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<p>Peritoneal carcinomatosis is an advanced stage of cancer with very limited treatment options. Locoregional immunotherapy is being evaluated as a way to improve efficacy and limit toxicity. This study assessed the efficacy of a cationic polymer/lipid-based transfection compound in delivering mRNA molecules intraperitoneally. Our investigation of the transfer of luciferase mRNA in murine models of peritoneal carcinomatosis revealed preferential luciferase expression in the omentum upon the intraperitoneal administration of complexed mRNAs. Macrophages were identified as key cells that capture and express the mRNA complexes, and accordingly, depletion of resident macrophages led to reduced reporter luciferase expression. To explore the therapeutic potential of this approach, mRNA complexes encoding single-chain interleukin-12 (IL12), an immunostimulatory molecule (mRNA-IL12), were investigated. mRNA-IL12-treated mice exhibited a significant survival advantage in models of peritoneal carcinomatosis and acquired immune memory, as shown upon subcutaneous rechallenge. Tumor microenvironment analyses revealed increased numbers of CD4<sup>+</sup> and CD8<sup>+</sup> T cells with a more proliferative phenotype, accompanied by decreased myeloid populations in the omentum. Overall, our study underscores the potential of mRNA complexes for efficient mRNA delivery, eliciting effective antitumor responses and modulating the tumor microenvironment to treat peritoneal carcinomatosis.</p>

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Intraperitoneal administration of mRNA encoding interleukin-12 for immunotherapy in peritoneal carcinomatosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月17日

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  • Leire Arrizabalaga,
  • Claudia Augusta Di Trani,
  • Myriam Fernández-Sendin,
  • Ángela Bella,
  • Joan Salvador Russo-Cabrera,
  • Celia Gomar,
  • Nuria Ardaiz,
  • Virginia Belsue,
  • José González-Gomariz,
  • Sara Zalba,
  • Adrián Gil-Korilis,
  • Maria J. Garrido,
  • Ignacio Melero,
  • Fernando Aranda,
  • Pedro Berraondo

摘要

Peritoneal carcinomatosis is an advanced stage of cancer with very limited treatment options. Locoregional immunotherapy is being evaluated as a way to improve efficacy and limit toxicity. This study assessed the efficacy of a cationic polymer/lipid-based transfection compound in delivering mRNA molecules intraperitoneally. Our investigation of the transfer of luciferase mRNA in murine models of peritoneal carcinomatosis revealed preferential luciferase expression in the omentum upon the intraperitoneal administration of complexed mRNAs. Macrophages were identified as key cells that capture and express the mRNA complexes, and accordingly, depletion of resident macrophages led to reduced reporter luciferase expression. To explore the therapeutic potential of this approach, mRNA complexes encoding single-chain interleukin-12 (IL12), an immunostimulatory molecule (mRNA-IL12), were investigated. mRNA-IL12-treated mice exhibited a significant survival advantage in models of peritoneal carcinomatosis and acquired immune memory, as shown upon subcutaneous rechallenge. Tumor microenvironment analyses revealed increased numbers of CD4+ and CD8+ T cells with a more proliferative phenotype, accompanied by decreased myeloid populations in the omentum. Overall, our study underscores the potential of mRNA complexes for efficient mRNA delivery, eliciting effective antitumor responses and modulating the tumor microenvironment to treat peritoneal carcinomatosis.