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Gene-modified dendritic cell vaccines for cancer

  • Rebecca S. Abraham
    Affiliations
    UF Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Department of Neurosurgery, University of Florida, Gainesville, FL 32605
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  • Duane A. Mitchell
    Correspondence
    Correspondence: Duane A. Mitchell, MD, PhD, University of Florida, PO Box 100265, Gainesville, FL 32605, USA.
    Affiliations
    UF Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Department of Neurosurgery, University of Florida, Gainesville, FL 32605
    Search for articles by this author

      Abstract

      Dendritic cell (DC) vaccines are an immunotherapeutic approach to cancer treatment that use the antigen-presentation machinery of DCs to activate an endogenous anti-tumor response. In this treatment strategy, DCs are cultured ex vivo, exposed to tumor antigens and administered to the patient. The ex vivo culturing provides a unique and powerful opportunity to modify and enhance the DCs. As such, a variety of genetic engineering approaches have been employed to optimize DC vaccines, including the introduction of messenger RNA and small interfering RNA, viral gene transduction, and even fusion with whole tumor cells. In general, these modifications aim to improve targeting, enhance immunogenicity, and reduce susceptibility to the immunosuppressive tumor microenvironment. It has been demonstrated that several of these modifications can be employed in tandem, allowing for fine-tuning and optimization of the DC vaccine across multiple metrics. Thus, the application of genetic engineering techniques to the dendritic cell vaccine platform has the potential to greatly enhance its efficacy in the clinic.
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      References

        • Turnis M.E.
        • Rooney C.M.
        Enhancement of dendritic cells as vaccines for cancer.
        Immunotherapy. 2010; 2: 847-862
        • Constantino J.
        • Gomes C.
        • Falcao A.
        • Cruz M.T.
        • Neves B.M.
        Antitumor dendritic cell-based vaccines: lessons from 20 years of clinical trials and future perspectives.
        Transl Res. 2016; 168: 74-95
        • Van Tendeloo V.F.
        • Ponsaerts P.
        • Lardon F.
        • Nijs G.
        • Lenjou M.
        • Van Broeckhoven C.
        • et al.
        Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells.
        Blood. 2001; 98: 49-56
        • Nair S.K.
        • Boczkowski D.
        • Morse M.
        • Cumming R.I.
        • Lyerly H.K.
        • Gilboa E.
        Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA.
        Nat Biotechnol. 1998; 16: 364-369
        • Boczkowski D.
        • Nair S.K.
        • Snyder D.
        • Gilboa E.
        Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo.
        J Exp Med. 1996; 184: 465-472
        • Dewitte H.
        • Van Lint S.
        • Heirman C.
        • Thielemans K.
        • De Smedt S.C.
        • Breckpot K.
        • et al.
        The potential of antigen and TriMix sonoporation using mRNA-loaded microbubbles for ultrasound-triggered cancer immunotherapy.
        J Control Release. 2014; 194: 28-36
        • Van Meirvenne S.
        • Straetman L.
        • Heirman C.
        • Dullaers M.
        • De Greef C.
        • Van Tendeloo V.
        • et al.
        Efficient genetic modification of murine dendritic cells by electroporation with mRNA.
        Cancer Gene Ther. 2002; 9: 787-797
        • Heiser A.
        • Maurice M.A.
        • Yancey D.R.
        • Coleman D.M.
        • Dahm P.
        • Vieweg J.
        Human dendritic cells transfected with renal tumor RNA stimulate polyclonal T-cell responses against antigens expressed by primary and metastatic tumors.
        Cancer Res. 2001; 61: 3388-3393
        • Sousa-Canavez J.M.
        • Canavez F.C.
        • Leite K.R.
        • Camara-Lopes L.H.
        Therapeutic dendritic cell vaccine preparation using tumor RNA transfection: a promising approach for the treatment of prostate cancer.
        Genet Vaccines Ther. 2008; 6: 2
        • Wang K.
        • Zhou Q.
        • Guo A.L.
