B7H6-Specific Bispecific T Cell Engagers Lead to Tumor Elimination and Host Antitumor Immunity.
Substantial evidence showed that T cells are the key effectors in immune-mediated tumor eradication; however, most T cells do not exhibit antitumor specificity. In this study, a bispecific T cell engager (BiTE) approach was used to direct T cells to recognize B7H6(+) tumor cells. B7H6 is a specific ligand for the NK cell-activating receptor NKp30. B7H6 is expressed on various types of primary human tumors, including leukemia, lymphoma, and gastrointestinal stromal tumors, but it is not constitutively expressed on normal tissues. Data from this study showed that B7H6-specific BiTEs direct T cells to mediate cellular cytotoxicity and IFN-γ secretion upon coculturing with B7H6(+) tumors. Furthermore, B7H6-specific BiTE exhibited no self-reactivity to proinflammatory monocytes. In vivo, B7H6-specific BiTE greatly enhanced the survival benefit of RMA/B7H6 lymphoma-bearing mice through perforin and IFN-γ effector mechanisms. In addition, long-term survivor mice were protected against an RMA lymphoma tumor rechallenge. The B7H6-specific BiTE therapy also decreased tumor burden in murine melanoma and ovarian cancer models. In conclusion, B7H6-specific BiTE activates host T cells and has the potential to treat various B7H6(+) hematological and solid tumors.
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756; and.
Ming-Ru
MR
Wu
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756; and.
Tong
T
Zhang
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756; and.
Albert T
AT
Gacerez
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756; and.
Tiffany A
TA
Coupet
Department of Obstetrics and Gynecology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756.
Leslie R
LR
DeMars
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756; and Charles.L.Sentman@dartmouth.edu.
Charles L
CL
Sentman
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000276:immunology* / Q000627:therapeutic use; D060887:B7 Antigens / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008223:Lymphoma / Q000276:immunology / Q000628:therapy; D008545:Melanoma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy; D054353:Perforin / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D060887:B7 Antigens; C542363:NCR3LG1 protein, human; D054353:Perforin; D007371:Interferon-gamma