DNA Vaccines Against Cancer

  • Adam D. Cohen
  • Jedd D. Wolchok


Human Immunodeficiency Virus Type Tumor Immunity Tumor Challenge Genetic Immunization Genetic Adjuvant 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Coley WB. The treatment of malignant tumors by repeated inoculationsof erysipelas. With a report of ten original cases. Am J Med Sci 1893; 105: 487–511.CrossRefGoogle Scholar
  2. 2.
    Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: movingbeyond current vaccines. Nat Med 2004; 10: 909–915.PubMedCrossRefGoogle Scholar
  3. 3.
    Tang DC, DeVit M, Johnston SA. Genetic immunization is a simplemethod for eliciting an immune response. Nature 1992; 356: 152–154.PubMedCrossRefGoogle Scholar
  4. 4.
    Ulmer JB, Donnelly JJ, Parker SE et al. Heterologous protectionagainst influenza by injection of DNA encoding a viral protein. Science 1993; 259: 1745–1749.PubMedCrossRefGoogle Scholar
  5. 5.
    Fynan EF, Webster RG, Fuller DH et al. DNA vaccines: protectiveimmunizations by parenteral, mucosal, and gene-gun inoculations. Proc Natl Acad Sci U S A 1993; 90: 1147811482..CrossRefGoogle Scholar
  6. 6.
    Wang B, Ugen KE, Srikantan V et al. Gene inoculation generatesimmune responses against human immunodeficiency virus type 1. ProcNatl Acad Sci U S A 1993; 90: 4156–4160.CrossRefGoogle Scholar
  7. 7.
    Davis HL, Michel ML, Mancini M et al. Direct gene transfer inskeletal muscle: plasmid DNA-based immunization against thehepatitis B virus surface antigen. Vaccine 1994; 12: 15031509..Google Scholar
  8. 8.
    Wang R, Doolan DL, Le TP et al. Induction of antigen-specificcytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science 1998; 282: 476–480.PubMedCrossRefGoogle Scholar
  9. 9.
    MacGregor RR, Boyer JD, Ugen KE et al. First human trial of aDNA-based vaccine for treatment of human immunodeficiency virus type1 infection: safety and host response. J Infect Dis 1998; 178:92–100.PubMedGoogle Scholar
  10. 10.
    Rottinghaus ST, Poland GA, Jacobson RM et al. Hepatitis B DNAvaccine induces protective antibody responses in humannon-responders to conventional vaccination. Vaccine 2003; 21:4604–4608.PubMedCrossRefGoogle Scholar
  11. 11.
    Casares S, Inaba K, Brumeanu TD et al. Antigen presentation bydendritic cells after immunization with DNA encoding a majorhistocompatibility complex class II-restricted viral epitope. J ExpMed 1997; 186: 1481–1486.CrossRefGoogle Scholar
  12. 12.
    Corr M, von Damm A, Lee DJ, Tighe H. In vivo priming by DNAinjection occurs predominantly by antigen transfer. J Immunol 1999;163: 4721–4727.PubMedGoogle Scholar
  13. 13.
    Porgador A, Irvine KR, Iwasaki A et al. Predominant role fordirectly transfected dendritic cells in antigen presentation to CD8+T cells after gene gun immunization. J Exp Med 1998; 188:1075–1082.PubMedCrossRefGoogle Scholar
  14. 14.
    14. Akbari O, Panjwani N, Garcia S et al. DNA vaccination:transfection and activation of dendritic cells as key events forimmunity. J Exp Med 1999; 189: 169–178.PubMedCrossRefGoogle Scholar
  15. 15.
    Krieg AM, Yi AK, Matson S et al. CpG motifs in bacterial DNA triggerdirect B-cell activation. Nature 1995; 374: 546–549.PubMedCrossRefGoogle Scholar
  16. 16.
    Sato Y, Roman M, Tighe H et al. Immunostimulatory DNA sequencesnecessary for effective intradermal gene immunization. Science 1996;273: 352–354.PubMedCrossRefGoogle Scholar
  17. 17.
    Hemmi H, Takeuchi O, Kawai T et al. A Toll-like receptor recognizesbacterial DNA. Nature 2000; 408: 740–745.PubMedCrossRefGoogle Scholar
  18. 18.
    Feltquate DM, Heaney S, Webster RG, Robinson HL. Different T helpercell types and antibody isotypes generated by saline and gene gunDNA immunization. J Immunol 1997; 158: 2278–2284.PubMedGoogle Scholar
  19. 19.
    Pertmer TM, Roberts TR, Haynes JR. Influenza virusnucleoprotein-specific immunoglobulin G subclass and cytokineresponses elicited by DNA vaccination are dependent on the route ofvector DNA delivery. J Virol 1996; 70: 6119–6125.PubMedGoogle Scholar
  20. 20.
    Turk MJ, Wolchok JD, Guevara-Patino JA et al. Multiple pathways totumor immunity and concomitant autoimmunity. Immunol Rev 2002; 188:122–135.PubMedCrossRefGoogle Scholar
  21. 21.
    Wlazlo AP, Deng H, Giles-Davis W, Ertl HC. DNA vaccines against thehuman papillomavirus type 16 E6 or E7 oncoproteins. Cancer Gene Ther2004; 11: 457–464.PubMedCrossRefGoogle Scholar
  22. 22.
