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Efficacy pharmacology studies of OCV-501 using PBMC from healthy donor. Th1: Type 1 T-helper, WT1: Wilms’ tumor 1. Induction of OCV-501-specific Th1 cells in PBMC (a). PBMC were cultured with OCV-501 (filled circle) or solvent (circle) (data are expressed as mean ± SE: n = 20, *P = 0.0058: main effect in mixed model for repeated measures method, crossover type). The HLA class II-restriction of OCV-501-derived antigen stimulation was evaluated using OCV-501-specific T cells induced in PBMC by blockade with anti-HLA class II antibody (b) (data are expressed as mean ± SD, triplicates). Dose-dependence of OCV-501 activation of specific T cells (c) (data are expressed as mean ± SE: n = 20, *P < 0.05: randomized block design, Dunnett’s test). WT1-specific CTLs were increased by OCV-501 and OCV-501-specific T cells: changes in the number of WT1-126-specific CTLs following addition of OCV-501 (d) (data are expressed as proportions of 3 independent samples). Changes in the number of WT1-235mu-specific CTLs following addition of OCV-501 (e) (data are expressed as proportions of 8 independent samples)
Source publication
Wilms’ tumor 1 (WT1) is a promising target of new immunotherapies for acute myeloid leukemia (AML) as well as for other cancers. OCV-501 is a helper peptide derived from the WT1 protein. OCV-501 induced OCV-501-specific Type 1 T-helper (Th1) responses dose-dependently and stimulated helper activity of the specific Th1 cells in peripheral blood mono...
Citations
... OCV-501, a tumor vaccine, is an HLA class II-binding polypeptide consisting of 16 amino acid residues derived from WT1 protein [9,10]. Previous studies revealed that OCV-501 induces not only peptide-specific Th1 cells but also WT1-specific cytotoxic T-lymphocytes, suggesting its potential as a cancer vaccine [9]. ...
... Briefly, AML patients who were ≥ 60 years, achieved initial CR with one or two cycles of induction chemotherapy, finished consolidation, and were not eligible for transplantation were enrolled. Since binding of OCV-501 to HLA class II molecules can be expected in 83.8-98.8% of Japanese [10], HLA genotyping was not performed for patient recruitment. Patients were randomly assigned to receive either OCV-501 emulsified with Montanide ISA 51 adjuvant (Seppic Inc., Pris, France) or placebo (adjuvant only) for 2 years. ...
We previously conducted a randomized phase II trial of OCV-501, a WT1 peptide presented by helper T cells, in elderly AML (acute myeloid leukemia) patients in first remission, indicating no difference in 2-year disease-free survival (DSF) between the OCV-501 and placebo groups. Here, we analyzed 5-year outcome and biomarkers. Five-year DFS was 36.0% in the OCV-501 group (N = 52) and 33.7% in the placebo group (N = 53), with no significant difference (p = 0.74). The peripheral WT1 mRNA levels were marginally suppressed in the OCV-501 group compared with the placebo group. Enhanced anti-OCV-501 IgG response by the 25th week was an independent favorable prognostic factor. Anti-OCV-501 IFNγ responses were less frequent than the IgG reactions. These findings suggest that host immunoreactivity has a significant impact on the prognosis of AML and that further improvement of the WT1 peptide vaccine is needed.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00262-023-03432-4.
... A phase I clinical trial suggested that the subcutaneous administration of OCV-501 once weekly for 4 weeks at doses of 0.3, 1, and 3 mg in older patients with AML during complete remission was safe and well tolerated. 73 ...
Although complete remission could be achieved in about 60%–70% of acute myeloid leukemia (AML) patients after conventional chemotherapy, relapse and the state of being refractory to treatment remain the main cause of death. In addition, there is a great need for less intensive regimens for all medically frail patients (both due to age/comorbidity and treatment-related). Immune therapy anticipates improved prognosis and reduced toxicities, which may offer novel therapeutic rationales. However, one of the major difficulties in developing immune therapies against AML is that the target antigens are also significantly expressed on healthy hematopoietic stem cells; B-cell malignancies are different because CD20/CD19/healthy B-cells are readily replaceable. Only the anti-CD33 antibody-drug conjugate gemtuzumab-ozogamicin is approved by the FDA for AML. Thus, drug development remains extremely active, although it is still in its infancy. This review summarizes the clinical results of immune therapeutic agents for AML, such as antibody-based drugs, chimeric antigen receptor therapy, checkpoint inhibitors, and vaccines.
