https://orcid.org/0000-0002-7919-7146
ABSTRACT
This mini-review explores recent advancements in cancer vaccines that target Wilms’ tumor (WT1). Phase I/II trials of WT1 peptide vaccines have demonstrated their safety and efficacy against various cancers. Early trials employing HLA class I peptides evolved through their combination with HLA class II peptides, resulting in improved clinical outcomes. Additionally, WT1-targeted dendritic cell vaccines have exhibited favorable results. Studies focusing on hematological malignancies have revealed promising outcomes, including long-term remission and extended survival times. The combination of vaccines with immune checkpoint inhibitors has shown synergistic effects. Current preclinical developments are focused on enhancing the effectiveness of WT1 vaccines, underscoring the necessity for future large-scale Phase III trials to further elucidate their efficacy.
Introduction
Cellular immunity plays a crucial role in tumor rejection. Since their initial cloning by Boon et al in 1991,Citation1 numerous tumor-associated antigens (TAA) recognized by T cells, have been identified. These TAAs are processed into 9–16 amino acid fragments, presented in conjunction with HLA molecules, and recognized by T cell receptors.Citation2 Highly immunogenic epitope peptides have been identified based on their capacity to bind to HLA molecules and T cell responses. Although numerous clinical trials have been conducted using these peptides, the overall clinical outcomes have remained limited and unsatisfactory.Citation3 However, the advent of immune check point inhibitors (ICI) has provided new possibilities. In this mini-review, I discuss the recent advancements in cancer vaccines targeting Wilms’ tumor 1 (WT1). Clinical and preclinical reports on the WT1 vaccine were retrieved from PubMed using keywords such as “WT1”, “vaccine”, “dendritic cell” and “tumor-associated antigen”. Representative reports were selected based on their originality and informativeness at the time of writing.
WT1 peptide vaccine
The WT1 gene, identified as the causative gene for pediatric renal cancer, known as Wilms’ tumor, encodes a Zn-finger transcription factor that plays a significant role in cell proliferation and differentiation.Citation4 While the WT1 protein is overexpressed in various malignant tumors, its expression in normal tissues is limited to the gonads, uterus, kidneys, mesothelium, and hematopoietic progenitor cells. This restricted expression reduces the likelihood of adverse events resulting from immunotherapies targeting WT1.Citation4,Citation5 WT1 has received the highest evaluation among 75 TAAs for cancer vaccines, based on criteria such as therapeutic effects, immunogenicity, specificity, carcinogenicity, positive rate, and stem cell expression.Citation6
The group led by Sugiyama at Osaka University identified human WT1 epitope peptides restricted to HLA-A *0201 or HLA-A *2402 and clinical trials were conducted with peptide vaccines.Citation4 Oka et al. reported the results of a Phase I/II trial of a WT1 peptide vaccine in patients with leukemia, lung cancer, and breast cancer.Citation7 They observed no serious adverse events except for severe leukocytopenia in patients with myelodysplastic syndrome (MDS). In 12 of 20 patients (60%), a reduction in tumor size or tumor markers was noted. Additionally, they observed a significant correlation between WT1-specific responses and clinical efficacy. Subsequently, various pilot studies and Phase I/II trials demonstrated its efficacy in pancreatic cancer,Citation8 renal cell carcinoma,Citation9 glioblastoma,Citation10 ovarian cancer,Citation11 and thyroid cancerCitation12 ().
Table 1. Representative clinical trials of WT1peptide vaccine in cancer patients in the last five years.
In a recent report, Nishida et al. conducted a clinical trial of the HLA-A *2402-restricted modified peptide (WT1-235) vaccine in patients with advanced or recurrent ovarian cancer and examined the correlation between the immune response and clinical efficacy.Citation11 Patients who had a WT1-specific tetramer ratio of 0.25% or more against CD8+ T cells or a WT1-235-specific IgG level of 0.1 U/ml or more significantly extended progression-free survival (PFS), suggesting that these could serve as prognostic markers for the WT1 vaccine. Oji et al. conducted a clinical trial of a WT1 class I peptide vaccine in patients with thymic tumors.Citation12 Despite the absence of complete responses or partial responses (PRs), 75% of the evaluable patients achieved stable disease (SD), suggesting the potential of the WT1 vaccine to exert an anti-tumor effect on thymic malignancies.
