Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response.
Despite the development of human epidermal growth factor receptor-2 (ErbB-2/HER2)-targeted therapies, there remains an unmet medical need for breast cancer patients with ErbB-2 overexpression. We investigated the therapeutic activity of an agonist mAb to mouse tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 (DR5) against ErbB2-driven breast cancer. Established tumors in BALB/c transgenic mice expressing a constitutively active ErbB-2/neuT were treated with anti-DR5 mAb and/or anti-ErbB-2 mAb and monitored for tumor progression. Treatment with anti-DR5 or anti-ErbB2 mAb as single agents significantly delayed tumor growth, although all tumors eventually progressed. Remarkably, treatment with a combination of anti-DR5 and anti-ErbB-2 mAbs induced complete response in a majority of mice. In vivo blockade of CD11b(+) cells, but not natural killer cell depletion, significantly abrogated the early antitumor response. Notably, depletion of CD8(+) T cells provoked primary and secondary tumor relapse, revealing the induction of antitumor immunity by the combination treatment. Combined therapy with anti-DR5 and anti-ErbB-2 mAbs further significantly suppressed the growth of advanced spontaneous tumors in ErbB-2/neuT transgenic mice, even when treatment was delayed until tumors were palpable. We thus demonstrated that the combination of anti-DR5 and anti-ErbB2 mAbs might be an effective form of treatment for ErbB-2-overexpressing breast cancer.
Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.
John
J
Stagg
Janelle
J
Sharkey
Sandra
S
Pommey
Richard
R
Young
Kazuyoshi
K
Takeda
Hideo
H
Yagita
Ricky W
RW
Johnstone
Mark J
MJ
Smyth
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002460:Cell Line; D004357:Drug Synergism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007167:Immunotherapy; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology* / Q000378:metabolism*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018719:Erb-b2 Receptor Tyrosine Kinases; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand