barriers to translate the potential of these vaccines into effective clinical therapies.

Author contributions

SV and AZT wrote the manuscript comprehensively in all parts, and SV supervised and edited the manuscript scientifically and technically. All the authors read the manuscript comprehensively and confirmed the final revised version. Importantly, there is no conflict of interest.

Funding

There is no funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval

Not applicable.

Competing interests

The authors declare no competing interests.