Vaccine Design pp 763-777 | Cite as

Dendritic Cell Vaccines

  • Rachel Lubong SabadoEmail author
  • Marcia Meseck
  • Nina Bhardwaj
Part of the Methods in Molecular Biology book series (MIMB, volume 1403)


Exploitation of the patient’s own immune system to induce antitumor immune responses using dendritic cell (DC) immunotherapy has been established in early clinical trials as a safe and promising therapeutic approach for cancer. However, their limited success in larger clinical trials highlights the need to optimize DC vaccine preparations. This chapter describes the methodologies utilized for the preparation of the DC vaccine most commonly used in clinical trials. Optional variations at different stages in DC vaccine preparation, based on the nature of antigen, delivery of antigen, maturation stimuli, and mode of administration for DC vaccines, are also presented for consideration as these are often dependent on the disease setting, desired immune response, and/or resources available.

Key words

Dendritic cell Vaccine Immunotherapy Immune response Tumor 



We would like to thank Andres Salazar for providing the poly-ICLC. We would also like to thank the staff of the Vaccine and Cell Therapy Laboratory—Farah Hasan, Hanqing Dong, Bike Su Oner, and Marina Aziz—for the help in refining the procedure.


  1. 1.
    Palucka K, Banchereau J (2013) Dendritic-cell-based therapeutic cancer vaccines. Immunity 39:38–48CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146CrossRefPubMedGoogle Scholar
  3. 3.
    Vignali DA, Kuchroo VK (2012) IL-12 family cytokines: immunological playmakers. Nat Immunol 13:722–728CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    McKenna K, Beignon AS, Bhardwaj N (2005) Plasmacytoid dendritic cells: linking innate and adaptive immunity. J Virol 79:17–27CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Drobits B, Holcmann M, Amberg N, Swiecki M et al (2012) Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest 122:575–585CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gandhi RT, O’Neill D, Bosch RJ, Chan ES, Bucy RP, Shopis J et al (2009) A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy. Vaccine 27:6088–6094CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Palucka AK, Ueno H, Connolly J, Kerneis-Norvell F et al (2006) Dendritic cells loaded with killed allogeneic melanoma cells can induce objective clinical responses and MART-1 specific CD8+ T-cell immunity. J Immunother 29:545–557CrossRefPubMedGoogle Scholar
  8. 8.
    Redman BG, Chang AE, Whitfield J, Esper P et al (2008) Phase Ib trial assessing autologous, tumor-pulsed dendritic cells as a vaccine administered with or without IL-2 in patients with metastatic melanoma. J Immunother 31:591–598CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sabado RL, Miller E, Spadaccia M, Vengco I, Hasan F, Bhardwaj N (2013) Preparation of tumor antigen-loaded mature dendritic cells for immunotherapy. J Vis Exp (78)Google Scholar
  10. 10.
    Miller E, Spadaccia M, Sabado R, Chertova E et al (2015) Autologous aldrithiol-2-inactivated HIV-1 combined with polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose as a vaccine platform for therapeutic dendritic cell immunotherapy. Vaccine 33: 388–395CrossRefPubMedGoogle Scholar
  11. 11.
    Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S et al (2001) Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res 61:6451–6458PubMedGoogle Scholar
  12. 12.
    Marroquin CE, Westwood JA, Lapointe R, Mixon A et al (2002) Mobilization of dendritic cell precursors in patients with cancer by flt3 ligand allows the generation of higher yields of cultured dendritic cells. J Immunother 25:278–288CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kantoff PW, Higano CS, Shore ND, Berger ER et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422CrossRefPubMedGoogle Scholar
  14. 14.
