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<p>Glioblastoma remains a challenging indication for immunotherapy: the blood-brain barrier hampers accessibility for systemic treatments and the immunosuppressive microenvironment impedes immune attack. Intratumoral therapy with the proinflammatory cytokine interleukin-12 (IL-12) can revert immunosuppression but leakage into the circulation causes treatment-limiting toxicity. Here we engineer an IL-12Fc fusion cytokine with reduced binding to the neonatal Fc receptor FcRn. FcRn-silenced IL-12Fc avoids FcRn-mediated brain export, thus exhibits prolonged brain retention and reduced blood levels, which prevents toxicity. In murine glioblastoma, FcRn-silenced IL-12Fc induces more durable responses with negligible systemic cytokine exposure and boosts the efficacy of radio- and chemotherapy. It triggers anti-tumor responses independently of peripheral T cell influx or lymphopenia and leads to inflammatory polarization of the tumor microenvironment in patient-derived glioblastoma explants. FcRn-silencing of IL-12Fc may unlock the full potential of IL-12 for brain cancer therapy and could be further applied to containing the activity of other therapeutics targeting neurological diseases.</p>

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FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月22日

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  • Michal Beffinger,
  • Linda Schellhammer,
  • Betül Taskoparan,
  • Sereina Deplazes,
  • Ulisse Salazar,
  • Nazanin Tatari,
  • Frauke Seehusen,
  • Leopold von Balthazar,
  • Carl Philipp Zinner,
  • Sabine Spath,
  • Tala Shekarian,
  • Marie-Françoise Ritz,
  • Marta McDaid,
  • Pascal Egloff,
  • Iwan Zimmermann,
  • Hideho Okada,
  • E. Sally Ward,
  • Jack Rohrer,
  • Markus A. Seeger,
  • Thorsten Buch,
  • Gregor Hutter,
  • Johannes vom Berg

摘要

Glioblastoma remains a challenging indication for immunotherapy: the blood-brain barrier hampers accessibility for systemic treatments and the immunosuppressive microenvironment impedes immune attack. Intratumoral therapy with the proinflammatory cytokine interleukin-12 (IL-12) can revert immunosuppression but leakage into the circulation causes treatment-limiting toxicity. Here we engineer an IL-12Fc fusion cytokine with reduced binding to the neonatal Fc receptor FcRn. FcRn-silenced IL-12Fc avoids FcRn-mediated brain export, thus exhibits prolonged brain retention and reduced blood levels, which prevents toxicity. In murine glioblastoma, FcRn-silenced IL-12Fc induces more durable responses with negligible systemic cytokine exposure and boosts the efficacy of radio- and chemotherapy. It triggers anti-tumor responses independently of peripheral T cell influx or lymphopenia and leads to inflammatory polarization of the tumor microenvironment in patient-derived glioblastoma explants. FcRn-silencing of IL-12Fc may unlock the full potential of IL-12 for brain cancer therapy and could be further applied to containing the activity of other therapeutics targeting neurological diseases.