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Clinical Trial
. 2019 Feb 19;21(3):348-359.
doi: 10.1093/neuonc/noy200.

A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma

Yoshitaka Narita  1 , Yoshiki Arakawa  2 , Fumiyuki Yamasaki  3 , Ryo Nishikawa  4 , Tomokazu Aoki  5 , Masayuki Kanamori  6 , Motoo Nagane  7 , Toshihiro Kumabe  8 , Yuichi Hirose  9 , Tomotsugu Ichikawa  10 , Hiroyuki Kobayashi  11 , Takamitsu Fujimaki  12 , Hisaharu Goto  13 , Hideo Takeshima  14 , Tetsuya Ueba  15 , Hiroshi Abe  16 , Takashi Tamiya  17 , Yukihiko Sonoda  18 , Atsushi Natsume  19 , Tatsuyuki Kakuma  20 , Yasuo Sugita  21 , Nobukazu Komatsu  21 , Akira Yamada  21 , Tetsuro Sasada  22 , Satoko Matsueda  23 , Shigeki Shichijo  24 , Kyogo Itoh  24 , Mizuhiko Terasaki  21
Affiliations
Clinical Trial

A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma

Yoshitaka Narita et al. Neuro Oncol. .

Abstract

Background: We conducted a phase III trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)-A24+ recurrent glioblastoma to develop a new treatment modality.

Methods: We randomly assigned 88 recurrent glioblastoma patients to receive PPV (n = 58) or the placebo (n = 30) at a 2-to-1 ratio. Four of 12 warehouse peptides selected based on preexisting peptide-specific immunoglobulin G levels or the corresponding placebos were injected 1×/week for 12 weeks.

Results: Our trial met neither the primary (overall survival [OS]) nor secondary endpoints. Unfavorable factors for OS of 58 PPV patients compared with 30 placebo patients were SART2-93 peptide selection (n = 13 vs 8, hazard ratio [HR]: 15.9), ≥70 years old (4 vs 4, 7.87), >70 kg body weight (10 vs 7, 4.11), and performance status (PS)3 (8 vs 2, 2.82), respectively. Consequently, the median OS for PPV patients without SART2-93 selection plus one of these 3 favorable factors (<70 y old, ≤70 kg, or PS0-2) was significantly longer than that for the corresponding placebo patients (HR: 0.49, 0.44, and 0.51), respectively. Preexisting immunity against both all 12 warehouse peptides besides SART2-93 and the other cytotoxic T lymphocyte epitope peptides was significantly depressed in the patients with SART2-93 selection (n = 21) compared with that of the patients without SART2-93 selection (n = 67). Biomarkers correlative for favorable OS of the PPV patients were a lower percentage of CD11b+CD14+HLA-DRlow immunosuppressive monocytes and a higher percentage of CD4+CD45RA- activated T cells, the intermediate levels of chemokine C-C ligand 2 (CCL2), vascular endothelial growth factor, interleukin (IL)-6, IL-17, or haptoglobin, respectively.

Conclusion: This phase III trial met neither the primary nor secondary endpoints.

Keywords: biomarker for overall survival; personalized peptide vaccine; phase III trial; pre-existing immunity; recurrent glioblastoma.

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Figures

Fig. 1
Fig. 1
(A) CONSORT diagram. (B) Median overall survival (OS) in the PPV (n = 58) vs BSC (n = 30) groups.
Fig. 2
Fig. 2
(A) Forest plot of the factors involved in OS. HR of the 58 PPV vs the 30 placebo group. (B) Median OS for 13 PPV patients with SART2-93 peptide selection vs the 8 corresponding placebo patients. (C) Median OS for 42 PPV patients without SART2-93 selection plus age <70 years old vs the 18 corresponding placebo patients.
Fig. 3
Fig. 3
Preexisting CTL responses against the 4 peptides selected for PPV (A) or against a mix of the control viral epitope peptides consisting of cytomegalovirus, Epstein–Barr virus, and influenza virus (B) in the patients of the 67 SART2-93(−) group vs those of the 21 SART2-93(+) group. Preexisting IgG responses against the 4 selected peptides for PPV (C), all the 12 HLA-A24–restricted peptides used in this study (D), 12 HLA-A2–restricted CTL peptides (E), or 5 HLA-A3 superfamily (A3, A11, A31, A33)–restricted CTL peptides (F) in these 2 groups, respectively.
Fig. 4
Fig. 4
Median OS of the PPV patients with lower pre-vaccination percentages of CD11b+CD14+HLA-DRlow cells (A) or higher percentages of CD3+CD4+CD45RA− T cells (B) vs those with higher or lower percentages of these cells, respectively. (C) Relationship between pre-vaccination levels of CCL2 and OS in each of 53 PPV patients tested. (D) The median OS between the 2 groups by defining the 12 patients consisting of both the 6 patients from the lowest CCL2 level (lower tail 11th percentile) and the 6 patients from the highest level (upper tail 11th percentile) as CCL2low/high, and the remaining 41 patients (remaining 78th percentile) as CCL2im. (E) Relationship between pre-vaccination levels of VEGF and OS in each of 53 PPV patients tested. (F) The median OS between the 2 groups by defining the 12 patients consisting of both the 6 patients from the lowest VEGF level (lower tail 11th percentile) and the 6 patients from the highest level (upper tail 11th percentile) as VEGFlow/high, and the remaining 41 patients (remaining 78th percentile) as VEGFim.
Fig. 5
Fig. 5
(A) Relationship between pre-vaccination levels of CCL2 and OS in each of 30 placebo patients. (B) The median OS of 7 placebo patients with CCL2low/high vs that of the remaining 23 patients with CCL2im. (C) Relationship between pre-vaccination levels of IL-6 and OS in each of 30 placebo patients. (D) The median OS of 8 placebo patients with IL-6low/high vs the remaining 23 patients with IL-6im. (E) The median OS of 12 PPV patients with CCL2 low/high vs that of the 7 corresponding placebo patients.
See this image and copyright information in PMC

Comment in

  • Bespoke immunotherapy: how close are we?
    Jackson C, Lim M. Jackson C, et al. Neuro Oncol. 2019 Feb 19;21(3):289-290. doi: 10.1093/neuonc/noz017. Neuro Oncol. 2019. PMID: 31222359 Free PMC article. No abstract available.

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