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An IL‐2 proaerolysin fusion toxin that selectively eliminates regulatory t cells to enhance antitumor immune response
Author(s) -
Rogers Oliver,
Yen Hung,
Solomon Anna,
Drake Charles,
Denmeade Samuel
Publication year - 2019
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.23819
Subject(s) - immune system , toxin , immunology , biology , medicine , cancer research , pharmacology , microbiology and biotechnology
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.