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 journalArticle

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

Fingerprint

Interleukin-2
Immunosuppressive Agents
Hemagglutinins
Neoplasms
Prostatic Neoplasms
Bacterial Toxins
Antigens
Tumor Microenvironment
Interleukin-2 Receptors
Poisons
Neoplasm Antigens
Regulatory T-Lymphocytes
proaerolysin
Mesenchymal Stromal Cells
Immune System
Vaccination
Proteins
Therapeutics
Vaccines
Cytokines

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

An IL-2 proaerolysin fusion toxin that selectively eliminates regulatory t cells to enhance antitumor immune response. / Rogers, Oliver; Yen, Hung; Solomon, Anna; Drake, Charles; Denmeade, Samuel R.

In: Prostate, Vol. 79, No. 10, 01.07.2019, p. 1071-1078.

Research output: Contribution to journalArticle

Rogers, Oliver ; Yen, Hung ; Solomon, Anna ; Drake, Charles ; Denmeade, Samuel R. / An IL-2 proaerolysin fusion toxin that selectively eliminates regulatory t cells to enhance antitumor immune response. In: Prostate. 2019 ; Vol. 79, No. 10. pp. 1071-1078.
@article{ba709731eacb4ef29b794d5ce60581bf,
title = "An IL-2 proaerolysin fusion toxin that selectively eliminates regulatory t cells to enhance antitumor immune response",
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 = "fusion protein, IL-2, proaerolysin (PA), regulatory T cells (Tregs), vaccine",
author = "Oliver Rogers and Hung Yen and Anna Solomon and Charles Drake and Denmeade, {Samuel R}",
year = "2019",
month = "7",
day = "1",
doi = "10.1002/pros.23819",
language = "English (US)",
volume = "79",
pages = "1071--1078",
journal = "Prostate",
issn = "0270-4137",
publisher = "Wiley-Liss Inc.",
number = "10",

}

TY - JOUR

T1 - An IL-2 proaerolysin fusion toxin that selectively eliminates regulatory t cells to enhance antitumor immune response

AU - Rogers, Oliver

AU - Yen, Hung

AU - Solomon, Anna

AU - Drake, Charles

AU - Denmeade, Samuel R

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

KW - fusion protein

KW - IL-2

KW - proaerolysin (PA)

KW - regulatory T cells (Tregs)

KW - vaccine

UR - http://www.scopus.com/inward/record.url?scp=85066396321&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066396321&partnerID=8YFLogxK

U2 - 10.1002/pros.23819

DO - 10.1002/pros.23819

M3 - Article

C2 - 31059598

AN - SCOPUS:85066396321

VL - 79

SP - 1071

EP - 1078

JO - Prostate

JF - Prostate

SN - 0270-4137

IS - 10

ER -