        • Xu C.R.
        • An S.J.
        • Wu Y.L.
        An autologous therapeutic dendritic cell vaccine transfected with total lung carcinoma RNA stimulates cytotoxic T lymphocyte responses against non-small cell lung cancer.
        Immunol Invest. 2009; 38: 665-680
        • Gao L.
        • Fan H.H.
        • Lu H.Z.
        • Nie X.X.
        • Liu Y.
        • Yang Y.M.
        • et al.
        Impact of transfection with total RNA of K562 cells upon antigen presenting, maturation, and function of human dendritic cells from peripheral blood mononuclear cells.
        Transfusion. 2007; 47: 256-265
        • Geiger C.
        • Regn S.
        • Weinzierl A.
        • Noessner E.
        • Schendel D.J.
        A generic RNA-pulsed dendritic cell vaccine strategy for renal cell carcinoma.
        J Transl Med. 2005; 3: 29
        • Su Z.
        • Dannull J.
        • Heiser A.
        • Yancey D.
        • Pruitt S.
        • Madden J.
        • et al.
        Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells.
        Cancer Res. 2003; 63: 2127-2133
        • Caruso D.A.
        • Orme L.M.
        • Amor G.M.
        • Neale A.M.
        • Radcliff F.J.
        • Downie P.
        • et al.
        Results of a Phase I study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children with Stage 4 neuroblastoma.
        Cancer. 2005; 103: 1280-1291
        • Caruso D.A.
        • Orme L.M.
        • Neale A.M.
        • Radcliff F.J.
        • Amor G.M.
        • Maixner W.
        • et al.
        Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer.
        Neuro Oncol. 2004; 6: 236-246
        • Kyte J.A.
        • Gaudernack G.
        Immuno-gene therapy of cancer with tumour-mRNA transfected dendritic cells.
        Cancer Immunol Immunother. 2006; 55: 1432-1442
        • Osada T.
        • Nagaoka K.
        • Takahara M.
        • Yang X.Y.
        • Liu C.X.
        • Guo H.
        • et al.
        Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors.
        J Immunother. 2015; 38: 155-164
        • Pan K.
        • Zhao J.J.
        • Wang H.
        • Li J.J.
        • Liang X.T.
        • Sun J.C.
        • et al.
        Comparative analysis of cytotoxic T lymphocyte response induced by dendritic cells loaded with hepatocellular carcinoma-derived RNA or cell lysate.
        Int J Biol Sci. 2010; 6: 639-648
        • Hatfield P.
        • Merrick A.E.
        • West E.
        • O'Donnell D.
        • Selby P.
        • Vile R.
        • et al.
        Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy.
        J Immunother. 2008; 31: 620-632
        • Lu Y.C.
        • Robbins P.F.
        Cancer immunotherapy targeting neoantigens.
        Semin Immunol. 2016; 28: 22-27
        • Javorovic M.
        • Pohla H.
        • Frankenberger B.
        • Wölfel T.
        • Schendel D.J.
        RNA transfer by electroporation into mature dendritic cells leading to reactivation of effector-memory cytotoxic T lymphocytes: a quantitative analysis.
        Mol Ther. 2005; 12: 734-743
        • Javorovic M.
        • Wilde S.
        • Zobywalski A.
        • Noessner E.
        • Lennerz V.
        • Wölfel T.
        • et al.
        Inhibitory effect of RNA pool complexity on stimulatory capacity of RNA-pulsed dendritic cells.
        J Immunother. 2008; 31: 52-62
        • Turksma A.W.
        • Bontkes H.J.
        • Ruizendaal J.J.
        • Scholten K.B.
        • Akershoek J.
        • Rampersad S.
        • et al.
        Exploring dendritic cell based vaccines targeting survivin for the treatment of head and neck cancer patients.
        J Transl Med. 2013; 11: 152
        • Liao X.
        • Li Y.
        • Bonini C.
        • Nair S.
        • Gilboa E.
        • Greenberg P.D.
        • et al.