    Wolfel T, Hauer M, Schneider J et al. A p16INK4a-insensitive CDK4mutant targeted by cytolytic T lymphocytes in a human melanoma.Science 1995; 269: 1281–1284.Google Scholar
  23. 23.
    Robbins PF, El-Gamil M, Li YF et al. A mutated beta-catenin geneencodes a melanoma-specific antigen recognized by tumor infiltratinglymphocytes. J Exp Med 1996; 183: 1185–1192.PubMedCrossRefGoogle Scholar
  24. 24.
    Pinilla-Ibarz J, Cathcart K, Korontsvit T et al. Vaccination ofpatients with chronic myelogenous leukemia with bcr-abl oncogenebreakpoint fusion peptides generates specific immune responses. Blood 2000; 95: 1781–1787.PubMedGoogle Scholar
  25. 25.
    Scanlan MJ, Gure AO, Jungbluth AA et al. Cancer/testis antigens: anexpanding family of targets for cancer immunotherapy. Immunol Rev2002; 188: 22–32.PubMedCrossRefGoogle Scholar
  26. 26.
    O’Garra A, Vieira P. Regulatory T cells and mechanisms of immunesystem control. Nat Med 2004; 10: 801–805.PubMedCrossRefGoogle Scholar
  27. 27.
    Brichard V, Van Pel A, Wolfel T et al. The tyrosinase gene codes foran antigen recognized by autologous cytolytic T lymphocytes onHLA-A2 melanomas. J Exp Med 1993; 178: 489–495.PubMedCrossRefGoogle Scholar
  28. 28.
    Wang RF, Appella E, Kawakami Y et al. Identification of TRP-2 as ahuman tumor antigen recognized by cytotoxic T lymphocytes. J Exp Med1996; 184: 2207–2216.PubMedCrossRefGoogle Scholar
  29. 29.
    Bakker AB, Schreurs MW, de Boer AJ et al. Melanocytelineage-specific antigen gp100 is recognized by melanoma-derivedtumor-infiltrating lymphocytes. J Exp Med 1994; 179: 10051009..CrossRefGoogle Scholar
  30. 30.
    Kawakami Y, Eliyahu S, Delgado CH et al. Cloning of the gene codingfor a shared human melanoma antigen recognized by autologous T cellsinfiltrating into tumor. Proc Natl Acad Sci U S A 1994; 91:3515–3519.PubMedCrossRefGoogle Scholar
  31. 31.
    Vijayasaradhi S, Bouchard B, Houghton AN. The melanoma antigen gp75is the human homologue of the mouse b (brown) locus gene product. JExp Med 1990; 171: 1375–1380.CrossRefGoogle Scholar
  32. 32.
    Naftzger C, Takechi Y, Kohda H et al. Immune response to adifferentiation antigen induced by altered antigen: a study of tumorrejection and autoimmunity. Proc Natl Acad Sci U S A 1996; 93:14809–14814.PubMedCrossRefGoogle Scholar
  33. 33.
    Weber LW, Bowne WB, Wolchok JD et al. Tumor immunity andautoimmunity induced by immunization with homologous DNA. J ClinInvest 1998; 102: 1258–1264.Google Scholar
  34. 34.
    Bowne WB, Srinivasan R, Wolchok JD et al. Coupling and uncoupling oftumor immunity and autoimmunity. J Exp Med 1999; 190: 1717–1722.PubMedCrossRefGoogle Scholar
  35. 35.
    Hawkins WG, Gold JS, Dyall R et al. Immunization with DNA coding forgp100 results in CD4 T-cell independent antitumor immunity. Surgery2000; 128: 273–280.PubMedCrossRefGoogle Scholar
  36. 36.
    Steitz J, Bruck J, Steinbrink K et al. Genetic immunization of micewith human tyrosinase-related protein 2: implications for theimmunotherapy of melanoma. Int J Cancer 2000; 86: 89–94.PubMedCrossRefGoogle Scholar
  37. 37.
    Rakhmilevich AL, Imboden M, Hao Z et al. Effective particle-mediatedvaccination against mouse melanoma by coadministration of plasmidDNA encoding Gp100 and granulocyte-macrophage colony-stimulatingfactor. Clin Cancer Res 2001; 7: 952–961.PubMedGoogle Scholar
  38. 38.
    Schreurs MW, de Boer AJ, Figdor CG, Adema GJ. Genetic vaccinationagainst the melanocyte lineage-specific antigen gp100 inducescytotoxic T lymphocyte-mediated tumor protection. Cancer Res 1998;58: 2509–2514.PubMedGoogle Scholar
  39. 39.
    Bergman PJ, McKnight J, Novosad A et al. Long-term survival of dogswith advanced malignant melanoma after DNA vaccination withxenogeneic human tyrosinase: a phase I trial. Clin Cancer Res 2003;9: 1284–1290.PubMedGoogle Scholar
  40. 40.
    Gold JS, Ferrone CR, Guevara-Patino JA et al. A single heterocliticepitope determines cancer immunity after xenogeneic DNA immunizationagainst a tumor differentiation antigen. J Immunol 2003; 170:5188–5194.PubMedGoogle Scholar
  41. 41.
    Marshall J. Carcinoembryonic antigen-based vaccines. Semin Oncol2003; 30: 30–36.PubMedCrossRefGoogle Scholar
  42. 42.