    Small EJ, Schellhammer PF, Higano CS, Redfern CH et al (2006) Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089–3094CrossRefPubMedGoogle Scholar
  15. 15.
    Sikora AG, Hailemichael Y, Overwijk WW (2012) Conference scene: immune effector mechanisms in tumor immunity. Immunotherapy 4:141–143CrossRefPubMedGoogle Scholar
  16. 16.
    Adams S, O’Neill D, Bhardwaj N (2004) Maturation matters: importance of maturation for antitumor immunity of dendritic cell vaccines. J Clin Oncol 22:3834–3835CrossRefPubMedGoogle Scholar
  17. 17.
    Lee AW, Truong T, Bickham K, Fonteneau JF et al (2002) A clinical grade cocktail of cytokines and PGE2 results in uniform maturation of human monocyte-derived dendritic cells: implications for immunotherapy. Vaccine 20(Suppl 4):A8–A22CrossRefPubMedGoogle Scholar
  18. 18.
    Jongmans W, Tiemessen DM, van Vlodrop IJ, Mulders PF, Oosterwijk E (2005) Th1-polarizing capacity of clinical-grade dendritic cells is triggered by Ribomunyl but is compromised by PGE2: the importance of maturation cocktails. J Immunother 28:480–487CrossRefPubMedGoogle Scholar
  19. 19.
    Krause P, Singer E, Darley PI, Klebensberger J et al (2007) Prostaglandin E2 is a key factor for monocyte-derived dendritic cell maturation: enhanced T cell stimulatory capacity despite IDO. J Leukoc Biol 82:1106–1114CrossRefPubMedGoogle Scholar
  20. 20.
    Morelli AE, Thomson AW (2003) Dendritic cells under the spell of prostaglandins. Trends Immunol 24:108–111CrossRefPubMedGoogle Scholar
  21. 21.
    Kwissa M, Nakaya HI, Oluoch H, Pulendran B (2012) Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates. Blood 119:2044–2055CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R (2001) Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2:947–950CrossRefPubMedGoogle Scholar
  23. 23.
    Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A (2005) Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol 6:769–776CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Boullart AC, Aarntzen EH, Verdijk P, Jacobs JF et al (2008) Maturation of monocyte-derived dendritic cells with Toll-like receptor 3 and 7/8 ligands combined with prostaglandin E2 results in high interleukin-12 production and cell migration. Cancer Immunol Immunother 57:1589–1597CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bogunovic D, Manches O, Godefroy E, Yewdall A et al (2011) TLR4 engagement during TLR3-induced proinflammatory signaling in dendritic cells promotes IL-10-mediated suppression of antitumor immunity. Cancer Res 71:5467–5476CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mailliard RB, Wankowicz-Kalinska A, Cai Q et al (2004) alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity. Cancer Res 64:5934–5937CrossRefPubMedGoogle Scholar
  27. 27.
    Lee JJ, Foon KA, Mailliard RB, Muthuswamy R, Kalinski P (2008) Type 1-polarized dendritic cells loaded with autologous tumor are a potent immunogen against chronic lymphocytic leukemia. J Leukoc Biol 84:319–325CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Whitehurst AW (2014) Cause and consequence of cancer/testis antigen activation in cancer. Annu Rev Pharmacol Toxicol 54:251–272CrossRefPubMedGoogle Scholar
  29. 29.
    Andrews MC, Woods K, Cebon J, Behren A (2014) Evolving role of tumor antigens for future melanoma therapies. Future Oncol 10: 1457–1468CrossRefPubMedGoogle Scholar
  30. 30.
    Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348:69–74CrossRefPubMedGoogle Scholar
  31. 31.
    Carreno BM, Magrini V, Becker-Hapak M et al (2015) A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348:803–808CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    O’Neill D, Bhardwaj N (2005) Generation of autologous peptide- and protein-pulsed dendritic cells for patient-specific immunotherapy. Methods Mol Med 109:97–112PubMedGoogle Scholar
  33. 33.
    Melief CJ, van der Burg SH (2008) Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nat Rev Cancer 8:351–360CrossRefPubMedGoogle Scholar
  34. 34.