        Transfection of RNA encoding tumor antigens following maturation of dendritic cells leads to prolonged presentation of antigen and the generation of high-affinity tumor-reactive cytotoxic T lymphocytes.
        Mol Ther. 2004; 9: 757-764
        • Kang T.H.
        • Lee J.H.
        • Bae H.C.
        • Noh K.H.
        • Kim J.H.
        • Song C.K.
        • et al.
        Enhancement of dendritic cell-based vaccine potency by targeting antigen to endosomal/lysosomal compartments.
        Immunol Lett. 2006; 106: 126-134
        • Hosoi A.
        • Takeda Y.
        • Sakuta K.
        • Ueha S.
        • Kurachi M.
        • Kimura K.
        • et al.
        Dendritic cell vaccine with mRNA targeted to the proteasome by polyubiquitination.
        Biochem Biophys Res Commun. 2008; 371: 242-246
        • Morse M.A.
        • Nair S.K.
        • Mosca P.J.
        • Hobeika A.C.
        • Clay T.M.
        • Deng Y.
        • et al.
        Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA.
        Cancer Invest. 2003; 21: 341-349
        • Lesterhuis W.J.
        • De Vries I.J.
        • Schreibelt G.
        • Schuurhuis D.H.
        • Aarntzen E.H.
        • De Boer A.
        • et al.
        Immunogenicity of dendritic cells pulsed with CEA peptide or transfected with CEA mRNA for vaccination of colorectal cancer patients.
        Anticancer Res. 2010; 30: 5091-5097
        • Mitchell D.A.
        • Batich K.A.
        • Gunn M.D.
        • Huang M.N.
        • Sanchez-Perez L.
        • Nair S.K.
        • et al.
        Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.
        Nature. 2015; 519: 366-369
        • Schaft N.
        • Dörrie J.
        • Thumann P.
        • Beck V.E.
        • Müller I.
        • Schultz E.S.
        • et al.
        Generation of an optimized polyvalent monocyte-derived dendritic cell vaccine by transfecting defined RNAs after rather than before maturation.
        J Immunol. 2005; 174: 3087-3097
        • Hobo W.
        • Strobbe L.
        • Maas F.
        • Fredrix H.
        • Greupink-Draaisma A.
        • Esendam B.
        • et al.
        Immunogenicity of dendritic cells pulsed with MAGE3, Survivin and B-cell maturation antigen mRNA for vaccination of multiple myeloma patients.
        Cancer Immunol Immunother. 2013; 62: 1381-1392
        • Aarntzen E.H.
        • Schreibelt G.
        • Bol K.
        • Lesterhuis W.J.
        • Croockewit A.J.
        • de Wilt J.H.
        • et al.
        Vaccination with mRNA-electroporated dendritic cells induces robust tumor antigen-specific CD4+ and CD8+ T cells responses in stage III and IV melanoma patients.
        Clin Cancer Res. 2012; 18: 5460-5470
        • Wilgenhof S.
        • Corthals J.
        • Van Nuffel A.M.
        • Benteyn D.
        • Heirman C.
        • Bonehill A.
        • et al.
        Long-term clinical outcome of melanoma patients treated with messenger RNA-electroporated dendritic cell therapy following complete resection of metastases.
        Cancer Immunol Immunother. 2015; 64: 381-388
        • Nakamura M.
        • Iwahashi M.
        • Nakamori M.
        • Ueda K.
        • Ojima T.
        • Naka T.
        • et al.
        Dendritic cells transduced with tumor-associated antigen gene elicit potent therapeutic antitumor immunity: comparison with immunodominant peptide-pulsed DCs.
        Oncology. 2005; 68: 163-170
        • Chan T.
        • Sami A.
        • El-Gayed A.
        • Guo X.
        • Xiang J.
        HER-2/neu-gene engineered dendritic cell vaccine stimulates stronger HER-2/neu-specific immune responses compared to DNA vaccination.
        Gene Ther. 2006; 13: 1391-1402
        • Blalock L.T.
        • Landsberg J.
        • Messmer M.
        • Shi J.
        • Pardee A.D.
        • Haskell R.
        • et al.
        Human dendritic cells adenovirally-engineered to express three defined tumor antigens promote broad adaptive and innate immunity.
        Oncoimmunology. 2012; 1: 287-357
        • Schumacher L.
        • Ribas A.
        • Dissette V.B.
        • McBride W.H.
        • Mukherji B.
        • Economou J.S.
        • et al.
        Human dendritic cell maturation by adenovirus transduction enhances tumor antigen-specific T-cell responses.
        J Immunother. 2004; 27: 191-200
        • Vujanovic L.
        • Whiteside T.L.
        • Potter D.M.
        • Chu J.
        • Ferrone S.
        • Butterfield L.H.
        Regulation of antigen presentation machinery in human dendritic cells by recombinant adenovirus.
        Cancer Immunol Immunother. 2009; 58: 121-133
        • Liu X.
        • Song N.
        • Liu Y.
        • Li J.
        • Ding J.
        • Tong Z.
        Efficient induction of anti-tumor immune response in esophageal squamous cell carcinoma via dendritic cells expressing MAGE-A3 and CALR antigens.
        Cell Immunol. 2015; 295: 77-82
        • Tan P.H.
        • Beutelspacher S.C.
        • Xue S.A.
        • Wang Y.H.
        • Mitchell P.
        • McAlister J.C.
        • et al.
        Modulation of human dendritic-cell function following transduction with viral vectors: implications for gene therapy.
        Blood. 2005; 105: 3824-3832
        • Chiappori A.A.
        • Soliman H.
        • Janssen W.E.
        • Antonia S.J.
        • Gabrilovich D.I.
        INGN-225: a dendritic cell-based p53 vaccine (Ad.p53-DC) in small cell lung cancer: observed association between immune response and enhanced chemotherapy effect.
        Expert Opin Biol Ther. 2010; 10: 983-991
        • Chia W.K.
        • Wang W.W.
        • Teo M.
        • Tai W.M.
        • Lim W.T.
        • Tan E.H.
        • et al.
        A phase II study evaluating the safety and efficacy of an adenovirus-ΔLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma.
        Ann Oncol. 2012; 23: 997-1005
        • Butterfield L.H.
        • Comin-Anduix B.
        • Vujanovic L.
        • Lee Y.
        • Dissette V.B.
        • Yang J.Q.
        • et al.
        Adenovirus MART-1-engineered autologous dendritic cell vaccine for metastatic melanoma.
        J Immunother. 2008; 31: 294-309
        • McNamara M.A.
        • Nair S.K.
        • Holl E.K.
        RNA-Based Vaccines in Cancer Immunotherapy.
        J Immunol Res. 2015; 2015: 794528
        • Schneble E.J.
        • Yu X.
        • Wagner T.E.
        • Peoples G.E.
        Novel dendritic cell-based vaccination in late stage melanoma.
        Hum Vaccin Immunother. 2014; 10: 3132-3138
        • Lindner M.
        • Schirrmacher V.
        Tumour cell-dendritic cell fusion for cancer immunotherapy: comparison of therapeutic efficiency of polyethylen-glycol versus electro-fusion protocols.
        Eur J Clin Invest. 2002; 32: 207-217
        • Gong J.
        • Chen L.
        • Chen D.
        • Kashiwaba M.
        • Manome Y.
        • Tanaka T.
        • et al.
        Induction of antigen-specific antitumor immunity with adenovirus-transduced dendritic cells.
        Gene Ther. 1997; 4: 1023-1028
        • Koido S.
        • Homma S.
        • Takahara A.
        • Namiki Y.
        • Komita H.
        • Nagasaki E.
        • et al.
        Immunologic monitoring of cellular responses by dendritic/tumor cell fusion vaccines.
        J Biomed Biotechnol. 2011; 2011: 910836
        • Vasir B.
        • Wu Z.
        • Crawford K.
