Encouraging Clinical Evolution of a Pediatric Patient With Relapsed Diffuse Midline Glioma Who Underwent WT1-Targeting Immunotherapy: A Case Report and Literature Review

Hashii, Yoshiko; Oka, Y.; Kagawa, Naoki; Hashimoto, Naoya; Saitou, Hiroyuki; Fukuya, Shogo; Kanegae, Mizuki; Ikejima, Sayaka; Oji, Yusuke; Ozono, Keiichi; Tsuboi, Akihiro; Sugiyama, Haruo

doi:10.3389/fonc.2020.01188

“…Diffuse midline glioma (DMG) in children is a highly aggressive, malignant brain tumor.DMG is fatal when relapsed. An encouraging case report of a pediatric patient who had DMG that regrew after chemoradiotherapy and underwent WT1 peptide vaccination (formulated with Montanide and injected intradermally) was published [44]. A 13-year-old Japanese boy was diagnosed with DMG, which is a grade IV glioma.…”

Section: ) Wt1 Peptide Vaccinementioning

confidence: 99%

Immunotherapeutic Peptide Vaccine Approaches to Glioma

Lin¹,

Anekoji²,

Ichim³

2021

J Can Res Rev Rep

1

0

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Heretofore, there are no FDA-approved immunotherapeutics for malignant gliomas despite many novel therapies currently in different stages of clinical trials. Malignant gliomas are immunosuppressive tumors and are difficult for immune effector cells to infiltrate the tumor sites in the central nervous system. This inefficiency results in median survival of about only two years with a few long-term survivors. Recent clinical trials of vaccine-based immunotherapies against malignant gliomas have demonstrated encouraging results in enhancing progression-free survival and overall survival of patients. The vaccine-based treatments include peptide and heat-shock proteins, dendritic cell-based vaccines, as well as viral-based immunotherapy. In this review, we will focus on recent clinical trials of neoantigen peptide vaccines on gliomas, the delivery routes of such peptide vaccines, their adjuvants, clinical challenges, and its future strategies, respectively.

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A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies

Fu

¹

,

Piccioni²,

Liu

³

et al. 2021

Sci Rep

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WT2725 is a Wilms’ tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56–81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309–648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6–19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development.Trial registration: NCT01621542.

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Adjuvant Wilms’ tumour 1-specific dendritic cell immunotherapy complementing conventional therapy for paediatric patients with high-grade glioma and diffuse intrinsic pontine glioma: protocol of a monocentric phase I/II clinical trial in Belgium

Van Genechten,

De Laere,

Van den Bossche

et al. 2024

BMJ Open

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Introduction Diffuse intrinsic pontine glioma (DIPG) and paediatric high-grade glioma (pHGG) are aggressive glial tumours, for which conventional treatment modalities fall short. Dendritic cell (DC)-based immunotherapy is being investigated as a promising and safe adjuvant therapy. The Wilms’ tumour protein (WT1) is a potent target for this type of antigen-specific immunotherapy and is overexpressed in DIPG and pHGG. Based on this, we designed a non-randomised phase I/II trial, assessing the feasibility and safety ofWT1mRNA-loaded DC (WT1/DC) immunotherapy in combination with conventional treatment in pHGG and DIPG. Methods and analysis 10 paediatric patients with newly diagnosed or pretreated HGG or DIPG were treated according to the trial protocol. The trial protocol consists of leukapheresis of mononuclear cells, the manufacturing of autologous WT1/DC vaccines and the combination of WT1/DC-vaccine immunotherapy with conventional antiglioma treatment. In newly diagnosed patients, this comprises chemoradiation (oral temozolomide 90 mg/m2daily+radiotherapy 54 Gy in 1.8 Gy fractions) followed by three induction WT1/DC vaccines (8–10×106cells/vaccine) given on a weekly basis and a chemoimmunotherapy booster phase consisting of six 28-day cycles of oral temozolomide (150–200 mg/m2on days 1–5) and a WT1/DC vaccine on day 21. In pretreated patients, the induction and booster phase are combined with best possible antiglioma treatment at hand. Primary objectives are to assess the feasibility of the production of mRNA-electroporated WT1/DC vaccines in this patient population and to assess the safety and feasibility of combining conventional antiglioma treatment with the proposed immunotherapy. Secondary objectives are to investigate in vivo immunogenicity of WT1/DC vaccination and to assess disease-specific and general quality of life. Ethics and dissemination The ethics committee of the Antwerp University Hospital and the University of Antwerp granted ethics approval. Results of the clinical trial will be shared through publication in a peer-reviewed journal and presentations at conferences. Trial registration number NCT04911621

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Encouraging Clinical Evolution of a Pediatric Patient With Relapsed Diffuse Midline Glioma Who Underwent WT1-Targeting Immunotherapy: A Case Report and Literature Review

Cited by 3 publications

References 27 publications

Immunotherapeutic Peptide Vaccine Approaches to Glioma

Immunotherapeutic Peptide Vaccine Approaches to Glioma

A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies

Adjuvant Wilms’ tumour 1-specific dendritic cell immunotherapy complementing conventional therapy for paediatric patients with high-grade glioma and diffuse intrinsic pontine glioma: protocol of a monocentric phase I/II clinical trial in Belgium

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