A phase I clinical study of a cocktail vaccine of Wilms\u2019 tumor 1 (WT1) HLA class I and II peptides for recurrent malignant glioma

Akihiro Tsuboi,Hiroko Nakajima,Satoshi Morita,Soyoko Morimoto,Naoki Hosen,Junichi Sakamoto,Yusuke Oji,Naoya Hashimoto,Jun Nakata,Haruo Sugiyama,Yoshihiro Oka,Fumihiro Fujiki,Naoki Kagawa,Sumiyuki Nishida

doi:10.1007/s00262-018-2274-1

Abstract

PurposeThe safety and clinical efficacy of WT1 human leukocyte antigen (HLA) class I peptide vaccine have been established, but the safety of a cocktail vaccine of WT1 HLA class I and II peptides has not. To verify its safety, we performed a phase I clinical trial for patients with recurrent malignant gliomas and assessed the immunological responses and survival data.Patients and methodsFourteen HLA-A*24:02-positive patients with recurrent malignant glioma (2 with grade 3, 12 with grade 4) were enrolled. Every week, the patients received alternately a vaccine containing 3 mg of WT1 HLA-A*24:02-restricted (HLA class I) peptide and a cocktail vaccine of the HLA class I peptide and one of 0.75, 1.5 or 3 mg of the WT1 HLA class II peptide. For patients who showed no significant adverse effects within 6 weeks, the WT1 vaccine was continued at 2–4-week intervals.ResultsEleven of the 14 patients completed WT1 vaccination for 6 weeks, while 3 patients dropped out earlier due to disease progression. All patients showed grade I level of skin disorders at the injection sites. No grade III/IV toxicity or dose-limiting toxicity was observed for any dose of WT1 HLA class II peptide. Six of the 14 patients had stable disease at 6 weeks. Median OS and 1-year OS rates were 24.7 weeks and 36%, respectively.ConclusionThe safety of a cocktail vaccine of WT1 HLA class I and II peptides for malignant gliomas was verified. This vaccine is, therefore, considered promising for patients with recurrent malignant glioma.

Highlights

Prognosis of recurrent glioblastoma multiforme (GBM) is extremely poor and treatment options are limited
Advancements in tumor immunology have resulted in the identification of tumor-associated antigen (TAA) that can be used for cancer vaccines, in which the TAA-derived epitopes are combined with human leukocyte antigen (HLA) class I molecules, followed by recognition by C D8+ cytotoxic T lymphocytes (CTLs)
Three of the patients were vaccinated with 0.75 mg, four with 1.5 mg, and four with 3.0 mg of WT1 HLA class II peptide, as well as with 3.0 mg of WT1 HLA class I peptide for all 14 subjects

Summary

Introduction

Prognosis of recurrent glioblastoma multiforme (GBM) is extremely poor and treatment options are limited. We previously identified a WT1 protein-derived 16-mer HLA class II peptide, WT1332 (KRYFKLSHLQMHSRKH), which can elicit WT1332-specific CD4+ T-cell responses, and demonstrated that this WT1332 peptide was endogenously generated from the WT1 protein in WT1-expressing tumor cells. DTH delayed-type hypersensitivity, Doses doses of WT1 class II peptide, Times times of WT1 vaccine, AE adverse effect, SD stable disease, PD progressive disease a Frequencies of WT1 tetramer+ CD8+ T cells, IFN-γ-producing CD8+ T cells, and IFN-α-producing CD4+ T cells were analyzed after 1-week culture of PBMCs. Statistical analysis was performed by means of the Mann–Whitney’s U test. &XOWXUHLQWKHSUHVHQFHRI:7+/$FODVV, SHSPWLGJHP:O7DQG,/PJP,8OPFOODVV,,SHSWLGH:

Results

Discussion

Compliance with ethical standards