    Bijker MS, van den Eeden SJ, Franken KL, Melief CJ, van der Burg SH, Offringa R (2008) Superior induction of anti-tumor CTL immunity by extended peptide vaccines involves prolonged, DC-focused antigen presentation. Eur J Immunol 38:1033–1042CrossRefPubMedGoogle Scholar
  35. 35.
    Barrou B, Benoit G, Ouldkaci M, Cussenot O et al (2004) Vaccination of prostatectomized prostate cancer patients in biochemical relapse, with autologous dendritic cells pulsed with recombinant human PSA. Cancer Immunol Immunother 53:453–460CrossRefPubMedGoogle Scholar
  36. 36.
    Salcedo M, Bercovici N, Taylor R, Vereecken P et al (2006) Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate. Cancer Immunol Immunother 55:819–829CrossRefPubMedGoogle Scholar
  37. 37.
    Mahdian R, Kokhaei P, Najar HM, Derkow K, Choudhury A, Mellstedt H (2006) Dendritic cells, pulsed with lysate of allogeneic tumor cells, are capable of stimulating MHC-restricted antigen-specific antitumor T cells. Med Oncol 23:273–282CrossRefPubMedGoogle Scholar
  38. 38.
    Schnurr M, Galambos P, Scholz C, Then F, Dauer M, Endres S, Eigler A (2001) Tumor cell lysate-pulsed human dendritic cells induce a T-cell response against pancreatic carcinoma cells: an in vitro model for the assessment of tumor vaccines. Cancer Res 61:6445–6450PubMedGoogle Scholar
  39. 39.
    Thumann P, Moc I, Humrich J, Berger TG, Schultz ES, Schuler G, Jenne L (2003) Antigen loading of dendritic cells with whole tumor cell preparations. J Immunol Methods 277:1–16CrossRefPubMedGoogle Scholar
  40. 40.
    Wheeler CJ, Black KL (2009) DCVax-Brain and DC vaccines in the treatment of GBM. Expert Opin Investig Drugs 18:509–519CrossRefPubMedGoogle Scholar
  41. 41.
    Schnurr M, Chen Q, Shin A, Chen W, Toy T, Jenderek C et al (2005) Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery. Blood 105:2465–2472CrossRefPubMedGoogle Scholar
  42. 42.
    Jenne L, Schuler G, Steinkasserer A (2001) Viral vectors for dendritic cell-based immunotherapy. Trends Immunol 22:102–107CrossRefPubMedGoogle Scholar
  43. 43.
    Brockstedt DG, Dubensky TW (2008) Promises and challenges for the development of Listeria monocytogenes-based immunotherapies. Expert Rev Vaccines 7:1069–1084CrossRefPubMedGoogle Scholar
  44. 44.
    Bellone S, El-Sahwi K, Cocco E, Casagrande F et al (2009) Human papillomavirus type 16 (HPV-16) virus-like particle L1-specific CD8+ cytotoxic T lymphocytes (CTLs) are equally effective as E7-specific CD8+ CTLs in killing autologous HPV-16-positive tumor cells in cervical cancer patients: implications for L1 dendritic cell-based therapeutic vaccines. J Virol 83:6779–6789CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Carrasco J, Van Pel A, Neyns B, Lethe B, Brasseur F et al (2008) Vaccination of a melanoma patient with mature dendritic cells pulsed with MAGE-3 peptides triggers the activity of nonvaccine anti-tumor cells. J Immunol 180:3585–3593CrossRefPubMedGoogle Scholar
  46. 46.
    Butterfield LH, Comin-Anduix B, Vujanovic L et al (2008) Adenovirus MART-1-engineered autologous dendritic cell vaccine for metastatic melanoma. J Immunother 31:294–309CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Veron P, Allo V, Riviere C, Bernard J, Douar AM, Masurier C (2007) Major subsets of human dendritic cells are efficiently transduced by self-complementary adeno-associated virus vectors 1 and 2. J Virol 81:5385–5394CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Nair SK, Morse M, Boczkowski D, Cumming RI, Vasovic L, Gilboa E, Lyerly HK (2002) Induction of tumor-specific cytotoxic T lymphocytes in cancer patients by autologous tumor RNA-transfected dendritic cells. Ann Surg 235:540–549CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Muller MR, Tsakou G, Grunebach F, Schmidt SM, Brossart P (2004) Induction of chronic lymphocytic leukemia (CLL)-specific CD4- and CD8-mediated T-cell responses using RNA-transfected dendritic cells. Blood 103: 1763–1769CrossRefPubMedGoogle Scholar