Utilization of vaccines with helper peptides
Early trials utilized HLA class I antigen-restricted peptides (Cytotoxic T lymphocyte (CTL) peptides). However, subsequent mouse experiments indicated the potential usefulness of major histocompatibility complex (MHC) class II antigen-restricted peptides (helper peptides).Citation4,Citation13,Citation14 Recently, trials using both CTL and helper peptides have been conducted, and improvements in clinical outcomes have been reportedCitation15–17 ().
Several research groups have identified human WT1 helper epitopes.Citation18–21 Fujiki et al. identified a 16-mer WT1 helper peptide in humans (WT1332), that induced HLA class II-restricted helper T cells in vitro and promoted the generation of WT1-specific CD8+ T cells.Citation18 In trials involving patients with recurrent glioma, those receiving a combined vaccine of CTL and helper peptides exhibited stronger induction of WT1-specific CTLs than those receiving a CTL peptide alone.Citation22 Some were WT1-tetramer-high, WT1-T cell receptor (TCR)-high and CD5-high CTLs, which are thought to survive in vivo for extended periods due to their resistance to activation-induced cell death. This finding indicated that the helper peptide vaccine contributed to the induction and activation o WT1-specific CTLs by the CTL peptide.
In a Phase I trial by Tsuboi et al. patients with temozolomide-resistant brain tumors were administered WT1 CTL and helper peptides.Citation15 No severe adverse events were reported, and after completing the administration, six patients (43%) maintained SD. The one-year overall survival (OS) was 36%, with a median OS (mOS) of 24.7 weeks. Following vaccine administration, the immune response specific to WT1 CTL and helper peptides was enhanced and sustained for more than a year. As immune responses to vaccines with only CTL peptides tend to diminish rapidly, the study suggested that activation of type 1 helper T cells (Th1) by helper peptides is vital for maintaining anti-tumor immunity and clinical efficacy.
Oji et al. conducted a clinical trial where they administered the WT1 CTL peptide (WT1-235) along with a helper peptide (WT1–332) to 45 patients with rare cancers such as glioblastoma multiforme, soft-tissue cancer, thymic cancer, and malignant pleural mesothelioma, all expressing WT1.Citation16 They monitored the titers of WT1-specific IgG antibodies against each peptide over time. After vaccine administration, they observed an increase in antibody titers. The combined treatment group exhibited a significantly higher positivity rate for WT1-235-specific antibodies than the control group, which only received the CTL peptide, This indicated an enhancement of anti-tumor immunity through the activation of helper T cells by the helper peptide. Specifically, 33% of patients achieved SD, showcasing a positive clinical efficacy. This study suggests that this approach can provide a viable treatment option for rare cancers without established standard treatments.
WT1-targeted dendritic cell vaccine
Dendritic cells (DC) are professional antigen-presenting cells that have been deployed as cellular vaccines, because of their capability to induce anti-cancer immunity and bridge adaptive and innate immunity.Citation23 Clinical trials investigating immunotherapy using dendritic cells have been conducted in patients with various solid tumors, such as malignant melanoma, prostate cancer, and renal cell carcinoma, and have shown a clinically meaningful improvement in mOS, although the objective response rate is approximately 10%.Citation24
While reports on DC vaccines targeting WT1 in solid tumors have been scarce, a recent study by Zhang et al. featured a Phase I/II trial of a WT1 peptide-pulsed DC vaccine in patients with advanced breast, ovarian, and stomach cancers (n = 10)Citation25 (). Among these patients, seven exhibited SD, and 43% of them experienced tumor shrinkage. In addition, a significant correlation was observed between WT1-specific immune response and low levels of peripheral blood myeloid-derived suppressor cells (MDSC) before DC vaccination.
Table 2. Representative clinical trials of DC vaccine targeting WT1 in various cancers and myeloma in the last five years.