... The ability of CD4 + T cells to augment CD8 + T-cell antitumor responses is supported by data from a WT1-based therapeutic cancer vaccine containing only HLA-II antigens. This vaccine was shown to not only stimulate the proliferation of WT1-specific helper T cells, but to enhance WT1-specific cytotoxic T-cell numbers [25]. Therefore, the antitumor activity of WT1-based therapeutic cancer vaccines will likely be maximized by the inclusion of epitope sequences that stimulate both cytotoxic and helper T cells. ...
Background:
Wilms' tumor 1 (WT1) is highly expressed in various solid tumors and hematologic malignancies. DSP-7888 (adegramotide/nelatimotide) Emulsion is an investigational therapeutic cancer vaccine comprising three synthetic epitopes derived from WT1. We evaluated the mechanism of action of DSP-7888 Emulsion, which is hypothesized to induce WT1-specific cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs).
Methods:
The ability of nelatimotide and adegramotide to induce WT1-specific CD8+ T cells and CD4+ T cells was assessed in human peripheral blood mononuclear cells (PBMCs). The ability of DSP-7888 Emulsion to induce WT1-specific CTLs in vivo was assessed using human leukocyte antigen-I (HLA-I) transgenic mice. To assess how adegramotide, the helper peptide in DSP-7888 Emulsion, enhances WT1-specific CTLs, HLA-I transgenic mice were administered DSP-7888 or nelatimotide-only Emulsion. Interferon-gamma secretion under antigen stimulation by splenocytes co-cultured with or without tumor cells was then quantified. The effects of combination treatment with DSP-7888 Emulsion and an anti-programmed cell death protein 1 (PD-1) antibody on tumor volume and the frequency of tumor-infiltrating WT1-specific T cells were assessed in HLA-I transgenic mice implanted with WT1 antigen-positive tumors.
Results:
The peptides in DSP-7888 Emulsion were shown to induce WT1-specific CTLs and HTLs in both human PBMCs and HLA-I transgenic mice. Unlike splenocytes from nelatimotide-only Emulsion-treated mice, splenocytes from DSP-7888 Emulsion-treated mice exhibited high levels of interferon-gamma secretion, including when co-cultured with tumor cells; interferon-gamma secretion was further enhanced by concomitant treatment with anti-PD-1. HLA-I transgenic mice administered DSP-7888 Emulsion plus anti-PD-1 experienced significantly greater reductions in tumor size than mice treated with either agent alone. This reduction in tumor volume was accompanied by increased numbers of tumor-infiltrating WT1-specific CTLs.
Conclusions:
DSP-7888 Emulsion can promote both cytotoxic and helper T-cell-mediated immune responses against WT1-positive tumors. Adegramotide enhances CTL numbers, and the CTLs induced by treatment with both nelatimotide and adegramotide are capable of functioning within the immunosuppressive tumor microenvironment. The ability of anti-PD-1 to enhance the antitumor activity of DSP-7888 Emulsion in mice implanted with WT1-positive tumors suggests the potential for synergy.
... Cancerspecific Th1 cells play a significant role in the control of cancer immunity; they increase antitumor effects, thus stimulating the proliferation and activation of CTLs by the induction of activated dendritic cells [14,15]. OCV-501, an HLA class II-restricted WT1 helper peptide, consists of 16 amino acid residues derived from the WT1 gene product [16]. In in vitro studies, OCV-501 not only activated HLA class II-restricted OCV-501-specific Th1 cells but also increased the induction of WT1-specific CTLs, suggesting that it is a promising peptide for use in cancer immunotherapy [16]. ...
... OCV-501, an HLA class II-restricted WT1 helper peptide, consists of 16 amino acid residues derived from the WT1 gene product [16]. In in vitro studies, OCV-501 not only activated HLA class II-restricted OCV-501-specific Th1 cells but also increased the induction of WT1-specific CTLs, suggesting that it is a promising peptide for use in cancer immunotherapy [16]. A phase I study of OCV-501, which involved elderly AML patients, showed that the maximum tolerated dose was greater than or equal to 3 mg with no major safety concerns. ...
... A phase I study of OCV-501, which involved elderly AML patients, showed that the maximum tolerated dose was greater than or equal to 3 mg with no major safety concerns. It also showed that OCV-501 induced Th1 responses and enhanced the increase of WT1-killer peptide-specific cytotoxic T lymphocytes [16]. ...
Purpose
Complete remission (CR) of acute myeloid leukemia (AML) in elderly patients has a short duration, and there is no suitable post-remission therapy. We explored the role of the Wilms’ tumor 1 helper peptide OCV-501 to prevent recurrence after remission.
