Combined natural killer T-cell based immunotherapy eradicates established tumors in mice.
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.
Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Michele W L
MW
Teng
Jennifer A
JA
Westwood
Phillip K
PK
Darcy
Janelle
J
Sharkey
Moriya
M
Tsuji
Richard W
RW
Franck
Steven A
SA
Porcelli
Gurdyal S
GS
Besra
Kazuyoshi
K
Takeda
Hideo
H
Yagita
Michael H
MH
Kershaw
Mark J
MJ
Smyth
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005699:Galactosylceramides / Q000276:immunology*; D007167:Immunotherapy; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology; D008213:Lymphocyte Activation; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D015996:Survival Rate; D053221:TNF-Related Apoptosis-Inducing Ligand; D000637:Transaminases / Q000097:blood
D000911:Antibodies, Monoclonal; D005699:Galactosylceramides; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D000637:Transaminases