, Volume 27, Issue 5, pp 453–468 | Cite as

A Review of Dendritic Cell Therapy for Cancer: Progress and Challenges

Review Article


Dendritic cells are the professional antigen-presenting cells of the innate immune system with the potential to generate robust antigen-specific T cell immune responses. Immunotherapeutic strategies have attempted to monopolize on this ability of dendritic cells to deliver antigens as a means of therapeutic vaccination in individuals with advanced malignancies. Since the publication of the first clinical trial in melanoma patients in 1995, therapeutic dendritic cell cancer vaccines have been extensively studied in numerous phase I and II trials. While advances have been encountered (especially with prostate cancer), there are still considerable challenges that need to be addressed in future clinical trials. In this review, we describe the current methodology and highlight trials which have contributed to the development of dendritic cell vaccines. We then review strategies to optimize dendritic cell vaccines in order to improve antitumor responses in cancer patients.


  1. 1.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J Exp Med. 2011;208(10):2005–16.PubMedCrossRefGoogle Scholar
  3. 3.
    Appay V, Douek DC, Price DA. CD8+ T cell efficacy in vaccination and disease. Nat Med. 2008;14(6):623–8.PubMedCrossRefGoogle Scholar
  4. 4.
    MacDonald KP, Munster DJ, Clark GJ, Dzionek A, Schmitz J, Hart DN. Characterization of human blood dendritic cell subsets. Blood. 2002;100(13):4512–20.PubMedCrossRefGoogle Scholar
  5. 5.
    Klechevsky E, Morita R, Liu M, Cao Y, Coquery S, Thompson-Snipes L, et al. Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity. 2008;29(3):497–510.PubMedCrossRefGoogle Scholar
  6. 6.
    Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res. 1999;5(10):2963–70.PubMedGoogle Scholar
  7. 7.
    Benencia F, Sprague L, McGinty J, Pate M, Muccioli M. Dendritic cells the tumor microenvironment and the challenges for an effective antitumor vaccination. J Biomed Biotechnol. 2012;2012:425476.PubMedCrossRefGoogle Scholar
  8. 8.
    Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12(4):265–77.PubMedCrossRefGoogle Scholar
  9. 9.
    Steinman RM. Dendritic cells: understanding immunogenicity. Eur J Immunol. 2007;37(Suppl 1):S53–60.PubMedCrossRefGoogle Scholar
  10. 10.
    Reichardt VL, Brossart P, Kanz L. Dendritic cells in vaccination therapies of human malignant disease. Blood Rev. 2004;18(4):235–43.PubMedCrossRefGoogle Scholar
  11. 11.
    Cannon MJ, O’Brien TJ. Cellular immunotherapy for ovarian cancer. Expert Opin Biol Ther. 2009;9(6):677–88.PubMedCrossRefGoogle Scholar
  12. 12.
    Gustafsson K, Junevik K, Werlenius O, Holmgren S, Karlsson-Parra A, Andersson PO. Tumour-loaded alpha-type 1-polarized dendritic cells from patients with chronic lymphocytic leukaemia produce a superior NK-, NKT- and CD8+ T cell-attracting chemokine profile. Scand J Immunol. 2011;74(3):318–26.PubMedCrossRefGoogle Scholar
  13. 13.
    Fong L, Brockstedt D, Benike C, Wu L, Engleman EG. Dendritic cells injected via different routes induce immunity in cancer patients. J Immunol. 2001;166(6):4254–9.PubMedGoogle Scholar
  14. 14.
    Mukherji B, Chakraborty NG, Yamasaki S, Okino T, Yamase H, Sporn JR, et al. Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells. Proc Natl Acad Sci U S A. 1995;92(17):8078–82.PubMedCrossRefGoogle Scholar
  15. 15.
    Ridgway D. The first 1000 dendritic cell vaccinees. Cancer Invest. 2003;21(6):873–86.PubMedCrossRefGoogle Scholar
  16. 16.
    Turnis ME, Rooney CM. Enhancement of dendritic cells as vaccines for cancer. Immunotherapy. 2010;2(6):847–62.PubMedCrossRefGoogle Scholar
  17. 17.
    Ridolfi L, Petrini M, Fiammenghi L, Granato AM, Ancarani V, Pancisi E, et al. Unexpected high response rate to traditional therapy after dendritic cell-based vaccine in advanced melanoma: update of clinical outcome and subgroup analysis. Clin Dev Immunol. 2010;2010:504979.PubMedCrossRefGoogle Scholar
  18. 18.