Methods
This placebo-controlled phase 2 study was designed to evaluate accurately the efficacy and immunogenicity of OCV-501 in elderly AML patients. Elderly AML patients who achieved first CR were randomly allocated to receive either OCV-501 (N = 69) or placebo (N = 65) once a week for eight weeks and then every two weeks until week 104. The primary endpoint was disease-free survival (DFS).
Results
Nineteen (27.5%) patients in the OCV-501 group and 23 (35.4%) patients in the placebo group completed the study without relapse. The median DFS in the OCV-501 and placebo groups was 12.1 and 8.4 months, respectively (p = 0.7671, hazard ratio [95% confidence interval]: 0.933 [0.590, 1.477]). The major drug adverse reactions were injection-site reactions. Although treatment with OCV-501 did not prolong DFS for elderly AML patients, post hoc analysis found that immune responders to OCV-501 whose specific IgG was > 10,000 ng/mL (N = 16) and whose WT1-specific interferon-γ response was > 10 pg/mL (N = 26) had significantly longer overall survival compared with placebo.
Conclusions
The placebo-controlled design of this study and quantitative immunological monitoring provides new insight into the relationship between peptide-induced immune responses and survival, suggesting future perspectives for cancer immunotherapy.
... HTLs play a critical role in anti-cancer responses by promoting dendritic cell presentation of antigen to CTLs, secreting cytokines that maintain CTL proliferation and effector function, and generating CTL memory responses [22][23][24]. A WT1-specific helper peptide vaccine (OCV-501) has been studied in the clinical setting, but it only induces WT1-specific HTLs (human leukocyte antigen [HLA] class II-restricted), not CTLs [25]. ...
Background
Wilms’ tumor 1 (WT1) is overexpressed in various malignancies. DSP-7888 Dosing Emulsion, also known as ombipepimut-S (United States Adopted Name; International Nonproprietary Name: adegramotide/nelatimotide), is an investigational therapeutic cancer vaccine comprising two synthetic peptides derived from WT1 to promote both cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte–mediated immune responses against WT1-expressing tumors.Objective
The aim of this study was to report the results from a phase I dose-escalation study (NCT02498665) that evaluated DSP-7888, administered either intradermally (ID) or subcutaneously (SC), in patients with recurrent or advanced malignancies associated with overexpression of WT1.Patients and Methods
In this phase I dose-escalation study, patients with recurrent or advanced malignancies associated with overexpression of WT1 who progressed on, were intolerant to, or not a candidate for standard therapy or who presented with a malignancy that had no definite standard therapy received escalating doses of ID or SC DSP-7888 in a rolling-six study design. DSP-7888 3.5, 10.5, or 17.5 (ID only) mg was administered until disease progression or other discontinuation event. Primary objectives were safety, tolerability, and identification of the recommended phase II dose (RP2D). Overall survival (OS) and WT1-specific CTL induction were included as secondary and exploratory objectives, respectively.ResultsTwenty-four patients received either ID (3.5 mg, n = 4; 10.5 mg, n = 3; 17.5 mg, n = 3) or SC DSP-7888 (3.5 mg, n = 9; 10.5 mg, n = 5). No dose-limiting toxicity was observed. The most frequent treatment-emergent adverse event was injection site reactions (ID, 100% [10/10]; SC, 35.7% [5/14]); all were grade 1 or 2. Four patients (ID 17.5 mg, n = 1; SC 3.5 mg, n = 1; SC 10.5 mg, n = 2) had stable disease, 16 had progressive disease, and four were not evaluable. Median (95% confidence interval) OS duration was 180.0 (136.0–494.0) days. Among evaluable patients, WT1-specific CTL induction was observed in 66.7% (6/9) and 41.7% (5/12) of those administered ID and SC DSP-7888, respectively.ConclusionsDSP-7888 Dosing Emulsion was well tolerated, with no dose-limiting toxicities, in patients with recurrent or advanced malignancies. Higher WT1-specific CTL induction activity was noted with ID compared with SC administration; because of this, the ID route was selected for further evaluation in the clinical program.Trial registrationClinicalTrials.gov identifier: NCT02498665.
... For the simultaneous induction of WT1specific HTLs and WT1-specific CTLs, we, in addition to the killer peptides, have identified WT1 332 (KRYFKLSH-LQMHSRKH) as a WT1-derived HLA class II-restricted epitope (helper peptide) [12]. WT1 332 can bind multiple HLA class II molecules such as HLA-DRB1*01:01, DRB1*04:05, DRB1*07:01, DRB1*08:02, DRB1*08:03, DRB1*13:02, DRB1*14:03, DRB1*14:05, DRB1*15:01, DRB1*15:02, DRB3*02:02, DQB1*04:01, DPB1*05:01, and DPB1*09:01 and induce Th1-type HTLs that can promote CTL responses [12][13][14][15][16]. We previously demonstrated that WT1 332 -specific Th1 cells and/or WT1 332 could enhance the induction of WT1-specific CTLs in vitro [12,16]. ...
