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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]