    Conry RM, LoBuglio AF, Loechel F et al. A carcinoembryonic antigenpolynucleotide vaccine has in vivo antitumor activity. Gene Ther1995; 2: 59–65.PubMedGoogle Scholar
  43. 43.
    Niethammer AG, Primus FJ, Xiang R et al. An oral DNA vaccine againsthuman carcinoembryonic antigen (CEA) prevents growth anddissemination of Lewis lung carcinoma in CEA transgenic mice. Vaccine 2001; 20: 421–429.PubMedCrossRefGoogle Scholar
  44. 44.
    Zhou H, Luo Y, Mizutani M et al. A novel transgenic mouse model forimmunological evaluation of carcinoembryonic antigen-based DNAminigene vaccines. J Clin Invest 2004; 113: 1792–1798.PubMedCrossRefGoogle Scholar
  45. 45.
    Disis ML, Calenoff E, McLaughlin G et al. Existent T-cell andantibody immunity to HER-2/neu protein in patients with breastcancer. Cancer Res 1994; 54: 16–20.PubMedGoogle Scholar
  46. 46.
    Peoples GE, Goedegebuure PS, Smith R et al. Breast and ovariancancer-specific cytotoxic T lymphocytes recognize the sameHER2/neu-derived peptide. Proc Natl Acad Sci U S A 1995; 92:432–436.PubMedCrossRefGoogle Scholar
  47. 47.
    Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus amonoclonal antibody against HER2 for metastatic breast cancer thatoverexpresses HER2. N Engl J Med 2001; 344: 783–792.PubMedCrossRefGoogle Scholar
  48. 48.
    Vogel CL, Cobleigh MA, Tripathy D et al. Efficacy and safety oftrastuzumab as a single agent in first-line treatment ofHER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20:719–726.PubMedCrossRefGoogle Scholar
  49. 49.
    Chen Y, Hu D, Eling DJ et al. DNA vaccines encoding full-length ortruncated Neu induce protective immunity against Neu-expressingmammary tumors. Cancer Res 1998; 58: 1965–1971.PubMedGoogle Scholar
  50. 50.
    Piechocki MP, Pilon SA, Wei WZ. Complementary antitumor immunityinduced by plasmid DNA encoding secreted and cytoplasmic humanErbB-2. J Immunol 2001; 167: 33673374..Google Scholar
  51. 51.
    Foy TM, Bannink J, Sutherland RA et al. Vaccination with Her-2/neuDNA or protein subunits protects against growth of aHer-2/neu-expressing murine tumor. Vaccine 2001; 19: 2598–2606.PubMedCrossRefGoogle Scholar
  52. 52.
    Amici A, Venanzi FM, Concetti A. Genetic immunization againstneu/erbB2 transgenic breast cancer. Cancer Immunol Immunother 1998;47: 183–190.PubMedCrossRefGoogle Scholar
  53. 53.
    Quaglino E, Iezzi M, Mastini C et al. Electroporated DNA vaccineclears away multifocal mammary carcinomas in her-2/neu transgenicmice. Cancer Res 2004; 64: 2858–2864.PubMedCrossRefGoogle Scholar
  54. 54.
    Spadaro M, Ambrosino E, Iezzi M et al. Cure of mammary carcinomas inHer-2 transgenic mice through sequential stimulation of innate(neoadjuvant interleukin-12) and adaptive (DNA vaccineelectroporation) immunity. Clin Cancer Res 2005; 11: 1941–1952.PubMedCrossRefGoogle Scholar
  55. 55.
    Syrengelas AD, Chen TT, Levy R. DNA immunization induces protectiveimmunity against B-cell lymphoma. Nat Med 1996; 2: 1038–1041.PubMedCrossRefGoogle Scholar
  56. 56.
    King CA, Spellerberg MB, Zhu D et al. DNA vaccines with single-chainFv fused to fragment C of tetanus toxin induce protective immunityagainst lymphoma and myeloma. Nat Med 1998; 4: 1281–1286.PubMedCrossRefGoogle Scholar
  57. 57.
    Stevenson FK, Ottensmeier CH, Johnson P et al. DNA vaccines toattack cancer. Proc Natl Acad Sci U S A 2004; 101 Suppl 2:14646–14652.Google Scholar
  58. 58.
    Thirdborough SM, Radcliffe JN, Friedmann PS, Stevenson FK. Vaccination with DNA encoding a single-chain TCR fusion proteininduces anticlonotypic immunity and protects against T-celllymphoma. Cancer Res 2002; 62: 1757–1760.PubMedGoogle Scholar
  59. 59.
    Palomba ML, Roberts WK, Dao T et al. CD8+ T-cell-dependent immunityfollowing xenogeneic DNA immunization against CD20 in a tumorchallenge model of B-cell lymphoma. Clin Cancer Res 2005; 11:370–379.PubMedGoogle Scholar
  60. 60.
    Padua RA, Larghero J, Robin M et al. PML-RARA-targeted DNA vaccineinduces protective immunity in a mouse model of leukemia. Nat Med2003; 9: 1413–1417.PubMedCrossRefGoogle Scholar
  61. 61.
    Johnen H, Kulbe H, Pecher G. Long-term tumor growth suppression inmice immunized with naked DNA of the human tumor antigen mucin(MUC1). Cancer Immunol Immunother 2001; 50: 356–360.PubMedCrossRefGoogle Scholar
  62. 62.
