Combined natural killer T-cell based immunotherapy eradicates established tumors in mice.

Abstract

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-gamma. NKTMab therapy containing either alpha-galactosylceramide (alpha-GC) or alpha-C-galactosylceramide (alpha-c-GC) at high concentrations induced similar rates of tumor rejection in mice; however, toxicity was observed at the highest doses of alpha-GC (>250 ng/injection), limiting the use of this glycolipid. By contrast, even very low doses of alpha-c-GC (25 ng/injection) retained considerable antitumor activity when used in combination with anti-DR5/anti-4-1BB, and thus, alpha-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.

• Authors: Michele W L Teng, Jennifer A Westwood, Phillip K Darcy, Janelle Sharkey, Moriya Tsuji, Richard W Franck, Steven A Porcelli, Gurdyal S Besra, Kazuyoshi Takeda, Hideo Yagita, Michael H Kershaw, Mark J Smyth
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 15 Pg. 7495-504 (Aug 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17671220 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Galactosylceramides
• Membrane Glycoproteins
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• Transaminases

Topics

• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• Apoptosis
• CD8-Positive T-Lymphocytes
• Carcinoma, Renal Cell (immunology, pathology, therapy)
• Cell Line, Tumor
• Combined Modality Therapy
• Galactosylceramides (immunology)
• Immunotherapy
• Kidney Neoplasms (immunology, pathology, therapy)
• Killer Cells, Natural (immunology)
• Liver (immunology)
• Lymphocyte Activation
• Mammary Neoplasms, Experimental (immunology, pathology, therapy)
• Membrane Glycoproteins (immunology)
• Mice
• Mice, Inbred BALB C
• Receptors, TNF-Related Apoptosis-Inducing Ligand (immunology)
• Survival Rate
• TNF-Related Apoptosis-Inducing Ligand
• Transaminases (blood)