Certain anti-cancer drugs exhibit immunomodulatory effects that complement their direct tumoricidal capabilities. For instance, gemcitabine augments the number of CD11c+DCs and CD14+ monocytes in the blood while reducing regulatory T cells (Treg).Citation26 Fluorouracil (5-FU) fosters the differentiation and reduction of MDSCs and enhances tumor-infiltrating CTLs. As a result, the integration of chemotherapy with a WT1 peptide-pulsed DC vaccine could amplify its effectiveness, a hypothesis corroborated by the encouraging results from our group and others.Citation8,Citation27–30
We conducted a clinical trial that combined chemotherapy with the DC vaccine in patients with head and neck,Citation27 esophageal,Citation28 and pancreatic cancers.Citation29 Our results indicated a significant prolongation of survival time compared to historical controls. The incidence of adverse events was comparable with that of chemotherapy alone, underscoring the safety of our approach. Moreover, approximately 50% of the cases demonstrated increased WT1-specific immune responses, which correlated with clinical efficacy. We infer that the enhancement of the immune response involves the proliferation of WT1-specific CTLs owing to lymphocyte homeostatic proliferation following chemotherapy, along with the suppression of Tregs and MDSCs.Citation29
In agreement with the results of vaccine trials using CTL and helper peptides, Koido et al. reported positive outcomes in a trial in which a DC vaccine pulsed with WT1 CTL and helper peptides was administered along with chemotherapy in patients with advanced pancreatic cancer (n = 10).Citation30 The combined peptide group exhibited an increase in WT1-specific interferonɤ (IFNɤ)-producing CD4+T cells and a higher frequency of positive delayed-type hypersensitivity (DTH) reactions in four out of seven patients, observations absent in the single peptide group. Additionally, the combined peptide group revealed significant improvements in both mOS and median PFS (mPFS), suggesting the advantages of incorporating helper peptides.
The administration of the DC vaccine in an adjuvant setting holds promise, as evidenced by Nagai et al.Citation31 They conducted a trial administering WT1 peptide-pulsed DC vaccines to patients who had undergone surgery for pancreatic cancer and reported an extended mOS compared with historical controls.
WT1 vaccine for hematological malignancies
Phase I/II trials, in which the WT1-235 peptide vaccine was administered to HLA-A *2402 positive patients with acute myeloid leukemia (AML) or MDS-related diseases, The result indicated a decrease in WT1 mRNA in five out of eight cases (62.5%) of patients with AML.Citation7 Remarkably, a single dose induced WT1-specific CTLs, leading to a rapid decrease in leukemia cells and severe leukocytopenia in patients with MDS, highlighting the efficacy of the WT1 peptide vaccine against hematological malignancies. Safety and efficacy were observed in Phase I/II trials of a vaccine using the HLA-A *0201-restricted WT1 CTL peptide (WT1-126) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) and KLH for HLA-A *0201 positive patients with treatment-resistant AML or MDS.Citation32
The ratio of tumor-specific T cells induced by the vaccine to the remaining tumor cells is believed to be high when the tumor volume is small during remission, thereby enhancing anti-tumor effects. Furthermore, the post-remission period is considered an optimal time for tumor vaccines, as proliferation of tumor-specific T cells is promoted during recovery from bone marrow suppression. Nakata et al. conducted a Phase II trial of the WT1 CTL peptide (WT1-126, WT1-235) vaccine in patients with AML at high risk of relapse who achieved complete remission (CR) (n = 20)Citation33 (). The 2-year relapse-free survival (RFS) and OS rates were 25% and 40%, respectively, reflecting favorable outcomes compared with historical controls. A correlation was observed between the frequency of WT1-specific CTLs before vaccination and clinical outcomes, suggesting a synergistic effect with anti-leukemic immunity induced by chemotherapy.
Table 3. Representative clinical trials of WT1peptide vaccine in hematological malignancies in the last five years.
Maslak et al. demonstrated long-term maintenance of remission after WT1 vaccine administration by conducting a Phase II trial of the multivalent WT1 vaccine (Galinpepimut-S) in 22 AML-CR patients.Citation34 The median disease-free survival (mDFS) from CR was 16.9 months, and the OS from diagnosis has not yet been reached but is estimated to be more than 67.6 months.
Similar results were observed in a Phase II trial conducted by Anguille et al. using a WT1 mRNA-transduced DC vaccine in AML-CR patients with a high recurrence risk (n = 30).Citation35 Nine patients showed normalized WT1 mRNA levels and achieved molecular remission, with five maintaining long-term molecular remission. The 5-year OS and DFS were significantly higher in responders than in non-responders, with long-term clinical effects correlating with an increase in the proportion of WT1 polyepitope-specific CD8+ T cells in the peripheral blood.
These Phase II trial results suggest peptide or DC vaccines targeting WT1 may be valuable treatment options for maintaining remission or even curing hematological malignancies. A phase III randomized trial of a WT1-peptide vaccine in AML-CR patients was initiated by a group at the Memorial Sloan-Kettering Cancer Center utilizing a multivalent heteroclitic WT1 peptide vaccine, Galinpepimut-S (NCT04229979).Citation36 In this trial, eligible patients were randomly assigned to either the vaccine group or the best available treatment group. The study aims to evaluate OS as the primary endpoint, with safety and progression-free survival (PFS) as secondary endpoints.
