This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Teng, M. W.L. Articles by Smyth, M. J. Search for Related Content PubMed PubMed Citation Articles by Teng, M. W.L. Articles by Smyth, M. J.

Combined Natural Killer T-Cell–Based Immunotherapy Eradicates Established Tumors in Mice

¹ Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; ² HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, The Rockefeller University; ³ Hunter College, City University of New York, New York, New York; ⁴ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; ⁵ School of Biosciences, University of Birmingham, Birmingham, United Kingdom; ⁶ Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; and ⁷ Department of Pathology, University of Melbourne, Parkville, Victoria, Australia

Requests for reprints: Mark J. Smyth, Cancer Immunology Program, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne, Victoria 8006, Australia. Phone: 61-3-9656-3728; Fax: 61-3-9656-1411; E-mail: mark.smyth{at}petermac.org.

A rational monoclonal antibody (mAb)-based antitumor therapy approach has previously been shown to eradicate various established experimental and carcinogen-induced tumors in a majority of mice. This therapy comprised an agonistic mAb reactive with tumor necrosis factor–related apoptosis-inducing ligand receptor (DR5), expressed by tumor cells, an agonistic anti-CD40 mAb to mature dendritic cells, and an agonistic anti-4-1BB mAb to costimulate CD8⁺ T cells. Because agonists of CD40 have been toxic in patients, we were interested in substituting anti-CD40 mAb with other dendritic cell–maturing agents, such as glycolipid ligands recognized by invariant natural killer T (iNKT) cells. Here, we show that CD1d-restricted glycolipid ligands for iNKT cells effectively substitute for anti-CD40 mAb and reject established experimental mouse breast and renal tumors when used in combination with anti-DR5 and anti-4-1BB mAbs (termed "NKTMab" therapy). NKTMab therapy–induced tumor rejection was dependent on CD4⁺ and CD8⁺ T cells, NKT cells, and the cytokine IFN-. NKTMab therapy containing either -galactosylceramide (-GC) or -C-galactosylceramide (-c-GC) at high concentrations induced similar rates of tumor rejection in mice; however, toxicity was observed at the highest doses of -GC (>250 ng/injection), limiting the use of this glycolipid. By contrast, even very low doses of -c-GC (25 ng/injection) retained considerable antitumor activity when used in combination with anti-DR5/anti-4-1BB, and thus, -c-GC showed a considerably greater therapeutic index. In summary, sequential tumor cell apoptosis and amplification of dendritic cell function by NKT cell agonists represents an exciting and novel approach for cancer treatment. [Cancer Res 2007;67(15):7495–504]

This article has been cited by other articles:

				M. W. L. Teng, J. Sharkey, N. M. McLaughlin, M. A. Exley, and M. J. Smyth CD1d-Based Combination Therapy Eradicates Established Tumors in Mice J. Immunol., August 1, 2009; 183(3): 1911 - 1920. [Abstract] [Full Text] [PDF]

				S.-i. Fujii, A. Goto, and K. Shimizu Antigen mRNA-transfected, allogeneic fibroblasts loaded with NKT-cell ligand confer antitumor immunity Blood, April 30, 2009; 113(18): 4262 - 4272. [Abstract] [Full Text] [PDF]

				M. Terabe and J. A. Berzofsky NKT Cells and Cancer: Two Subsets Form a New Immunoregulatory Axis Am. Assoc. Cancer Res. Educ. Book, April 18, 2009; 2009(1): 203 - 208. [Full Text] [PDF]

				K. A. Pilones, N. Kawashima, A. M. Yang, J. S. Babb, S. C. Formenti, and S. Demaria Invariant Natural Killer T Cells Regulate Breast Cancer Response to Radiation and CTLA-4 Blockade Clin. Cancer Res., January 15, 2009; 15(2): 597 - 606. [Abstract] [Full Text] [PDF]