    Kontani K, Taguchi O, Ozaki Y et al. Novel vaccination protocolconsisting of injecting MUC1 DNA and nonprimed dendritic cells atthe same region greatly enhanced MUC1-specific antitumor immunity ina murine model. Cancer Gene Ther 2002; 9: 330–337.PubMedCrossRefGoogle Scholar
  63. 63.
    Rosenberg SA, Yang JC, Sherry RM et al. Inability to ImmunizePatients with Metastatic Melanoma Using Plasmid DNA Encoding thegp100 Melanoma-Melanocyte Antigen. Hum Gene Ther 2003; 14: 709–714.PubMedCrossRefGoogle Scholar
  64. 64.
    Tagawa ST, Lee P, Snively J et al. Phase I study of intranodaldelivery of a plasmid DNA vaccine for patients with Stage IVmelanoma. Cancer 2003; 98: 144–154.PubMedCrossRefGoogle Scholar
  65. 65.
    Triozzi PL, Aldrich W, Allen KO et al. Phase I study of a plasmidDNA vaccine encoding MART-1 in patients with resected melanoma atrisk for relapse. J Immunother 2005; 28: 382–388.PubMedCrossRefGoogle Scholar
  66. 66.
    Mincheff M, Tchakarov S, Zoubak S et al. Naked DNA and adenoviralimmunizations for immunotherapy of prostate cancer: a phase I/IIclinical trial. Eur Urol 2000; 38: 208–217.PubMedCrossRefGoogle Scholar
  67. 67.
    Pavlenko M, Roos AK, Lundqvist A et al. A phase I trial of DNAvaccination with a plasmid expressing prostate-specific antigen inpatients with hormone-refractory prostate cancer. Br J Cancer 2004;91: 688–694.PubMedGoogle Scholar
  68. 68.
    Miller AM, Ozenci V, Kiessling R, Pisa P. Immune monitoring in aphase 1 trial of a PSA DNA vaccine in patients withhormone-refractory prostate cancer. J Immunother 2005; 28: 389–395.PubMedCrossRefGoogle Scholar
  69. 69.
    Timmerman JM, Singh G, Hermanson G et al. Immunogenicity of aplasmid DNA vaccine encoding chimeric idiotype in patients withB-cell lymphoma. Cancer Res 2002; 62: 5845–5852.PubMedGoogle Scholar
  70. 70.
    Conry RM, Curiel DT, Strong TV et al. Safety and immunogenicity of aDNA vaccine encoding carcinoembryonic antigen and hepatitis Bsurface antigen in colorectal carcinoma patients. Clin Cancer Res2002; 8: 2782–2787.PubMedGoogle Scholar
  71. 71.
    Smith CL, Dunbar PR, Mirza F et al. Recombinant modified vacciniaAnkara primes functionally activated CTL specific for a melanomatumor antigen epitope in melanoma patients with a high risk ofdisease recurrence. Int J Cancer 2005; 113: 259–266.PubMedCrossRefGoogle Scholar
  72. 72.
    Kadowaki N, Ho S, Antonenko S et al. Subsets of human dendritic cellprecursors express different toll-like receptors and respond todifferent microbial antigens. J Exp Med 2001; 194: 863–869.PubMedCrossRefGoogle Scholar
  73. 73.
    Hochrein H, O’Keeffe M, Wagner H. Human and mouse plasmacytoiddendritic cells. Hum Immunol 2002; 63: 1103–1110.PubMedCrossRefGoogle Scholar
  74. 74.
    Zou W. Immunosuppressive networks in the tumour environment andtheir therapeutic relevance. Nat Rev Cancer 2005; 5: 263–274.PubMedCrossRefGoogle Scholar
  75. 75.
    Toka FN, Pack CD, Rouse BT. Molecular adjuvants for mucosalimmunity. Immunol Rev 2004; 199: 100–112.PubMedCrossRefGoogle Scholar
  76. 76.
    Calarota SA, Weiner DB. Enhancement of human immunodeficiency virustype 1-DNA vaccine potency through incorporation of T-helper 1molecular adjuvants. Immunol Rev 2004; 199: 84–99.PubMedCrossRefGoogle Scholar
  77. 77.
    Prud’homme GJ. DNA vaccination against tumors. J Gene Med 2005; 7:3–17.PubMedCrossRefGoogle Scholar
  78. 78.
    Cohen AD, Boyer JD, Weiner DB. Modulating the immune response togenetic immunization. Faseb J 1998; 12: 1611–1626.PubMedGoogle Scholar
  79. 79.
    Barouch DH, Santra S, Schmitz JE et al. Control of viremia andprevention of clinical AIDS in rhesus monkeys by cytokine-augmentedDNA vaccination. Science 2000; 290: 486–492.PubMedCrossRefGoogle Scholar
  80. 80.
    Ferrone CR, Perales M-A, Somberg CJ et al. Enhancement of CD8 T-cellresponses and tumor protection following xenogeneic DNA immunizationagainst a tumor antigen with IL-12/Ig DNA and IL-15/Ig DNA.Submitted for publication.Google Scholar
  81. 81.
    Barouch DH, Truitt DM, Letvin NL. Expression kinetics of theinterleukin-2/immunoglobulin (IL-2/Ig) plasmid cytokine adjuvant. Vaccine 2004; 22: 3092–3097.PubMedCrossRefGoogle Scholar
  82. 82.
