title: Toll-Like Receptor Triggering and T-Cell Costimulation Induce Potent Antitumor Immunity in Mice.
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).
authors.affiliation: Authors' Affiliations: Cancer Immunology Research Program, Peter MacCallum Cancer Centre; Departments of Microbiology and Immunology and Pathology, University of Melbourne, Melbourne, Australia; and Laboratory of Liposome Research, Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Westwood
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
authors.forename: Janelle
authors.initials: J
authors.lastname: Sharkey
authors.forename: Nicole
authors.initials: N
authors.lastname: McLaughlin
authors.forename: Hollie J
authors.initials: HJ
authors.lastname: Pegram
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schwendener
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw