title: Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors.
abstract: Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy.
authors.affiliation: Departments of *Surgery §Medicine, Duke University Medical Center ‡Department of Biostatistics & Bioinformatics, Duke University, Durham, NC †Medinet Medical Institute, MEDINET Co., Ltd, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Osada
authors.forename: Koji
authors.initials: K
authors.lastname: Nagaoka
authors.forename: Masashi
authors.initials: M
authors.lastname: Takahara
authors.forename: Xiao Yi
authors.initials: XY
authors.lastname: Yang
authors.forename: Cong-Xiao
authors.initials: CX
authors.lastname: Liu
authors.forename: Hongtao
authors.initials: H
authors.lastname: Guo
authors.forename: Kingshuk
authors.initials: K
authors.lastname: Roy Choudhury
authors.forename: Amy
authors.initials: A
authors.lastname: Hobeika
authors.forename: Zachary
authors.initials: Z
authors.lastname: Hartman
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D002454:Cell Differentiation; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D015232:Dinoprostone / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology; D004359:Drug Therapy, Combination; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010844:Picibanil / Q000494:pharmacology; D057285:Precision Medicine; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000077211:Zoledronic Acid
chemical_list: D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D004164:Diphosphonates; D007093:Imidazoles; D014409:Tumor Necrosis Factor-alpha; D010844:Picibanil; D000077211:Zoledronic Acid; D015232:Dinoprostone