Toll-Like Receptor Triggering and T-Cell Costimulation Induce Potent Antitumor Immunity in Mice.
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).
Westwood
Jennifer A
JA
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.
Haynes
Nicole M
NM
Sharkey
Janelle
J
McLaughlin
Nicole
N
Pegram
Hollie J
HJ
Schwendener
Reto A
RA
Smyth
Mark J
MJ
Darcy
Phillip K
PK
Kershaw
Michael H
MH