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Prostate. 2019 May 6. doi: 10.1002/pros.23819. [Epub ahead of print]

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

Author information

1
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.

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.

KEYWORDS:

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

PMID:
31059598
DOI:
10.1002/pros.23819

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