Silencing of VEGFR2 by RGD-modified lipid nanoparticles enhanced the efficacy of anti-PD-1 antibody by accelerating vascular normalization and infiltration of T cells in tumors

Riki Cho, Yu Sakurai, Haleigh Sakura Jones, Hidetaka Akita, Akihiro Hisaka, Hiroto Hatakeyama

Research output: Contribution to journalArticlepeer-review

Abstract

Despite the promising anticancer effects of immune checkpoint inhibitors, their low objective response rate remains to be resolved; thus, combination therapies have been investigated. We investigated the combination of an anti-programmed cell death 1 (aPD-1) monoclonal antibody with the knockdown of vascular endothelial factor receptor 2 (VEGFR2) on tumor endothelial cells to overcome resistance to immune checkpoint inhibitors and improve the objective response rate. The successful delivery of small interfering RNA to tumor endothelial cells was achieved by RGD peptide-modified lipid nanoparticles composed of a novel, pH-sensitive, and biodegradable ssPalmO-Phe. RGD-modified lipid nanoparticles efficiently induced the knockdown of VEGFR2 in tumor endothelial cells (TECs), which induced vascular normalization. The combination of a PD-1 monoclonal antibody with Vegfr2 knockdown enhanced CD8+ T cell infiltration into tumors and successfully suppressed tumor growth and improved response rate compared with monotherapy. Our combination approach provides a promising strategy to improve therapeutic outcomes in immune checkpoint inhibitor-resistant cancers.

Original languageEnglish
Article number3630
Pages (from-to)1-14
Number of pages14
JournalCancers
Volume12
Issue number12
DOIs
Publication statusPublished - 2020 Dec
Externally publishedYes

Keywords

  • APD-1
  • Immune checkpoint inhibitor
  • Lipid nanoparticle
  • RGD
  • SiRNA
  • SsPalm
  • Vascular normalization

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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