High-risk MDS may be suitable for the WT1 vaccine, as evidenced by the rapid induction of WT1-specific CTLs and the reduction of leukemia cells with a single dose in a previous study.Citation7 However, recent Phase I/II trials have not demonstrated a remarkable efficacy in patients with high-risk MDS.Citation37
The utility of the WT1 peptide vaccine in elderly patients was examined in a placebo-controlled Phase II study of the WT1 helper peptide (OCV-501) vaccine in AML-CR patients (n = 134).Citation38 Although no significant difference was observed in the relapse rate or mDFS, a significant prolongation of OS was observed in patients who responded immunologically to OCV-501. This indicates that the effectiveness of the WT1 peptide vaccine in elderly patients may be limited.
Compared to acute leukemia and MDS, few reports exist regarding the use of the WT1 vaccine in other hematological malignancies, such as multiple myeloma and malignant lymphoma. A case report involving a WT1-peptide vaccine in multiple myeloma demonstrated a notable reduction in myeloma cells, decreased M protein levels, and radiographic improvement in bone lesions following WT1 vaccination.Citation39 A phase I vaccine trial in multiple myeloma using DC electroporated with triple antigen genes, including WT1, post-autologous stem cell transplantation with lenalidomide maintenance, demonstrated the induction of a WT1-specific immune response and clinical efficacy.Citation40 Additionally, in a pilot study involving five patients with malignant lymphoma, using WT1-peptide loaded DC vaccination yielded positive effects, in one CR and one PR.Citation41
In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the rejection of leukemia cells by a graft-versus-leukemia (GVL) effect mediated by donor lymphocytes has been demonstrated.Citation42 However, severe graft-versus-host disease (GVHD) may occur simultaneously and significantly influence prognosis. Vaccination after allo-HSCT is considered a promising strategy to enhance the GVL effect without provoking GVHD. Proliferation of tumor-specific T cells is promoted during recovery from bone marrow suppression after allo-HSCT, and donor-derived T cells that are not exposed to tumor antigens are not exhausted. Moreover, effector cells recover earlier than Tregs, reducing the risk of immune suppression.Citation43 Therefore, the post-HSCT period is considered optimal for tumor vaccines.
Hashii et al. reported a trial in which the WT1 CTL peptide vaccine was administered to pediatric patients with acute leukemia (n = 3) with minimal molecular residual disease after allo-HSCT.Citation44 All patients displayed a reduction in WT1 mRNA levels, with two out of three maintaining molecular CR for an extended period.
Similarly, Maeda et al. conducted a trial in adult patients with hematological malignancies (n = 9) at high risk of relapse or those who had relapsed after allo-HSCT.Citation45 Three patients in molecular CR sustained remission for more than two years following treatment, and two patients with molecular relapse achieved remission after treatment.
These Phase II trials imply that the WT1 peptide vaccine after allo-HSCT could augment the GVL effect without affecting GVHD and maintaining long-term remission.
Combination with other agents
Combination with molecularly-targeted agen
The hypomethylating agent such as azacitidine (AZA) induces the expression of methylated tumor antigens, while lenalidomide has immunomodulatory effects, activating T cells and natural killer cells. Combining these drugs may enhance the efficacy of vaccine.
A phase I trial of New York esophageal squamous cell carcinoma 1 (NY-ESO-1) vaccination in conjugation with decitabine in high-risk patients with MDS demonstrated the induction of antigen-specific immune responses and favorable clinical outcomes, including CR in three patients and SD in two out of nine patients.Citation46 However, a Phase I trial that combined a peptide vaccine derived from NY-ESO1, melanoma-associated antigen-A3 (MAGE-A3), preferentially expressed antigen in melanoma (PRAME), and WT1 with AZA in high-risk patients with MDS (n = 5) who responded to AZA monotherapy failed.Citation47 The discrepancy in clinical outcomes observed in these studies may be partially attributed to the pleiotropic effects of hypomethylating agents, patient backgrounds and variations in treatment protocols.
