An IL-2 proaerolysin fusion toxin that selectively eliminates regulatory t cells to enhance antitumor immune response

Oliver Rogers, Hung Yen, Anna Solomon, Charles Drake, Samuel R Denmeade

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Recent success with immune-checkpoint inhibitors in some tumor types has highlighted the power of the immune system to control and eradicate human cancer cells. However, these therapies have demonstrated a limited activity in prostate cancer, which has a more immunosuppressive microenvironment that can be because of the presence of a variety of inhibitory cell types, such as myeloid-derived suppressor cells, mesenchymal stem cells, and regulatory T cells (Tregs). One strategy to improve the efficacy of immune-based therapies for prostate cancer is to selectively eliminate these immunosuppressive cells within the tumor microenvironment. Methods: We developed and characterized a chimeric protein consisting of the cytokine IL-2 fused to binding mutant of the highly toxic bacterial toxin proaerolysin (ie IL2-R336A). Results: The IL2-R336A fusion protein selectively kills immunosuppressive Tregs that express the IL-2 receptor while having little to no effect on cells negative for this target. IL2-R336A depleted Tregs in both tumor bearing and nontumor bearing mice. Tumor bearing mice vaccinated with a GMCSF-expressing CT-26 GVAX vaccine had reduced tumor growth when given IL2-R336A before vaccination. IL2-R336A also enhanced immune response to a model hemagglutinin antigen (HA) in HA-tolerized mice. Conclusion: These results suggest that this IL2-R336A toxin may be a useful in improving the therapeutic efficacy of antitumor vaccines by enhancing the immune response against target tumor antigens.

Original languageEnglish (US)
Pages (from-to)1071-1078
Number of pages8
JournalProstate
Volume79
Issue number10
DOIs
StatePublished - Jul 1 2019

Keywords

  • fusion protein
  • IL-2
  • proaerolysin (PA)
  • regulatory T cells (Tregs)
  • vaccine

ASJC Scopus subject areas

  • Oncology
  • Urology

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