    Di Nicola M, Zappasodi R, Carlo-Stella C, Mortarini R, Pupa SM, Magni M, et al. Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunologic responses in indolent B-cell lymphoma patients with relapsed and measurable disease: a pilot study. Blood. 2009;113(1):18–27.PubMedCrossRefGoogle Scholar
  19. 19.
    Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115(16):3670–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24(19):3089–94.PubMedCrossRefGoogle Scholar
  21. 21.
    Peethambaram PP, Melisko ME, Rinn KJ, Alberts SR, Provost NM, Jones LA, et al. A phase I trial of immunotherapy with lapuleucel-T (APC8024) in patients with refractory metastatic tumors that express HER-2/neu. Clin Cancer Res. 2009;15(18):5937–44.PubMedCrossRefGoogle Scholar
  22. 22.
    Loveland BE, Zhao A, White S, Gan H, Hamilton K, Xing PX, et al. Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma. Clin Cancer Res. 2006;12(3 Pt 1):869–77.PubMedCrossRefGoogle Scholar
  23. 23.
    Apostolopoulos V, Pietersz GA, Loveland BE, Sandrin MS, McKenzie IF. Oxidative/reductive conjugation of mannan to antigen selects for T1 or T2 immune responses. Proc Natl Acad Sci U S A. 1995;92(22):10128–32.PubMedCrossRefGoogle Scholar
  24. 24.
    Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautes-Fridman C, et al. Trial Watch: experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology. 2012;1(5):699–716.PubMedCrossRefGoogle Scholar
  25. 25.
    Gnjatic S, Sawhney NB, Bhardwaj N. Toll-like receptor agonists: are they good adjuvants? Cancer J. 2010;16(4):382–91.PubMedCrossRefGoogle Scholar
  26. 26.
    Lesimple T, Neidhard EM, Vignard V, Lefeuvre C, Adamski H, Labarriere N, et al. Immunologic and clinical effects of injecting mature peptide-loaded dendritic cells by intralymphatic and intranodal routes in metastatic melanoma patients. Clin Cancer Res. 2006;12(24):7380–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Morse MA, Chapman R, Powderly J, Blackwell K, Keler T, Green J, et al. Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with Toll-like receptor stimulation to induce immunity to self-antigens in cancer patients. Clin Cancer Res. 2011;17(14):4844–53.PubMedCrossRefGoogle Scholar
  28. 28.
    Wilgenhof S, Van Nuffel AM, Corthals J, Heirman C, Tuyaerts S, Benteyn D, et al. Therapeutic vaccination with an autologous mRNA electroporated dendritic cell vaccine in patients with advanced melanoma. J Immunother. 2011;34(5):448–56.PubMedCrossRefGoogle Scholar
  29. 29.
    Romano E, Cotari JW, Barreira da Silva R, Betts BC, Chung DJ, Avogadri F, et al. Human Langerhans cells use an IL-15R-alpha/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1. Blood. 2012;119(22):5182–90.PubMedCrossRefGoogle Scholar
  30. 30.
    Romano E, Rossi M, Ratzinger G, de Cos MA, Chung DJ, Panageas KS, et al. Peptide-loaded Langerhans cells, despite increased IL15 secretion and T-cell activation in vitro, elicit antitumor T-cell responses comparable to peptide-loaded monocyte-derived dendritic cells in vivo. Clin Cancer Res. 2011;17(7):1984–97.PubMedCrossRefGoogle Scholar
  31. 31.
    Fujiwara S, Wada H, Miyata H, Kawada J, Kawabata R, Nishikawa H, et al. Clinical trial of the intratumoral administration of labeled DC combined with systemic chemotherapy for esophageal cancer. J Immunother. 2012;35(6):513–21.PubMedCrossRefGoogle Scholar
  32. 32.
    Alfaro C, Perez-Gracia JL, Suarez N, Rodriguez J, Fernandez de Sanmamed M, Sangro B, et al. Pilot clinical trial of type 1 dendritic cells loaded with autologous tumor lysates combined with GM-CSF, pegylated IFN, and cyclophosphamide for metastatic cancer patients. J Immunol. 2011;187(11):6130–42.PubMedCrossRefGoogle Scholar
  33. 33.
    Baek S, Kim CS, Kim SB, Kim YM, Kwon SW, Kim Y, et al. Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial. J Transl Med. 2011;9:178.PubMedCrossRefGoogle Scholar
  34. 34.
