title: Enhanced efficacy and reduced toxicity of multifactorial adjuvants compared with unitary adjuvants as cancer vaccines.
abstract: Identification of Toll-like receptors (TLRs) and their ligands, and tumor necrosis factor-tumor necrosis factor receptor (TNF-TNFR) pairs have provided the first logical, hypothesis-based strategies to molecularly concoct adjuvants to elicit potent cell-mediated immunity via activation of innate and adaptive immunity. However, isolated activation of one immune pathway in the absence of others can be toxic, ineffective, and detrimental to long-term, protective immunity. Effective engineered vaccines must include agents that trigger multiple immunologic pathways. Here, we report that combinatorial use of CD40 and TLR agonists as a cancer vaccine, compared with monotherapy, elicits high frequencies of self-reactive CD8(+) T cells, potent tumor-specific CD8(+) memory, CD8(+) T cells that efficiently infiltrate the tumor-burdened target organ; therapeutic efficacy; heightened ratios of CD8(+) T cells to FoxP3(+) cells at the tumor site; and reduced hepatotoxicity. These findings provide intelligent strategies for the formulation of multifactorial vaccines to achieve maximal efficacy in cancer vaccine trials in humans.
authors.affiliation: Department of Microbiology & Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: Cory L
authors.initials: CL
authors.lastname: Ahonen
authors.forename: Anna
authors.initials: A
authors.lastname: Wasiuk
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Fuse
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Turk
authors.forename: Marc S
authors.initials: MS
authors.lastname: Ernstoff
authors.forename: Arief A
authors.initials: AA
authors.lastname: Suriawinata
authors.forename: James D
authors.initials: JD
authors.lastname: Gorham
authors.forename: Ross M
authors.initials: RM
authors.lastname: Kedl
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Usherwood
authors.forename: Randolph J
authors.initials: RJ
authors.lastname: Noelle
mesh_terms: D000276:Adjuvants, Immunologic / Q000633:toxicity*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D019013:CD40 Antigens / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology* / Q000378:metabolism / Q000633:toxicity*; D045744:Cell Line, Tumor; D017690:Cell Transplantation; D007156:Immunologic Memory / Q000276:immunology; D007167:Immunotherapy; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000293:injuries; D008168:Lung / Q000276:immunology / Q000601:surgery; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000906:Antibodies; D019013:CD40 Antigens; D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7