... This finding raises the question of why WT1 332 helper peptide can be so high immunogenic. [15], which occupied the peptide-binding groove of HLA class II molecules and prevented the binding of endogenous selfpeptides to the molecules. This strong binding property to HLA class II molecules may determine high immunogenicity of WT1 332 . ...
... In this study, we demonstrated for the first time that WT1 332 was highly immunogenic and enhances the induction of WT1-specific CTLs, promising improvement of clinical outcomes in cancer patients. It should be noted that WT1 332 could induce not only HTLs but also CD4 + cytotoxic T cells [15,16,41]. Accordingly, WT1 332 could serve as both an enhancer and a direct inducer of anti-tumor immune responses, especially, in patients with cancer expressing both HLA class I and II. ...
Simultaneous induction of tumor antigen-specific cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs) is required for an optimal anti-tumor immune response. WT1332, a 16-mer WT1-derived helper peptide, induce HTLs in an HLA class II-restricted manner and enhance the induction of WT1-specific CTLs in vitro. However, in vivo immune reaction to WT1332 vaccination in tumor-bearing patients remained unclear. Here, a striking difference in WT1-specific T cell responses was shown between WT1 CTL + WT1 helper peptide and WT1 CTL peptide vaccines in patients with recurrent glioma. WT1-specific CTLs were more strongly induced in the patients who were immunized with WT1 CTL + WT1 helper peptide vaccine, compared to those who were immunized with WT1 CTL vaccine alone. Importantly, a clear correlation was demonstrated between WT1-specific CTL and WT1332-specific HTL responses. Interestingly, two novel distinct populations of WT1-tetramerlow WT1-TCRlow CD5low and WT1-tetramerhigh WT1-TCRhigh CD5high CTLs were dominantly detected in WT1 CTL + WT1 helper peptide vaccine. Although natural WT1 peptide-reactive CTLs in the latter population were evidently less than those in the former population, the latter population showed natural WT1 peptide-specific proliferation capacity comparable to the former population, suggesting that the latter population highly expressing CD5, a marker of resistance to activation-induced cell death, should strongly expand and persist for a long time in patients. These results demonstrated the advantage of WT1 helper peptide vaccine for the enhancement of WT1-specific CTL induction by WT1 CTL peptide vaccine.
... Analogous to CAR T cell therapy, antigen selection is crucial in development of cancer vaccine. Wilms' tumor protein 1 (WT1) is physiologically found at low levels in gonads, kidneys and normal hematopoietic tissue and is highly expressed in hematological malignancies including AML [97]. Yamaguchi et al. evaluated the safety and efficacy of OCV-501, a synthetic peptide containing natural sequence of WT1, in a randomized, multicenter, double-blind, placebo-controlled trial [98]. ...
Simple Summary
Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults, with an average first diagnosis at age 68, and has historically carried poor prognosis due to various genetic alterations and abnormalities that complicate approaches to treatment. Recently, numerous advancements have been made within the realm of AML therapy, including genetically targeted therapies against FLT3, IDH1/2 and tumor protein p53 (TP53), antibody-drug conjugates, and immunotherapies. Alongside these developments in targeted therapies, we have acquired a better understanding of mechanisms of resistance against conventional therapies that have been in use for decades. The goal of our review is to serve as a guide in the latest targeted and immunotherapeutic drugs available, as well as those currently in the pipeline. We review their specific mechanisms, their characteristic properties, indications for use, outcomes in efficacy in clinical trials prior to approval by the FDA, and their usage in combination with other available therapies.
