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CD1d-Based Combination Therapy Eradicates Established Tumors in Mice¹

Michele W. L. Teng^*, Janelle Sharkey^*, Nicole M. McLaughlin^*, Mark A. Exley and Mark J. Smyth^2,*,

^* Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Beth Israel Deaconess Medical Center, Boston, MA 02215; and Department of Pathology, University of Melbourne, Parkville, Australia

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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ M.J.S. was supported by a National Health and Medical Research Council of Australia Senior Principal Research Fellowship and a Cancer Council of Victoria Project Grant. M.W.L.T. was supported by a National Health and Medical Research Council Doherty Fellowship and the Cancer Council of Victoria. M.A.E. was supported by National Institutes of Health Grant DK66917.

² Address correspondence and reprint requests to Dr. Mark J. Smyth, Cancer Immunology Program, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, East Melbourne, 8006, Victoria, Australia. E-mail address: mark.smyth{at}petermac.org

³ Abbreviations used in this paper: DC, dendritic cell; -GC, -galactosylceramide; ASGM1, asialo GM1; cIg, control Ig; WT, wild type; GEM, gemcitabine; Dox, doxorubicin; 5-FU-, 5-fluoracil; Treg, regulatory T cell; DLN, draining lymph node.