        • Rosenblatt J.
        • Zarwan C.
        • Bissonnette A.
        • et al.
        Fusions of dendritic cells with breast carcinoma stimulate the expansion of regulatory T cells while concomitant exposure to IL-12, CpG oligodeoxynucleotides, and anti-CD3/CD28 promotes the expansion of activated tumor reactive cells.
        J Immunol. 2008; 181: 808-821
        • Koido S.
        • Hara E.
        • Homma S.
        • Namiki Y.
        • Ohkusa T.
        • Gong J.
        • et al.
        Cancer vaccine by fusions of dendritic and cancer cells.
        Clin Dev Immunol. 2009; 2009: 657369
        • Rosenblatt J.
        • Vasir B.
        • Uhl L.
        • Blotta S.
        • Macnamara C.
        • Somaiya P.
        • et al.
        Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma.
        Blood. 2011; 117: 393-402
        • Kikuchi T.
        • Akasaki Y.
        • Abe T.
        • Fukuda T.
        • Saotome H.
        • Ryan J.L.
        • et al.
        Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12.
        J Immunother. 2004; 27: 452-459
        • Takakura K.
        • Kajihara M.
        • Ito Z.
        • Ohkusa T.
        • Gong J.
        • Koido S.
        Dendritic-tumor fusion cells in cancer immunotherapy.
        Discov Med. 2015; 19: 169-174
        • Koido S.
        • Hara E.
        • Homma S.
        • Torii A.
        • Toyama Y.
        • Kawahara H.
        • et al.
        Dendritic cells fused with allogeneic colorectal cancer cell line present multiple colorectal cancer-specific antigens and induce antitumor immunity against autologous tumor cells.
        Clin Cancer Res. 2005; 11: 7891-7900
        • Yasuda T.
        • Kamigaki T.
        • Nakamura T.
        • Imanishi T.
        • Hayashi S.
        • Kawasaki K.
        • et al.
        Dendritic cell-tumor cell hybrids enhance the induction of cytotoxic T lymphocytes against murine colon cancer: a comparative analysis of antigen loading methods for the vaccination of immunotherapeutic dendritic cells.
        Oncol Rep. 2006; 16: 1317-1324
        • Chen J.
        • Guo X.Z.
        • Li H.Y.
        • Wang D.
        • Shao X.D.
        Comparison of cytotoxic T lymphocyte responses against pancreatic cancer induced by dendritic cells transfected with total tumor RNA and fusion hybrided with tumor cell.
        Exp Biol Med (Maywood). 2015; 240: 1310-1318
        • Baumeister S.H.
        • Freeman G.J.
        • Dranoff G.
        • Sharpe A.H.
        Coinhibitory pathways in immunotherapy for cancer.
        Annu Rev Immunol. 2016; 34: 539-573
        • Hu X.
        • Cao Y.
        • Meng Y.
        • Hou M.
        A novel modulation of structural and functional changes of mouse bone marrow derived dendritic cells (BMDCs) by interleukin-2(IL-2).
        Hum Vaccin Immunother. 2015; 11: 516-521
        • Van den Bergh J.
        • Willemen Y.
        • Lion E.
        • Van Acker H.
        • De Reu H.
        • Anguille S.
        • et al.
        Transpresentation of interleukin-15 by IL-15/IL-15Rα mRNA-engineered human dendritic cells boosts antitumoral natural killer cell activity.
        Oncotarget. 2015; 6: 44123-44133
        • Willemen Y.
        • Van den Bergh J.M.
        • Lion E.
        • Anguille S.
        • Roelandts V.A.
        • Van Acker H.H.
        • et al.
        Engineering monocyte-derived dendritic cells to secrete interferon-α enhances their ability to promote adaptive and innate anti-tumor immune effector functions.
        Cancer Immunol Immunother. 2015; 64: 831-842
        • Dannull J.
        • Nair S.
        • Su Z.
        • Boczkowski D.
        • DeBeck C.
        • Yang B.
        • et al.