    Bowne WB, Wolchok JD, Hawkins WG et al. Injection of DNA encodinggranulocyte-macrophage colony-stimulating factor recruits dendriticcells for immune adjuvant effects. Cytokines Cell Mol Ther 1999; 5:217–225.PubMedGoogle Scholar
  83. 83.
    Perales MA, Fantuzzi G, Goldberg SM et al. GM-CSF DNA inducesspecific patterns of cytokines and chemokines in the skin:implications for DNA vaccines. Cytokines Cell Mol Ther 2002; 7:125–133.PubMedCrossRefGoogle Scholar
  84. 84.
    Chow YH, Chiang BL, Lee YL et al. Development of Th1 and Th2populations and the nature of immune responses to hepatitis B virusDNA vaccines can be modulated by codelivery of various cytokinegenes. J Immunol 1998; 160: 1320–1329.PubMedGoogle Scholar
  85. 85.
    Bertley FM, Kozlowski PA, Wang SW et al. Control of simian/humanimmunodeficiency virus viremia and disease progression afterIL-2-augmented DNA-modified vaccinia virus Ankara nasal vaccinationin nonhuman primates. J Immunol 2004; 172: 3745–3757.PubMedGoogle Scholar
  86. 86.
    Weiss WR, Ishii KJ, Hedstrom RC et al. A plasmid encoding murinegranulocyte-macrophage colony-stimulating factor increasesprotection conferred by a malaria DNA vaccine. J Immunol 1998; 161:2325–2332.PubMedGoogle Scholar
  87. 87.
    Sin JI, Kim JJ, Arnold RL et al. IL-12 gene as a DNA vaccineadjuvant in a herpes mouse model: IL-12 enhances Th1-type CD4+ Tcell-mediated protective immunity against herpes simplex virus-2challenge. J Immunol 1999; 162: 2912–2921.PubMedGoogle Scholar
  88. 88.
    Moore AC, Kong WP, Chakrabarti BK, Nabel GJ. Effects of antigen andgenetic adjuvants on immune responses to human immunodeficiencyvirus DNA vaccines in mice. J Virol 2002; 76: 243–250.PubMedCrossRefGoogle Scholar
  89. 89.
    Kim JJ, Yang JS, Dang K et al. Engineering enhancement of immuneresponses to DNA-based vaccines in a prostate cancer model in rhesusmacaques through the use of cytokine gene adjuvants. Clin Cancer Res2001; 7: 882.s-889s.Google Scholar
  90. 90.
    Geissler M, Gesien A, Tokushige K, Wands JR. Enhancement of cellularand humoral immune responses to hepatitis C virus core protein usingDNA-based vaccines augmented with cytokine-expressing plasmids. JImmunol 1997; 158: 1231–1237.Google Scholar
  91. 91.
    Kim JJ, Nottingham LK, Tsai A et al. Antigen-specific humoral andcellular immune responses can be modulated in rhesus macaquesthrough the use of IFN-gamma, IL-12, or IL-18 gene adjuvants. J MedPrimatol 1999; 28: 214–223.Google Scholar
  92. 92.
    Conry RM, Widera G, LoBuglio AF et al. Selected strategies toaugment polynucleotide immunization. Gene Ther 1996; 3: 67–74.PubMedGoogle Scholar
  93. 93.
    Kutzler MA, Robinson TM, Chattergoon MA et al. Coimmunization withan optimized IL-15 plasmid results in enhanced function andlongevity of CD8 T cells that are partially independent of CD4 Tcell help. J Immunol 2005; 175: 112–123.PubMedGoogle Scholar
  94. 94.
    Billaut-Mulot O, Idziorek T, Loyens M et al. Modulation of cellularand humoral immune responses to a multiepitopic HIV-1 DNA vaccine byinterleukin-18 DNA immunization/viral protein boost. Vaccine 2001;19: 2803–2811.PubMedCrossRefGoogle Scholar
  95. 95.
    Zhu M, Xu X, Liu H et al. Enhancement of DNA vaccine potency againstherpes simplex virus 1 by co-administration of an interleukin-18expression plasmid as a genetic adjuvant. J Med Microbiol 2003; 52:223–228.PubMedCrossRefGoogle Scholar
  96. 96.
    Hung CF, Hsu KF, Cheng WF et al. Enhancement of DNA vaccine potencyby linkage of antigen gene to a gene encoding the extracellulardomain of Fms-like tyrosine kinase 3-ligand. Cancer Res 2001; 61:1080–1088.PubMedGoogle Scholar
  97. 97.
    Sailaja G, Husain S, Nayak BP, Jabbar AM. Long-term maintenance ofgp120-specific immune responses by genetic vaccination with theHIV-1 envelope genes linked to the gene encoding Flt-3 ligand. JImmunol 2003; 170: 2496–2507.Google Scholar
  98. 98.
    Sang H, Pisarev VM, Munger C et al. Regional, but not systemicrecruitment/expansion of dendritic cells by a pluronic-formulatedFlt3-ligand plasmid with vaccine adjuvant activity. Vaccine 2003;21: 3019–3029.PubMedCrossRefGoogle Scholar
  99. 99.
