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Wang SZ , Astsaturov IA , Bingham CA , McCarthy KM , von Mehren M , Xu W , Alpaugh RK , Tang Y , Littlefield BA , Hawkins LD , Ishizaka ST , Weiner LM
Effective antibody therapy induces host-protective antitumor immunity that is augmented by TLR4 agonist treatment
Cancer Immunology Immunotherapy. 2012 Jan;61(1) :49-61
PMID: WOS:000300662700006    PMCID: PMC3517883   
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Toll-like receptors are potent activators of the innate immune system and generate signals leading to the initiation of the adaptive immune response that can be utilized for therapeutic purposes. We tested the hypothesis that combined treatment with a Toll-like receptor agonist and an antitumor monoclonal antibody is effective and induces host-protective antitumor immunity. C57BL/6 human mutated HER2 (hmHER2) transgenic mice that constitutively express kinase-deficient human HER2 under control of the CMV promoter were established. These mice demonstrate immunological tolerance to D5-HER2, a syngeneic human HER2-expressing melanoma cell line. This human HER2-tolerant model offers the potential to serve as a preclinical model to test both antibody therapy and the immunization potential of human HER2-targeted therapeutics. Here, we show that E6020, a Toll-like receptor-4 (TLR4) agonist effectively boosted the antitumor efficacy of the monoclonal antibody trastuzumab in immunodeficient C57BL/6 SCID mice as well as in C57BL/6 hmHER2 transgenic mice. E6020 and trastuzumab co-treatment resulted in significantly greater inhibition of tumor growth than was observed with either agent individually. Furthermore, mice treated with the combination of trastuzumab and the TLR4 agonist were protected against rechallenge with human HER2-transfected tumor cells in hmHER2 transgenic mouse strains. These findings suggest that combined treatment with trastuzumab and a TLR4 agonist not only promotes direct antitumor effects but also induces a host-protective human HER2-directed adaptive immune response, indicative of a memory response. These data provide an immunological rationale for testing TLR4 agonists in combination with antibody therapy in patients with cancer.
Wang, Shangzi Astsaturov, Igor A. Bingham, Catherine A. McCarthy, Kenneth M. von Mehren, Margaret Xu, Wei Alpaugh, R. Katherine Tang, Yong Littlefield, Bruce A. Hawkins, Lynn D. Ishizaka, Sally T. Weiner, Louis M. National Institutes of Health[R01 CA121033, R21 CA126932, R01 CA050633, CA051008]; Eisai Research Institute; Georgetown University We thank C. Shaller for technical assistance; S. Jablonski for review of this paper; and Antai Wang, Hongfang Liu and Ionut Bebu for help in statistical analyses. We are grateful to the support of Georgetown University's and Fox Chase Cancer Center's Animal Resources Facilities, Flow Cytometry and Cell Sorting Shared Resources, Microscopy and Imaging Shared Resources, Hybridoma facility and the Histology and Tissue Shared Resources. This work was supported by National Institutes of Health Grants R01 CA121033, R21 CA126932, R01 CA050633, CA051008 and by the Eisai Research Institute. B. A. Littlefield, L. D. Hawkins, S. T. Ishizaka are solely affiliated with Eisai Research Institute of Boston, Inc., a company fully owned by Eisai Co., Ltd. Other authors have no conflicting financial interests. 35 Springer New york 897ov