In contrast, combined treatment with lenalidomide appeared to be effective. Chug et al. conducted a Phase I trial administering Langerhans-type DC transduced with cancer testis antigen 7 (CT7), MAGE-A3, and WT1 mRNA to patients with multiple myeloma (n = 10) after autologous transplantation.Citation40 They were then administered lenalidomide maintenance therapy starting 3 months post-transplantation. Post-vaccine, there was an increase in the secretion of IFNɤ, interleukin-2 (IL-2), tumor necrotic factor α (TNFα) and other cytokines by antigen-specific CD4+ and CD8 T+ cells, and an increase in the expression of the cytotoxic marker CD107a was also noted. The therapeutic effect was better in the vaccine group than in the control group.
Combination with ICIs
Recently, there have been numerous reports of excellent results using ICIs against various solid tumors and Hodgkin lymphomas.
Phase I and II trials combining cancer peptide vaccines with ICIs show promising results.Citation48–50 These combinations include the human telomerase reverse transcriptase (hTERT) peptide vaccine and ipilimumab,Citation48 or indoleamine 2,3-dioxygenase (IDO)/programmed death ligand 1 (PD-L1)peptide vaccine and nivolumab for patients with advanced malignant melanoma,Citation49 or multi-peptide vaccine and nivolumab in adjuvant setting.Citation50 These combinations led to enhanced peptide-specific T cell responses, yielding excellent results with prolonged mPFS and mOS.
Regarding the combination of the WT1 peptide vaccine with ICIs, Manning-Geit et al. recently conducted a Phase I trial combining the heteroclitic WT1 vaccine (Galinpepimut-S) with nivolumab in patients with advanced ovarian cancer.Citation17 They observed WT1-specific T cell responses and IgG production in 91% of patients. The 1-year PFS rate was 70%, correlating with WT1-specific immune responses, suggesting a synergistic effect between the WT1 vaccine and ICIs.
Given the promising results of Phase I/II trials combining cancer peptide vaccines with ICIs, future studies should focus on confirming the presence or absence of synergistic effects through Phase III randomized trials.
Recent preclinical developments
Several preclinical studies have focused on enhancing the effectiveness of the WT1 peptide or DC vaccines, highlighting advancements in areas such as the identification of mouse helper peptide,Citation13,Citation14 cord blood-derived DC vaccine,Citation51 oral vaccines facilitated by intestinal immunity,Citation52 innovative adjuvants,Citation53 improvements in peptide transport,Citation54 and enhancement of antigen uptake and presentation by DCsCitation55,Citation56 ().
Table 4. Selected recent preclinical studies on WT1 vaccine.
Identification of mouse helper peptide
Nakajima et al. identified mouse helper peptides (WT1 35-52, WT1 86-102, WT1 294-312) and examined their efficacy in a vaccine incorporating them.Citation13 Compared with vaccines with CTL epitopes alone, vaccines containing both CTL and helper peptides induced and maintained more potent WT1-specific CTLs and facilitated the rejection of WT1-expressing tumors. Importantly, the WT1-specific CD4+ T cells induced by this combined vaccine not only activated WT1-specific CD8+ T cells but also played a vital role in the migration and infiltration of CD8+ T cells into the tumor.Citation14 This highlights the potential clinical applicability of vaccines utilizing both CTL and helper peptides.
Cord blood-derived DC vaccine
Allogeneic cord blood (CB) is an alternative source of hematopoietic stem cells for allo-HSCT, particularly for pediatric patients with acute leukemia. To prevent relapse after CB transplantation using a CB-derived DC (CB-DC) vaccine targeting WT1, Plantinga et al reported the production of CB-DC using a closed bag system for clinical applications.Citation51 They demonstrated that CB-DC exhibited an increased capacity to stimulate T cells and enhance their CCR7-dependent migratory ability. Notably, CB-DC, either electroporated with WT1-mRNA or loaded with WT1 long peptides, successfully generated WT1-specific CTLs capable of lysing primary pediatric AML cells in vitro.
Oral cancer vaccine
Nakagawa et al. developed a vector using Bifidobacterium longum containing the WT1 gene.Citation52 They observed tumor reduction in mice after administering the oral vaccine. An increase in CD103+CD11b+CD11c+ DC within Peyer’s patches was observed, along with a rise in T cells having a high capacity to produce IFNɤ specifically for multiple epitopes of WT1, and an increase in WT1-specific IgG antibodies. Additionally, infiltration of CD4+ T cells and CD8+ T cells into the tumor was observed.