        Enhancing the immunostimulatory function of dendritic cells by transfection with mRNA encoding OX40 ligand.
        Blood. 2005; 105: 3206-3213
        • Van Lint S.
        • Wilgenhof S.
        • Heirman C.
        • Corthals J.
        • Breckpot K.
        • Bonehill A.
        • et al.
        Optimized dendritic cell-based immunotherapy for melanoma: the TriMix-formula.
        Cancer Immunol Immunother. 2014; 63: 959-967
        • Naka T.
        • Iwahashi M.
        • Nakamura M.
        • Ojima T.
        • Nakamori M.
        • Ueda K.
        • et al.
        Tumor vaccine therapy against recrudescent tumor using dendritic cells simultaneously transfected with tumor RNA and granulocyte macrophage colony-stimulating factor RNA.
        Cancer Sci. 2008; 99: 407-413
        • Bontkes H.J.
        • Kramer D.
        • Ruizendaal J.J.
        • Kueter E.W.
        • van Tendeloo V.F.
        • Meijer C.J.
        • et al.
        Dendritic cells transfected with interleukin-12 and tumor-associated antigen messenger RNA induce high avidity cytotoxic T cells.
        Gene Ther. 2007; 14: 366-375
        • Bonehill A.
        • Van Nuffel A.M.
        • Corthals J.
        • Tuyaerts S.
        • Heirman C.
        • François V.
        • et al.
        Single-step antigen loading and activation of dendritic cells by mRNA electroporation for the purpose of therapeutic vaccination in melanoma patients.
        Clin Cancer Res. 2009; 15: 3366-3375
        • Okada N.
        • Mori N.
        • Koretomo R.
        • Okada Y.
        • Nakayama T.
        • Yoshie O.
        • et al.
        Augmentation of the migratory ability of DC-based vaccine into regional lymph nodes by efficient CCR7 gene transduction.
        Gene Ther. 2005; 12: 129-139
        • Yang S.C.
        • Hillinger S.
        • Riedl K.
        • Zhang L.
        • Zhu L.
        • Huang M.
        • et al.
        Intratumoral administration of dendritic cells overexpressing CCL21 generates systemic antitumor responses and confers tumor immunity.
        Clin Cancer Res. 2004; 10: 2891-2901
        • Terando A.
        • Roessler B.
        • Mulé J.J.
        Chemokine gene modification of human dendritic cell-based tumor vaccines using a recombinant adenoviral vector.
        Cancer Gene Ther. 2004; 11: 165-173
        • Steel J.C.
        • Ramlogan C.A.
        • Yu P.
        • Sakai Y.
        • Forni G.
        • Waldmann T.A.
        • et al.
        Interleukin-15 and its receptor augment dendritic cell vaccination against the neu oncogene through the induction of antibodies partially independent of CD4 help.
        Cancer Res. 2010; 70: 1072-1081
        • Li M.
        • Wang B.
        • Wu Z.
        • Zhang J.
        • Shi X.
        • Cheng W.
        • et al.
        A novel recombinant protein of ephrinA1-PE38/GM-CSF activate dendritic cells vaccine in rats with glioma.
        Tumour Biol. 2015; 36: 5497-5503
        • Liang W.
        • Wang X.F.
        In vitro induction of specific anti-tumoral immunity against laryngeal carcinoma by using human interleukin-12 gene-transfected dendritic cells.
        Chin Med J. 2011; 124: 1357-1361
        • Ojima T.
        • Iwahashi M.
        • Nakamura M.
        • Matsuda K.
        • Nakamori M.
        • Ueda K.
        • et al.
        Benefits of gene transduction of granulocyte macrophage colony-stimulating factor in cancer vaccine using genetically modified dendritic cells.
        Int J Oncol. 2007; 31: 931-939
        • Ojima T.
        • Iwahashi M.
        • Nakamura M.
        • Matsuda K.
        • Naka T.
        • Nakamori M.
        • et al.