    Sumida SM, McKay PF, Truitt DM et al. Recruitment and expansion ofdendritic cells in vivo potentiate the immunogenicity of plasmid DNAvaccines. J Clin Invest 2004; 114: 13341342..CrossRefGoogle Scholar
  100. 100.
    Zlotnik A, Yoshie O. Chemokines: a new classification system andtheir role in immunity. Immunity 2000; 12: 121–127.PubMedCrossRefGoogle Scholar
  101. 101.
    Kim JJ, Nottingham LK, Sin JI et al. CD8 positive T cells influenceantigen-specific immune responses through the expression ofchemokines. J Clin Invest 1998;Google Scholar
  102. 102.
    1112–1124. 102. Lu Y, Xin KQ, Hamajima K et al. Macrophageinflammatory protein-1alpha (MIP1alpha) expression plasmid enhancesDNA vaccine-induced immune response against HIV-1. Clin Exp Immunol1999; 115: 335–341.PubMedCrossRefGoogle Scholar
  103. 103.
    Pinto AR, Reyes-Sandoval A, Ertl HC. Chemokines and TRANCE asgenetic adjuvants for a DNA vaccine to rabies virus. Cell Immunol2003; 224: 106–113.PubMedCrossRefGoogle Scholar
  104. 104.
    Sin J, Kim JJ, Pachuk C et al. DNA vaccines encoding interleukin-8and RANTES enhance antigen-specific Th1-type CD4(+) T-cell-mediatedprotective immunity against herpes simplex virus type 2 in vivo. JVirol 2000; 74: 11173–11180.CrossRefGoogle Scholar
  105. 105.
    Eo SK, Lee S, Chun S, Rouse BT. Modulation of immunity againstherpes simplex virus infection via mucosal genetic transfer ofplasmid DNA encoding chemokines. J Virol 2001; 75: 569–578.PubMedCrossRefGoogle Scholar
  106. 106.
    Eo SK, Lee S, Kumaraguru U, Rouse BT. Immunopotentiation of DNAvaccine against herpes simplex virus via co-delivery of plasmid DNAexpressing CCR7 ligands. Vaccine 2001; 19: 4685–4693.PubMedCrossRefGoogle Scholar
  107. 107.
    Xiang R, Mizutani N, Luo Y et al. A DNA vaccine targeting survivincombines apoptosis with suppression of angiogenesis in lung tumoreradication. Cancer Res 2005; 65: 553–561.PubMedGoogle Scholar
  108. 108.
    Youssef S, Maor G, Wildbaum G et al. C-C chemokine-encoding DNAvaccines enhance breakdown of tolerance to their gene products andtreat ongoing adjuvant arthritis. J Clin Invest 2000; 106: 361–371.PubMedCrossRefGoogle Scholar
  109. 109.
    Kim JJ, Bagarazzi ML, Trivedi N et al. Engineering of in vivo immuneresponses toDNA immunization via codelivery of costimulatory molecule genes. NatBiotechnol 1997; 15: 641–646.Google Scholar
  110. 110.
    Iwasaki A, Stiernholm BJ, Chan AK et al. Enhanced CTL responsesmediated by plasmid DNA immunogens encoding costimulatory moleculesand cytokines. J Immunol 1997; 158: 4591–4601.PubMedGoogle Scholar
  111. 111.
    Schoenberger SP, Toes RE, van der Voort EI et al. T-cell help forcytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998; 393: 480–483.PubMedCrossRefGoogle Scholar
  112. 112.
    Bennett SR, Carbone FR, Karamalis F et al. Help for cytotoxic-T-cellresponses is mediated by CD40 signalling. Nature 1998; 393:478–480.PubMedCrossRefGoogle Scholar
  113. 113.
    Ridge JP, Di Rosa F, Matzinger P. A conditioned dendritic cell canbe a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 1998; 393: 474–478.PubMedCrossRefGoogle Scholar
  114. 114.
    Mendoza RB, Cantwell MJ, Kipps TJ. Immunostimulatory effects of aplasmid expressing CD40 ligand (CD154) on gene immunization. JImmunol 1997; 159: 5777–5781.Google Scholar
  115. 115.
    Xiang R, Primus FJ, Ruehlmann JM et al. A dual-function DNA vaccineencoding carcinoembryonic antigen and CD40 ligand trimer induces Tcell-mediated protective immunity against colon cancer incarcinoembryonic antigen-transgenic mice. J Immunol 2001; 167:4560–4565.PubMedGoogle Scholar
  116. 116.
    Sin JI, Kim JJ, Zhang D, Weiner DB. Modulation of cellular responsesby plasmid CD40L plasmid vectors enhance antigen-specific helper T cell type 1CD4+ T cell-mediated protective immunity against herpes simplexvirus type 2 in vivo. Hum Gene Ther 2001;12: 1091–1102.PubMedCrossRefGoogle Scholar
  117. 117.
    117. Hung CF, Cheng WF, Chai CY et al. Improving vaccine potencythrough intercellular spreading and enhanced MHC class Ipresentation of antigen. J Immunol 2001; 166: 5733–5740.PubMedGoogle Scholar
  118. 118.
    Hung CF, Cheng WF, Hsu KF et al. Cancer immunotherapy using a DNAvaccine encoding the translocation domain of a bacterial toxinlinked to a tumor antigen. Cancer Res 2001; 61: 3698–3703.PubMedGoogle Scholar
  119. 119.