Adjuvant human papillomavirus
Various adjuvants, such as Montanide ISA-51 and polyinosinic polycytidylic acid (poly-IC), have been used to enhance the immunological activity of peptide vaccines. When used as carriers for peptide vaccines, Polystyrene nanoparticles (PSNP) induce peptide-specific CD8+ T cells without causing inflammation.Citation53 Xiang et al. examined the effectiveness of a conjugate vaccine comprising the human papillomavirus (HPV) E7 protein, WT1, survivin molecules, and PSNPs for the development of a vaccine against gynecological cancer. Even when conventional adjuvants such as CpG are ineffective, peptide vaccines conjugated with PSNPs can induce peptide-specific immune responses, indicating that nanoparticle-based vaccine carriers could serve as alternatives to traditional adjuvants.
Transcutaneous delivery
Shimizu et al. utilized ionic liquids (ILs), known to increase skin permeability, for the transcutaneous delivery of the WT1 peptide and the TLR-7 agonist resiquimod (R848).Citation54 They evaluated the immune response and anti-tumor effects, demonstrating the induction of WT1-specific CTL and the suppression of tumor growth in a tumor-bearing mouse model. Moreover, the pre-administration of R848 increased leukocyte infiltration into the skin, leading to the finding that subsequent WT1 peptide administration more readily induced WT1-specific CTL.
DC vaccine using cytoplasmic transduction peptide
By leveraging the characteristics of cytoplasmic transduction peptide (CTP) fusion proteins, which do not translocate to the nucleus post-transcriptionally but remain in the cytoplasm, DCs pulsed with CTP-WT1 or CTP-survivin fusion proteins showed enhanced expression of MHC and co-stimulatory molecules.Citation55 These findings demonstrate CTL induction in glioblastoma cell lines and Th1 cytokine production in vitro. Furthermore, the addition of a PD-1 antibody enhanced the immune response, suggesting the potential to amplify the effect of the DC vaccine using CTP fusion protein antigens.
WT1 vaccine using microparticle, DNA and antibody conjugates
Enhancement of the WT1 vaccine effect using microparticle, DNA and antibody conjugates represents a promising aveneue. WT1 vaccines utilizing microparticles containing the WT1 peptide and CpG (PLGA nano-microparticle WT1 vaccine)Citation57 or innovative DNA vaccines comprising the consensus sequence of WT1Citation58 represent novel strategies to boost antigenicity and improve T-cell responses to WT1. The antibody-combined WT1 vaccine is another innovative approach that facilitates efficient antigen delivery to antigen-presenting cells and enhances T-cell responses.
CD141+ type 1 conventional DCs (cDC1) are crucial for cancer immune surveillance because of their superior capacity to cross-present exogenous antigens to CD8+ T cells.Citation56 CLEC9A, a C-type lectin-like receptor exclusively expressed on cDC1, plays a pivotal role in the regulation of CD8+ T cell responses. Pearson et al. developed a fusion gene product combining WT1 with human CLEC9A- specific antibodies (CLEC9A-WT1 vaccine) and investigated its priming efficacy through the cross-presentation of the WT1 epitope to naïve T cells. The CLEC9A-WT1 vaccine demonstrated a more potent priming effect than the fusion products of other C-type lectin-like receptors such as DEC-205 and WT1, highlighting its potential as a promising cancer vaccine targeting WT1.Citation56
Conclusions and future perspectives
Cancer vaccines targeting WT1 have shown promise, as evidenced by the results of Phase I/II trials. These prove most effective when administered during periods of low tumor burden and minimal immunosuppression. This suggests that the optimal timing for administration is post-remission or post-allo-HSCT in acute leukemia, and after surgery for solid tumors. Simultaneously inducing and activating helper T cells along with CTLs is essential, achieved by using both CTL and helper peptides or long peptides encompassing both epitopes. Moreover, the use of multiple peptides is crucial for counteracting tumor escape due to reduced or absent TAA expression through immunoediting. To enhance the efficacy of the WT1 vaccine, its combination with other agents, particularly ICIs, is required. Currently, clinical trials involving WT1 vaccines have progressed to phase I and II. The effectiveness of the WT1 vaccine is expected to be further clarified in large-scale Phase III trials.
Summary and take-home messages
Phase I/II trials have demonstrated favorable clinical outcomes in patients with solid tumors or hematological malignancies treated with WT1-targeting vaccines.
A combined WT1 vaccine comprising both CTL and helper peptides holds promise due to its ability to enhance the activation of both CTL and helper T cells.
The combination of WT1 vaccines with ICIs and other agents is expected to increase clinical efficacy.
Ongoing Phase III trials are expected to further elucidate the clinical benefits of the WT1 vaccine in the near future.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
References
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