  50. 50.
    Nencioni A, Muller MR, Grunebach F, Garuti A, Mingari MC, Patrone F, Ballestrero A, Brossart P (2003) Dendritic cells transfected with tumor RNA for the induction of antitumor CTL in colorectal cancer. Cancer Gene Ther 10:209–214CrossRefPubMedGoogle Scholar
  51. 51.
    Milazzo C, Reichardt VL, Muller MR, Grunebach F, Brossart P (2003) Induction of myeloma-specific cytotoxic T cells using dendritic cells transfected with tumor-derived RNA. Blood 101:977–982CrossRefPubMedGoogle Scholar
  52. 52.
    Gilboa E, Vieweg J (2004) Cancer immunotherapy with mRNA-transfected dendritic cells. Immunol Rev 199:251–263CrossRefPubMedGoogle Scholar
  53. 53.
    Heiser A, Maurice MA, Yancey DR, Coleman DM, Dahm P, Vieweg J (2001) Human dendritic cells transfected with renal tumor RNA stimulate polyclonal T-cell responses against antigens expressed by primary and metastatic tumors. Cancer Res 61:3388–3393PubMedGoogle Scholar
  54. 54.
    Strobel I, Berchtold S, Gotze A, Schulze U, Schuler G, Steinkasserer A (2000) Human dendritic cells transfected with either RNA or DNA encoding influenza matrix protein M1 differ in their ability to stimulate cytotoxic T lymphocytes. Gene Ther 7:2028–2035CrossRefPubMedGoogle Scholar
  55. 55.
    Koido S, Kashiwaba M, Chen D, Gendler S, Kufe D, Gong J (2000) Induction of antitumor immunity by vaccination of dendritic cells transfected with MUC1 RNA. J Immunol 165:5713–5719CrossRefPubMedGoogle Scholar
  56. 56.
    Heiser A, Coleman D, Dannull J, Yancey D et al (2002) Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest 109:409–417CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Routy JP, Boulassel MR, Yassine-Diab B, Nicolette C et al (2010) Immunologic activity and safety of autologous HIV RNA-electroporated dendritic cells in HIV-1 infected patients receiving antiretroviral therapy. Clin Immunol 134:140–147CrossRefPubMedGoogle Scholar
  58. 58.
    Teijeira A, Russo E, Halin C (2014) Taking the lymphatic route: dendritic cell migration to draining lymph nodes. Semin Immunopathol 36:261–274CrossRefPubMedGoogle Scholar
  59. 59.
    Verdijk P, Aarntzen EH, Lesterhuis WJ, Boullart AC et al (2009) Limited amounts of dendritic cells migrate into the T-cell area of lymph nodes but have high immune activating potential in melanoma patients. Clin Cancer Res 15:2531–2540CrossRefPubMedGoogle Scholar
  60. 60.
    Fujiwara S, Wada H, Miyata H, Kawada J, Kawabata R et al (2012) Clinical trial of the intratumoral administration of labeled DC combined with systemic chemotherapy for esophageal cancer. J Immunother 35:513–521CrossRefPubMedGoogle Scholar
  61. 61.
    Lesterhuis WJ, de Vries IJ, Schreibelt G, Lambeck AJ et al (2011) Route of administration modulates the induction of dendritic cell vaccine-induced antigen-specific T cells in advanced melanoma patients. Clin Cancer Res 17:5725–5735CrossRefPubMedGoogle Scholar
  62. 62.
    Yewdall AW, Drutman SB, Jinwala F, Bahjat KS, Bhardwaj N (2010) CD8+ T cell priming by dendritic cell vaccines requires antigen transfer to endogenous antigen presenting cells. PLoS One 5(6):e11144CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Mitchell DA, Batich KA, Gunn MD, Huang MN et al (2015) Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519:366–369CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Garcia F, Climent N, Guardo AC, Gil C, Leon A, Autran B, Lifson JD, Martinez-Picado J, Dalmau J, Clotet B, Gatell JM, Plana M, Gallart T (2013) A dendritic cell-based vaccine elicits t cell responses associated with control of HIV-1 replication. Sci Transl Med 5(166):166ra162CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Rachel Lubong Sabado
    • 1
    Email author
  • Marcia Meseck
    • 1
  • Nina Bhardwaj
    • 1
  1. 1.Division of Hematology and Medical Oncology, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA

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