2025-08-01 近畿大学
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図 mRNAワクチンと免疫チェックポイント阻害剤の併用による、腹膜転移型の胃がんの治療
<関連情報>
ネオアンチゲンmRNAワクチンは、腹膜転移を伴う胃がんにおける抗PD-1療法をサポートする前駆細胞消耗型T細胞を誘導する Neoantigen mRNA vaccines induce progenitor-exhausted T cells that support anti-PD-1 therapy in gastric cancer with peritoneal metastasis
Koji Nagaoka,Hideyuki Nakanishi,Hiroki Tanaka,Jessica Anindita,Takeshi Kawamura,Toshiya Tanaka,Takefumi Yamashita,Akihiro Kuroda,Sachiyo Nomura,Hidetaka Akita,Keiji Itaka,Tatsuhiko Kodama & Kazuhiro Kakimi
Gastric Cancer Published:31 July 2025
DOI:https://doi.org/10.1007/s10120-025-01640-8
Abstract
Background
Gastric cancer with peritoneal metastasis is associated with a poor prognosis. Current treatments, including the first-line therapy of combination chemotherapy with nivolumab for advanced recurrent gastric cancer, have shown limited efficacy against peritoneal dissemination. In this study, we evaluated neoantigen (neoAg)-mRNA lipid nanoparticle (LNP) as a potential agent in combination with anti-PD-1 therapy, focusing on its effects on neoAg-specific CD8+ T cell responses and antitumor efficacy in a murine gastric cancer model.
Methods
The mRNA, comprising a tandem minigene encoding three neoAgs identified from the murine gastric cancer YTN16 cell line, was synthesized by in vitro transcription and encapsulated within LNPs. NeoAg-specific CD8+ T cells in the spleens and tumors were assessed by flow cytometry. The antitumor efficacy of the neoAg-mRNA-LNP vaccine, alone or in combination with anti-PD-1 antibody, was evaluated in both subcutaneous and peritoneal metastasis models of YTN16.
Results
The neoAg-mRNA-LNP vaccine induced significantly higher frequencies of neoAg-specific CD8+ T cells than the neoAg-dendritic cell vaccine, confirming its enhanced immunogenicity. NeoAg-mRNA-LNP vaccination led to robust tumor regression, achieving complete eradication in all treated mice, especially when combined with anti-PD-1 therapy. This effect was associated with an increase in neoAg-specific progenitor-exhausted and intermediate-exhausted CD8+ T cells. In a peritoneal metastasis model, neoAg-mRNA-LNP monotherapy prevented peritoneal dissemination when administered prophylactically, and combination therapy with anti-PD-1 effectively suppressed tumor growth in a therapeutic setting.
Conclusions
NeoAg-mRNA-LNP vaccines elicit potent neoAg-specific CD8+ T cell responses and show enhanced antitumor efficacy with anti-PD-1 therapy in gastric cancer with peritoneal metastasis.
