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Toll-like receptor triggering and T-cell costimulation induce potent antitumor immunity in mice


Westwood, J A; Haynes, N M; Sharkey, J; McLaughlin, N; Pegram, H J; Schwendener, R A; Smyth, M J; Darcy, P K; Kershaw, M H (2009). Toll-like receptor triggering and T-cell costimulation induce potent antitumor immunity in mice. Clinical Cancer Research, 15(24):7624-7633.

Abstract

PURPOSE: To determine the antitumor activity of a novel combination of two immunomodulatory agents that simultaneously direct multiple components of immunity against cancer. EXPERIMENTAL DESIGN: We combined the Toll-like receptor agonist CpG 1826 with a T-cell costimulatory antibody specific for CD137 in an optimal treatment route and dosing schedule against established tumors in two mouse models. Mechanistic insight was gained using gene-deficient mice and cell-depleting antibodies. RESULTS: The combination was shown to eradicate tumors in a large proportion of mice. Crucial roles for CD8(+) T cells, natural killer cells, and IFNs were shown. CpG and anti-CD137 injection led to activation of dendritic cells and optimal expansion of activated T cells in the blood. Macrophages were not necessary for therapeutic effect, and indeed depletion of macrophages in vivo enhanced therapy leading to tumor rejection in 100% of mice, which has not been previously reported in the immunotherapeutic setting. Long-term surviving mice were resistant to tumor rechallenge, demonstrating immunologic memory. In addition, we show, for the first time, that mice lacking B cells have a total loss of a recall response against tumor, suggesting a role for B cells in the induction of antitumor immunologic memory. CONCLUSION: This study provides support for the use of a novel combination of immunomodulatory agents stimulating multiple facets of immunity for the effective immunotherapy of cancer. (Clin Cancer Res 2009;15(24):7624-33).

PURPOSE: To determine the antitumor activity of a novel combination of two immunomodulatory agents that simultaneously direct multiple components of immunity against cancer. EXPERIMENTAL DESIGN: We combined the Toll-like receptor agonist CpG 1826 with a T-cell costimulatory antibody specific for CD137 in an optimal treatment route and dosing schedule against established tumors in two mouse models. Mechanistic insight was gained using gene-deficient mice and cell-depleting antibodies. RESULTS: The combination was shown to eradicate tumors in a large proportion of mice. Crucial roles for CD8(+) T cells, natural killer cells, and IFNs were shown. CpG and anti-CD137 injection led to activation of dendritic cells and optimal expansion of activated T cells in the blood. Macrophages were not necessary for therapeutic effect, and indeed depletion of macrophages in vivo enhanced therapy leading to tumor rejection in 100% of mice, which has not been previously reported in the immunotherapeutic setting. Long-term surviving mice were resistant to tumor rechallenge, demonstrating immunologic memory. In addition, we show, for the first time, that mice lacking B cells have a total loss of a recall response against tumor, suggesting a role for B cells in the induction of antitumor immunologic memory. CONCLUSION: This study provides support for the use of a novel combination of immunomodulatory agents stimulating multiple facets of immunity for the effective immunotherapy of cancer. (Clin Cancer Res 2009;15(24):7624-33).

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2009
Deposited On:08 Jan 2010 08:33
Last Modified:05 Apr 2016 13:42
Publisher:American Association for Cancer Research
ISSN:1078-0432
Publisher DOI:https://doi.org/10.1158/1078-0432.CCR-09-2201
PubMed ID:19996209
Permanent URL: https://doi.org/10.5167/uzh-26751

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