CD1d-based combination therapy eradicates established tumors in mice

Michele W L Teng, Janelle Sharkey, Nicole M. McLaughlin, Mark A. Exley, Mark J. Smyth

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The use of Abs that induce tumor cell death together with immunostimulatory reagents to activate innate and adaptive immune cells has emerged as a potent approach for the treatment of cancer. We have previously demonstrated that the use of three mAbs (anti-DR5, anti-CD40, anti-CD137) termed TriMab can induce rejection in a majority of mice with established experimental or carcinogen-induced tumors. However, given the potential toxicity of CD40 agonists in the clinic, we tested an alternative approach to directly activate/mature APCs using anti-CD1d mAbs. In this study, we used a combination of three mAbs (anti-DR5, anti-CD137, anti-CD1d) that we termed 1DMab and demonstrated that this approach suppressed and/or eradicated established experimental renal, breast, and colon carcinomas in mice. Tumor suppression induced by 1DMab therapy required CD8+ T cells, IFN-γ, and CD1d, while NK cells and IL-12 were partially required. Interestingly 1DMab therapy was more effective than TriMab in tumor models regulated by CD1d-restricted type II NKT cells, but less efficacious against tumors where T regulatory cells were critical. Anti-CD1d mAbs could also be relatively effective in combination with anti-CD137 and conventional chemotherapeutics. This is the first study to illustrate the antitumor activity of CD1d-reactive mAbs in combination and our results strongly suggest that rational combination chemoimmunotherapies based on tumor immunoregulation may improve the efficacy of treatment. Copyright © 2009 by The American Association of Immunologists, Inc.
    Original languageEnglish
    Pages (from-to)1911-1920
    Number of pages9
    JournalJournal of Immunology
    Volume183
    Issue number3
    DOIs
    Publication statusPublished - 1 Aug 2009

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