    Steele JC, Rao A, Marsden JR, Armstrong CJ, Berhane S, Billingham LJ, et al. Phase I/II trial of a dendritic cell vaccine transfected with DNA encoding melan A and gp100 for patients with metastatic melanoma. Gene Ther. 2011;18(6):584–93.PubMedCrossRefGoogle Scholar
  35. 35.
    Himoudi N, Wallace R, Parsley KL, Gilmour K, Barrie AU, Howe K, et al. Lack of T-cell responses following autologous tumour lysate pulsed dendritic cell vaccination, in patients with relapsed osteosarcoma. Clin Transl Oncol. 2012;14(4):271–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Kandalaft LE, Powell DJ Jr, Singh N, Coukos G. Immunotherapy for ovarian cancer: what’s next? J Clin Oncol. 2011;29(7):925–33.PubMedCrossRefGoogle Scholar
  37. 37.
    Ribas A, Comin-Anduix B, Chmielowski B, Jalil J, de la Rocha P, McCannel TA, et al. Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. Clin Cancer Res. 2009;15(19):6267–76.PubMedCrossRefGoogle Scholar
  38. 38.
    Bjoern J, Brimnes MK, Andersen MH, Thor Straten P, Svane IM. Changes in peripheral blood level of regulatory T cells in patients with malignant melanoma during treatment with dendritic cell vaccination and low-dose IL-2. Scand J Immunol. 2011;73(3):222–33.PubMedCrossRefGoogle Scholar
  39. 39.
    Ercolini AM, Ladle BH, Manning EA, Pfannenstiel LW, Armstrong TD, Machiels JP, et al. Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. J Exp Med. 2005;201(10):1591–602.PubMedCrossRefGoogle Scholar
  40. 40.
    Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res. 2001;61(9):3689–97.PubMedGoogle Scholar
  41. 41.
    Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+ CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56(5):641–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Chu CS, Boyer J, Schullery DS, Gimotty PA, Gamerman V, Bender J, et al. Phase I/II randomized trial of dendritic cell vaccination with or without cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission. Cancer Immunol Immunother. 2011;61(5):629–41.PubMedCrossRefGoogle Scholar
  43. 43.
    Jacobs JF, Punt CJ, Lesterhuis WJ, Sutmuller RP, Brouwer HM, Scharenborg NM, et al. Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clin Cancer Res. 2010;16(20):5067–78.PubMedCrossRefGoogle Scholar
  44. 44.
    Shindo G, Endo T, Onda M, Miyamoto Y, Kaneko T, Goto S. Immuno-cell therapy with antecedent surgery has superior actuarial survival to immuno-cell therapy without antecedent surgery for advanced cancers. Cancer Immunol Immunother. 2011;60(10):1397–403.PubMedCrossRefGoogle Scholar
  45. 45.
    Kitawaki T, Kadowaki N, Fukunaga K, Kasai Y, Maekawa T, Ohmori K, et al. A phase I/IIa clinical trial of immunotherapy for elderly patients with acute myeloid leukaemia using dendritic cells co-pulsed with WT1 peptide and zoledronate. Br J Haematol. 2011;153(6):796–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Koski GK, Koldovsky U, Xu S, Mick R, Sharma A, Fitzpatrick E, et al. A novel dendritic cell-based immunization approach for the induction of durable Th1-polarized anti-HER-2/neu responses in women with early breast cancer. J Immunother. 2011;35(1):54–65.CrossRefGoogle Scholar
  47. 47.
    Sakakibara M, Kanto T, Hayakawa M, Kuroda S, Miyatake H, Itose I, et al. Comprehensive immunological analyses of colorectal cancer patients in the phase I/II study of quickly matured dendritic cell vaccine pulsed with carcinoembryonic antigen peptide. Cancer Immunol Immunother. 2011;60(11):1565–75.PubMedCrossRefGoogle Scholar
  48. 48.
    Lesterhuis WJ, De Vries IJ, Schreibelt G, Schuurhuis DH, Aarntzen EH, 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(12):5091–7.PubMedGoogle Scholar
  49. 49.
    Cho DY, Yang WK, Lee HC, Hsu DM, Lin HL, Lin SZ, et al. Adjuvant immunotherapy with whole-cell lysate dendritic cells vaccine for glioblastoma multiforme: a phase II clinical trial. World Neurosurg. 2011;77(5–6):736–44.PubMedGoogle Scholar
  50. 50.