    Rohrbach F, Weth R, Kursar M et al. Targeted delivery of theErbB2/HER2 tumor antigen to professional APCs results in effectiveantitumor immunity. J Immunol 2005; 174: 5481–5489.PubMedGoogle Scholar
  120. 120.
    Leitner WW, Hwang LN, deVeer MJ et al. Alphavirus-based DNA vaccinebreaks immunological tolerance by activating innate antiviralpathways. Nat Med 2003; 9: 33–39.PubMedCrossRefGoogle Scholar
  121. 121.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition ofdouble-stranded RNA and activation of NF-kappaB by Toll-likereceptor 3. Nature 2001; 413: 732–738.PubMedCrossRefGoogle Scholar
  122. 122.
    Xiang R, Lode HN, Chao TH et al. An autologous oral DNA vaccineprotects against murine melanoma. Proc Natl Acad Sci U S A 2000; 97:5492–5497.PubMedCrossRefGoogle Scholar
  123. 123.
    Woo PC, Wong LP, Zheng BJ, Yuen KY. Unique immunogenicity ofhepatitis B virus DNA vaccine presented by live-attenuatedSalmonella typhimurium. Vaccine 2001; 19: 29452954..CrossRefGoogle Scholar
  124. 124.
    Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into itsbiological function and use in tumor immunotherapy. Nat Immunol2002; 3: 611–618.PubMedCrossRefGoogle Scholar
  125. 125.
    van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy ofB16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4(CTLA-4) and granulocyte/macrophage colony-stimulating factor(GM-CSF)-producing vaccines induces rejection of subcutaneous andmetastatic tumors accompanied by autoimmune depigmentation. J ExpMed 1999; 190: 355–366.CrossRefGoogle Scholar
  126. 126.
    Phan GQ, Yang JC, Sherry RM et al. Cancer regression andautoimmunity induced by cytotoxic T lymphocyte-associated antigen 4blockade in patients with metastatic melanoma. Proc Natl Acad Sci US A 2003; 100: 8372–8377.CrossRefGoogle Scholar
  127. 127.
    Hodi FS, Mihm MC, Soiffer RJ et al. Biologic activity of cytotoxic Tlymphocyte-associated antigen 4 antibody blockade in previouslyvaccinated metastatic melanoma and ovarian carcinoma patients. ProcNatl Acad Sci U S A 2003; 100: 4712–4717.CrossRefGoogle Scholar
  128. 128.
    Attia P, Phan GQ, Maker AV et al. Autoimmunity Correlates With TumorRegression in Patients With Metastatic Melanoma Treated WithAnti-Cytotoxic T-Lymphocyte Antigen-4.break J Clin Oncol 2005.Google Scholar
  129. 129.
    Gregor PD, Wolchok JD, Turaga V et al. Induction of autoantibodiesto syngeneic prostate-specific membrane antigen by xenogeneicvaccination. Int J Cancer 2005; 116: 415–421.PubMedCrossRefGoogle Scholar
  130. 130.
    Nocentini G, Riccardi C. GITR: a multifaceted regulator of immunitybelonging to the tumor necrosis factor receptor superfamily. Eur JImmunol 2005; 35: 1016–1022.CrossRefGoogle Scholar
  131. 131.
    Shimizu J, Yamazaki S, Takahashi T et al. Stimulation ofCD25(+)CD4(+) regulatory T cells through GITR breaks immunologicalself-tolerance. Nat Immunol 2002; 3: 135–142.PubMedCrossRefGoogle Scholar
  132. 132.
    McHugh RS, Whitters MJ, Piccirillo CA et al. CD4(+)CD25(+)immunoregulatory T cells: gene expression analysis reveals afunctional role for the glucocorticoid-induced TNF receptor. Immunity 2002; 16: 311–323.PubMedCrossRefGoogle Scholar
  133. 133.
    Ko K, Yamazaki S, Nakamura K et al. Treatment of advanced tumorswith agonistic anti-GITR mAb and its effects on tumor-infiltratingFoxp3+CD25+CD4+ regulatory T cells. J Exp Med 2005; 202: 885–891.PubMedCrossRefGoogle Scholar
  134. 134.
    Cohen AD, Diab A, Perales M-A et al. Agonist anti-GITR antibodyenhances DNA vaccine-induced CD8+ T cell responses and tumorimmunity against melanoma. Submitted for publication.Google Scholar
  135. 135.
    Sun JY, Krouse RS, Forman SJ et al. Immunogenicity of ap210(BCR-ABL) fusion domain candidate DNA vaccine targeted todendritic cells by a recombinant adeno-associated virus vector invitro. Cancer Res 2002; 62: 3175–3183.PubMedGoogle Scholar
  136. 136.
    Park JH, Kim CJ, Lee JH et al. Effective immunotherapy of cancer byDNA vaccination. Mol Cells 1999; 9: 384–391.PubMedGoogle Scholar
  137. 137.
    Sypniewska RK, Hoflack L, Tarango M et al. Prevention of metastaseswith a Mage-b DNA vaccine in a mouse breast tumor model: potentialfor breast cancer therapy. Breast Cancer Res Treat 2005; 91: 19–28.PubMedCrossRefGoogle Scholar
  138. 138.