        The boosting effect of co-transduction with cytokine genes on cancer vaccine therapy using genetically modified dendritic cells expressing tumor-associated antigen.
        Int J Oncol. 2006; 28: 947-953
        • Ye Z.
        • Chen Z.
        • Sami A.
        • El-Gayed A.
        • Xiang J.
        Human dendritic cells engineered to express alpha tumor necrosis factor maintain cellular maturation and T-cell stimulation capacity.
        Cancer Biother Radiopharm. 2006; 21: 613-622
        • Sundarasetty B.S.
        • Singh V.K.
        • Salguero G.
        • Geffers R.
        • Rickmann M.
        • Macke L.
        • et al.
        Lentivirus-induced dendritic cells for immunization against high-risk WT1(+) acute myeloid leukemia.
        Hum Gene Ther. 2013; 24: 220-237
        • Roeven M.W.
        • Hobo W.
        • van der Voort R.
        • Fredrix H.
        • Norde W.J.
        • Teijgeler K.
        • et al.
        Efficient nontoxic delivery of PD-L1 and PD-L2 siRNA into dendritic cell vaccines using the cationic lipid SAINT-18.
        J Immunother. 2015; 38: 145-154
        • Warashina S.
        • Nakamura T.
        • Sato Y.
        • Fujiwara Y.
        • Hyodo M.
        • Hatakeyama H.
        • et al.
        A lipid nanoparticle for the efficient delivery of siRNA to dendritic cells.
        J Control Release. 2016; 225: 183-191
        • Sioud M.
        Cytoplasmic delivery of siRNAs to monocytes and dendritic cells via electroporation.
        Methods Mol Biol. 2015; 1218: 107-115
        • Kang T.H.
        • Lee J.H.
        • Noh K.H.
        • Han HD
        • Shin BC
        • Choi EY
        • et al.
        Enhancing dendritic cell vaccine potency by combining a BAK/BAX siRNA-mediated antiapoptotic strategy to prolong dendritic cell life with an intracellular strategy to target antigen to lysosomal compartments.
        Int J Cancer. 2007; 120: 1696-1703
        • Wu A.A.
        • Drake V.
        • Huang H.S.
        • Chiu S.
        • Zheng L.
        Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells.
        Oncoimmunology. 2015; 4: e1016700
        • Kim J.H.
        • Kang T.H.
        • Noh K.H.
        • Bae H.C.
        • Kim S.H.
        • Yoo Y.D.
        • et al.
        Enhancement of dendritic cell-based vaccine potency by anti-apoptotic siRNAs targeting key pro-apoptotic proteins in cytotoxic CD8(+) T cell-mediated cell death.
        Immunol Lett. 2009; 122: 58-67
        • Kim J.H.
        • Kang T.H.
        • Noh K.H.
        • Kim S.H.
        • Lee Y.H.
        • Kim K.W.
        • et al.
        Enhancement of DC vaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN.
        Immunol Lett. 2010; 134: 47-54
        • Zhu Y.
        • Zheng Y.
        • Mei L.
        • Liu M.
        • Li S.
        • Xiao H.
        • et al.
        Enhanced immunotherapeutic effect of modified HPV16 E7-pulsed dendritic cell vaccine by an adeno-shRNA-SOCS1 virus.
        Int J Oncol. 2013; 43: 1151-1159
        • Kim J.H.
        • Kang T.H.
        • Noh K.H.
        • Bae H.C.
        • Ahn Y.H.
        • Lee Y.H.
        • et al.
        Blocking the immunosuppressive axis with small interfering RNA targeting interleukin (IL)-10 receptor enhances dendritic cell-based vaccine potency.
        Clin Exp Immunol. 2011; 165: 180-189
        • Ahn Y.H.
        • Hong S.O.
        • Kim J.H.
        • Noh K.H.
        • Song K.H.
        • Lee Y.H.
        • et al.
        The siRNA cocktail targeting interleukin 10 receptor and transforming growth factor-β receptor on dendritic cells potentiates tumour antigen-specific CD8(+) T cell immunity.