    Jie X, Hua L, Jiang W, Feng F, Feng G, Hua Z. Clinical application of a dendritic cell vaccine raised against heat-shocked glioblastoma. Cell Biochem Biophys. 2011;62(1):91–9.CrossRefGoogle Scholar
  51. 51.
    Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH, et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res. 2011;17(6):1603–15.PubMedCrossRefGoogle Scholar
  52. 52.
    Fadul CE, Fisher JL, Hampton TH, Lallana EC, Li Z, Gui J, et al. Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J Immunother. 2011;34(4):382–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Bray SM, Vujanovic L, Butterfield LH. Dendritic cell-based vaccines positively impact natural killer and regulatory T cells in hepatocellular carcinoma patients. Clin Dev Immunol. 2011;2011:249281.PubMedCrossRefGoogle Scholar
  54. 54.
    Butterfield LH, Ribas A, Dissette VB, Lee Y, Yang JQ, De la Rocha P, et al. A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res. 2006;12(9):2817–25.PubMedCrossRefGoogle Scholar
  55. 55.
    Chang CN, Huang YC, Yang DM, Kikuta K, Wei KJ, Kubota T, et al. A phase I/II clinical trial investigating the adverse and therapeutic effects of a postoperative autologous dendritic cell tumor vaccine in patients with malignant glioma. J Clin Neurosci. 2011;18(8):1048–54.PubMedCrossRefGoogle Scholar
  56. 56.
    Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol. 2011;29(3):330–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Cornforth AN, Lee G, Dillman RO. Autologous peripheral blood mononuclear cell recognition of autologous proliferating tumor cells in the context of a patient-specific vaccine trial. J Biomed Biotechnol. 2011;2011:635850.PubMedCrossRefGoogle Scholar
  58. 58.
    Aguilera R, Saffie C, Tittarelli A, Gonzalez FE, Ramirez M, Reyes D, et al. Heat-shock induction of tumor-derived danger signals mediates rapid monocyte differentiation into clinically effective dendritic cells. Clin Cancer Res. 2011;17(8):2474–83.PubMedCrossRefGoogle Scholar
  59. 59.
    Lesterhuis WJ, Schreibelt G, Scharenborg NM, Brouwer HM, Gerritsen MJ, Croockewit S, et al. Wild-type and modified gp100 peptide-pulsed dendritic cell vaccination of advanced melanoma patients can lead to long-term clinical responses independent of the peptide used. Cancer Immunol Immunother. 2011;60(2):249–60.PubMedCrossRefGoogle Scholar
  60. 60.
    Zahradova L, Mollova K, Ocadlikova D, Kovarova L, Adam Z, Krejci M, et al. Efficacy and safety of Id-protein-loaded dendritic cell vaccine in patients with multiple myeloma—phase II study results. Neoplasma. 2012;59(4):440–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Rollig C, Schmidt C, Bornhauser M, Ehninger G, Schmitz M, Auffermann-Gretzinger S. Induction of cellular immune responses in patients with stage-I multiple myeloma after vaccination with autologous idiotype-pulsed dendritic cells. J Immunother. 2011;34(1):100–6.PubMedCrossRefGoogle Scholar
  62. 62.
    Chia WK, Wang WW, Teo M, Tai WM, Lim WT, Tan EH, et al. A phase II study evaluating the safety and efficacy of an adenovirus-DeltaLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma. Ann Oncol. 2011;23(4):997–1005.PubMedCrossRefGoogle Scholar
  63. 63.
    Perroud MW Jr, Honma HN, Barbeiro AS, Gilli SC, Almeida MT, Vassallo J, et al. Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study. J Exp Clin Cancer Res. 2011;30:65.PubMedCrossRefGoogle Scholar
  64. 64.
    Zhong R, Teng J, Han B, Zhong H. Dendritic cells combining with cytokine-induced killer cells synergize chemotherapy in patients with late-stage non-small cell lung cancer. Cancer Immunol Immunother. 2011;60(10):1497–502.PubMedCrossRefGoogle Scholar
  65. 65.
    Rahma OE, Ashtar E, Czystowska M, Szajnik ME, Wieckowski E, Bernstein S, et al. A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients. Cancer Immunol Immunother. 2011;61(3):373–84.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Division of Gynecologic OncologyHospital of the University of PennsylvaniaPhiladelphiaUSA
  2. 2.3 West Jordan Center for Gynecologic CancerPerelman Center for Advanced Medicine at the University of PennsylvaniaPhiladelphiaUSA

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