    Hanke P, Serwe M, Dombrowski F et al. DNA vaccination withAFP-encoding plasmid DNA prevents growth of subcutaneousAFP-expressing tumors and does not interfere with liver regenerationin mice. Cancer Gene Ther 2002; 9: 346–355.PubMedCrossRefGoogle Scholar
  139. 139.
    Meng WS, Butterfield LH, Ribas A et al. alpha-Fetoprotein-specifictumor immunity induced by plasmid prime-adenovirus boost geneticvaccination. Cancer Res 2001; 61: 8782–8786.PubMedGoogle Scholar
  140. 140.
    Tsuboi A, Oka Y, Ogawa H et al. Cytotoxic T-lymphocyte responseselicited to Wilms’tumor gene WT1 product by DNA vaccination. J ClinImmunol 2000; 20: 195–202.Google Scholar
  141. 141.
    Deng H, Kowalczyk D, O I et al. A modified DNA vaccine to p53induces protective immunity to challenge with a chemically inducedsarcoma cell line. Cell Immunol 2002; 215: 20–31.PubMedCrossRefGoogle Scholar
  142. 142.
    Tuting T, Gambotto A, Robbins PD et al. Co-delivery of T helper1-biasing cytokine genes enhances the efficacy of gene gunimmunization of mice: studies with the model tumor antigenbeta-galactosidase and the BALB/c Meth A p53 tumor-specific antigen. Gene Ther 1999; 6: 629–636.PubMedCrossRefGoogle Scholar
  143. 143.
    Lindinger P, Mostbock S, Hammerl P et al. Induction of murine rasoncogene peptide-specific T cell responses by immunization withplasmid DNA-based minigene vectors. Vaccine 2003; 21: 4285–4296.PubMedCrossRefGoogle Scholar
  144. 144.
    Bristol JA, Orsini C, Lindinger P et al. Identification of a rasoncogene peptide that contains both CD4(+) and CD8(+) T cellepitopes in a nested configuration and elicits both T cell subsetresponses by peptide or DNA immunization. Cell Immunol 2000; 205:73–83.PubMedCrossRefGoogle Scholar
  145. 145.
    Kim JJ, Tsai A, Nottingham LK et al. Intracellular adhesionmolecule-1 modulates beta-chemokines and directly costimulates Tcells in vivo. J Clin Invest 1999; 103: 869–877.PubMedGoogle Scholar
  146. 146.
    Jeannin P, Renno T, Goetsch L et al. OmpA targets dendritic cells,induces their maturation and delivers antigen into the MHC class Ipresentation pathway. Nat Immunol 2000; 1: 502–509.PubMedCrossRefGoogle Scholar
  147. 147.
    Chen CH, Wang TL, Hung CF et al. Enhancement of DNA vaccine potencyby linkage of antigen gene to an HSP70 gene. Cancer Res 2000; 60:1035–1042.PubMedGoogle Scholar
  148. 148.
    Otero M, Calarota SA, Felber B et al. Resiquimod is a modestadjuvant for HIV-1 gag-based genetic immunization in a mouse model.Vaccine 2004; 22: 1782–1790.Google Scholar
  149. 149.
    Zuber AK, Brave A, Engstrom G et al. Topical delivery of imiquimodto a mouse model as a novel adjuvant for human immunodeficiencyvirus (HIV) DNA. Vaccine 2004; 22: 1791–1798.PubMedCrossRefGoogle Scholar
  150. 150.
    Thomsen LL, Topley P, Daly MG et al. Imiquimod and resiquimodin a mouse model: adjuvants for DNA vaccination by particle-mediatedimmunotherapeutic delivery. Vaccine 2004; 22: 1799–1809.PubMedCrossRefGoogle Scholar
  151. 151.
    Niethammer AG, Xiang R, Becker JC et al. A DNA vaccine against VEGFreceptor 2 prevents effective angiogenesis and inhibits tumorgrowth. Nat Med 2002; 8: 1369–1375.PubMedCrossRefGoogle Scholar
  152. 152.
    Luo Y, Zhou H, Mizutani M et al. Transcription factor Fos-relatedantigen 1 is an effective target for a breast cancer vaccine. ProcNatl Acad Sci U S A 2003; 100: 8850–8855.CrossRefGoogle Scholar
  153. 153.
    Loeffler M, Kruger JA, Reisfeld RA. Immunostimulatory effects oflow-dose cyclophosphamide are controlled by inducible nitric oxidesynthase. Cancer Res 2005; 65: 5027–5030.PubMedCrossRefGoogle Scholar
  154. 154.
    Kim TW, Hung CF, Ling M et al. Enhancing DNA vaccine potency bycoadministration of DNA encoding antiapoptotic proteins. J ClinInvest 2003; 112: 109–117.Google Scholar
  155. 155.
    Widera G, Austin M, Rabussay D et al. Increased DNA vaccine deliveryand immunogenicity by electroporation in vivo. J Immunol 2000; 164:4635–4640.PubMedGoogle Scholar
  156. 156.
    Hermans IF, Chong TW, Palmowski MJ et al. Synergistic effect ofmetronomic dosing of cyclophosphamide combined with specificantitumor immunotherapy in a murine melanoma model. Cancer Res 2003;63: 8408–8413.PubMedGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Adam D. Cohen
    • 1
  • Jedd D. Wolchok
    • 1
  1. 1.Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Medical College of Cornell UniversityNew York

Personalised recommendations