        Clin Exp Immunol. 2015; 181: 164-178
        • Hobo W.
        • Novobrantseva T.I.
        • Fredrix H.
        • Wong J.
        • Milstein S.
        • Epstein-Barash H.
        • et al.
        Improving dendritic cell vaccine immunogenicity by silencing PD-1 ligands using siRNA-lipid nanoparticles combined with antigen mRNA electroporation.
        Cancer Immunol Immunother. 2013; 62: 285-297
        • van der Waart A.B.
        • Fredrix H.
        • van der Voort R.
        • Schaap N.
        • Hobo W.
        • Dolstra H.
        siRNA silencing of PD-1 ligands on dendritic cell vaccines boosts the expansion of minor histocompatibility antigen-specific CD8(+) T cells in NOD/SCID/IL2Rg(null) mice.
        Cancer Immunol Immunother. 2015; 64: 645-654
        • Sioud M.
        • Saebøe-Larssen S.
        • Hetland T.E.
        • Kaern J.
        • Mobergslien A.
        • Kvalheim G.
        Silencing of indoleamine 2,3-dioxygenase enhances dendritic cell immunogenicity and antitumour immunity in cancer patients.
        Int J Oncol. 2013; 43: 280-288
        • Sioud M.
        • Mobergslien A.
        • Sæbøe-Larssen S.
        Immunosuppressive factor blockade in dendritic cells via siRNAs results in objective clinical responses.
        Methods Mol Biol. 2015; 1218: 269-276
        • Wobser M.
        • Voigt H.
        • Houben R.
        • Eggert A.O.
        • Freiwald M.
        • Kaemmerer U.
        • et al.
        Dendritic cell based antitumor vaccination: impact of functional indoleamine 2,3-dioxygenase expression.
        Cancer Immunol Immunother. 2007; 56: 1017-1024
        • Zheng X.
        • Koropatnick J.
        • Chen D.
        • Velenosi T.
        • Ling H.
        • Zhang X.
        • et al.
        Silencing IDO in dendritic cells: a novel approach to enhance cancer immunotherapy in a murine breast cancer model.
        Int J Cancer. 2013; 132: 967-977
        • Dannull J.
        • Haley N.R.
        • Archer G.
        • Nair S.
        • Boczkowski D.
        • Harper M.
        • et al.
        Melanoma immunotherapy using mature DCs expressing the constitutive proteasome.
        J Clin Invest. 2013; 123: 3135-3145
        • Ahmed M.S.
        • Byeon S.E.
        • Jeong Y.
        • Miah M.A.
        • Salahuddin M.
        • Lee Y.
        • et al.
        Dab2, a negative regulator of DC immunogenicity, is an attractive molecular target for DC-based immunotherapy.
        Oncoimmunology. 2015; 4: e984550
        • Yi H.
        • Guo C.
        • Yu X.
        • Gao P.
        • Qian J.
        • Zuo D.
        • et al.
        Targeting the immunoregulator SRA/CD204 potentiates specific dendritic cell vaccine-induced T-cell response and antitumor immunity.
        Cancer Res. 2011; 71: 6611-6620
        • Kang S.
        • Xie J.
        • Ma S.
        • Liao W.
        • Zhang J.
        • Luo R.
        Targeted knock down of CCL22 and CCL17 by siRNA during DC differentiation and maturation affects the recruitment of T subsets.
        Immunobiology. 2010; 215: 153-162
        • Cathelin D.
        • Met Ö.
        • Svane I.M.
        Silencing of the glucocorticoid-induced leucine zipper improves the immunogenicity of clinical-grade dendritic cells.
        Cytotherapy. 2013; 15: 740-749
        • Gottschalk S.
        • Yu F.
        • Ji M.
        • Kakarla S.
        • Song X.T.
        A vaccine that co-targets tumor cells and cancer associated fibroblasts results in enhanced antitumor activity by inducing antigen spreading.
        PLoS ONE. 2013; 8: e82658