Abstract
Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy comprised of various cytogenetic and molecular abnormalities that has notoriously been difficult to treat with an overall poor prognosis. For decades, treatment options were limited to either intensive chemotherapy with anthracycline and cytarabine-based regimens (7 + 3) or lower intensity regimens including hypomethylating agents or low dose cytarabine, followed by either allogeneic stem cell transplant or consolidation chemotherapy. Fortunately, with the influx of rapidly evolving molecular technologies and new genetic understanding, the treatment landscape for AML has dramatically changed. Advances in the formulation and delivery of 7 + 3 with liposomal cytarabine and daunorubicin (Vyxeos) have improved overall survival in secondary AML. Increased understanding of the genetic underpinnings of AML has led to targeting actionable mutations such as FLT3, IDH1/2 and TP53, and BCL2 or hedgehog pathways in more frail populations. Antibody drug conjugates have resurfaced in the AML landscape and there have been numerous advances utilizing immunotherapies including immune checkpoint inhibitors, antibody-drug conjugates, bispecific T cell engager antibodies, chimeric antigen receptor (CAR)-T therapy and the development of AML vaccines. While there are dozens of ongoing studies and new drugs in the pipeline, this paper serves as a review of the advances achieved in the treatment of AML in the last several years and the most promising future avenues of advancement
... Numerous studies on WT immunotherapy have been carried till date using a variety of different vaccination strategies, for example (HLA-restricted versus non HLA-restricted peptides). Clinically meaningful responses have been reported in several trials in both AML and MDS cases, with associated increases in WT1-specific T-cell frequencies ( Table 1) [57][58][59][60][61][62][63][64][65][66]. The expression of WT1 on normal tissues and its role in normal haematopoiesis has been an issue of probable possibility of autoimmune phenomenon. ...
Wilms tumor gene 1 (WT1) is an important gene which is involved in growth and development of many organs. It is identified as a tumor suppressor gene in nephroblastoma. However, its role as a tumor oncogene has been highlighted by many studies in haematological as well as non haematological malignant neoplasm. The expression of WT1 on leukemic blast cells sensitised us to explore its impact on neoplastic phenomenon. WT1 is has been found both mutated as well as over expressed in different subsets of acute myeloid leukemia (AML). WT1 is a gene has been used as a biomarker for diagnosis, monitoring of minimal residual disease (MRD) and detection of relapse for molecular remission in AML. It also has potential of being a predictive molecular predictive biomarker for the treatment of leukemic cases after allogeneic transplantation. The WT1 specific expression on blast cells and its interaction with cytotoxic T cell has also been explored for its potential usage WT1 based immunotherapy. Here, we are reviewing molecular updates of WT1 gene and discuss its potential clinical applications as a predictive molecular biomarker for diagnosis, as MRD detection and as immunotherapy in AML.
... Although the selection of peptides, immune adjuvants, and the route of administration should be improved to enhance antitumor responses [14], peptide vaccine therapy has benefits such as cost-effectiveness, simplicity of synthesis, and a general acceptance in clinical practice [15]. Tumor antigen-specific CD8 cytotoxic T lymphocytes (CTLs) tend to reduce their cytotoxic activity without the aid of CD4 helper T lymphocytes (HTLs) [16]. As we and other researchers have reported, peptide-reactive HTLs play a pivotal role not only in helping CTLs, but also in exhibiting direct toxicity toward tumor cells [13,17]. ...
... We showed in the present study that phosphorylated vimentin peptides are likely to be useful as a helper peptide vaccine to treat CRC. Since CTLs are considered to be a direct player that kills tumors in cancer immunotherapy, clinical trials using HTLs have shown promising results [16,26]. Previously, we showed that peptide-reactive HTLs that were positive for granzyme B could directly kill tumor cells in a killing assay [27]. ...
Colorectal cancer (CRC) patients with metastatic lesions have low 5-year survival rates. During metastasis, cancer cells often obtain unique characteristics such as epithelial–mesenchymal transition (EMT). Vimentin a biomarker contributes to EMT by changing cell shape and motility. Since abnormal phosphorylation is a hallmark of malignancy, targeting phosphorylated vimentin is a feasible approach for the treatment of metastatic tumors while sparing non-tumor cells. Recent evidence has revealed that both CD8 cytotoxic T lymphocytes (CTLs) and also CD4 helper T lymphocytes (HTLs) can distinguish post-translationally modified antigens from normal antigens. Here, we showed that the expression of phosphorylated vimentin was upregulated in metastatic sites of CRC. We also showed that a chemotherapeutic reagent augmented the expression of phosphorylated vimentin. The novel phosphorylated helper peptide epitopes from vimentin could elicit a sufficient T cell response. Notably, precursor lymphocytes that specifically reacted to these phosphorylated vimentin-derived peptides were detected in CRC patients. These results suggest that immunotherapy targeting phosphorylated vimentin could be promising for metastatic CRC patients.
... Cytotoxic T cells (CTLs) as a 'killer' or cytotoxin that produces a specific antigenic response, can specifically target LSCs and play a crucial role in the control of leukemia 9 . CTLs express CD8 on their surface and can bind directly to tumour-associated antigen (TAA)-derived killer peptides to result in cancer cell death 10 . For leukemia, this TAA is leukemia-associated antigen (LAA). ...
