Current developments with peptide-based human tumor vaccines

Current Opinion in Oncology

Volumn 21, Issue 6, 2009, Pages 524-530

  Khazaie, Khashayarsha ^a   Bonertz, Andreas ^a,b   Beckhove, Philipp ^a,b  

^a NORTHWESTERN UNIVERSITY   (United States)

^b GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

Author keywords

Adjuvants; CD4 help; Immunomodulation; Long peptide; T cell memory; Treg; Tumor antigen; Vaccine

Indexed keywords

BCG VACCINE; CANCER VACCINE; CARRIER PROTEIN; CYCLOPHOSPHAMIDE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DENILEUKIN DIFTITOX; EPIDERMAL GROWTH FACTOR RECEPTOR 2; FLUDARABINE; IMATINIB; IMMUNOMODULATING AGENT; INTERLEUKIN 2; PEPTIDE VACCINE; PROGRAMMED DEATH RECEPTOR 1; TUMOR ANTIGEN; UNCLASSIFIED DRUG; CYTOTOXIC T-LYMPHOCYTE ANTIGEN 4; LEUKOCYTE ANTIGEN; SUBUNIT VACCINE;

ADULT; ADVANCED CANCER; ANTINEOPLASTIC ACTIVITY; BREAST CANCER; CANCER IMMUNIZATION; CANCER IMMUNOLOGY; CANCER IMMUNOTHERAPY; CANCER PATIENT; CANCER RADIOTHERAPY; CD4+ T LYMPHOCYTE; CLINICAL TRIAL; DRUG EFFICACY; DRUG MEGADOSE; DRUG RESPONSE; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; IMMUNOMODULATION; IMMUNOSUPPRESSIVE TREATMENT; IMMUNOSURVEILLANCE; LUNG ADENOCARCINOMA; MELANOMA; NONHUMAN; PANCREAS CARCINOMA; PRIORITY JOURNAL; REVIEW; TREATMENT OUTCOME; IMMUNOLOGY; IMMUNOTHERAPY; METHODOLOGY; NEOPLASM;

ANTIGENS, CD; ANTIGENS, NEOPLASM; CANCER VACCINES; HUMANS; IMMUNOTHERAPY; NEOPLASMS; TREATMENT OUTCOME; VACCINES, SUBUNIT;

EID: 74049106976     PISSN: 10408746     EISSN: None     Source Type: Journal    
DOI: 10.1097/CCO.0b013e328331a78e     Document Type: Review

References (110)

1. DePlaen E, Lurquin C, Van Pel A, et al. Immunogenic (tum-) variants of mouse tumor P815: cloning of the gene of tum- antigen P91A and identification of the tum- mutation. Proc Natl Acad Sci U S A 1988; 85:2274-2278. (Pubitemid 24315873)
2. Degiovanni G, Lahaye T, Herin M, et al. Antigenic heterogeneity of a human melanoma tumor detected by autologous CTL clones. Eur J Immunol 1988; 18:671-676. (Pubitemid 18153589)
3. Knuth A, Wolfel T, Klehmann E, et al. Cytolytic T-cell clones against an autologous human melanoma: specificity study and definition of three antigens by immunoselection. Proc Natl Acad Sci U S A 1989; 86:2804-2808. (Pubitemid 19112628)
4. Van den Eynde B, Hainaut P, Herin M, et al. Presence on a human melanoma of multiple antigens recognized by autologous CTL. Int J Cancer 1989; 44:634-640. (Pubitemid 19258736)
5. Degiovanni G, Hainaut P, Lahaye T, et al. Antigens recognized on a melanoma cell line by autologous cytolytic T lymphocytes are also expressed on freshly collected tumor cells. Eur J Immunol 1990; 20:1865-1868. (Pubitemid 20290925)
6. Van den Eynde B, Lethe B, Van Pel A, et al. The gene coding for a major tumor rejection antigen of tumor P815 is identical to the normal gene of syngeneic DBA/2 mice. J Exp Med 1991; 173:1373-1384.
7. van der Bruggen P, Traversari C, Chomez P, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991; 254:1643-1647.
8. Derbinski J, Schulte A, Kyewski B, Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2001; 2:1032-1039. (Pubitemid 33069498)
9. Magnusson FC, Liblau RS, von Boehmer H, et al. Direct presentation of antigen by lymph node stromal cells protects against CD8 T-cell-mediated intestinal autoimmunity. Gastroenterology 2008; 134:1028-1037.
10. Lee JW, Epardaud M, Sun J, et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol 2007; 8:181-190. (Pubitemid 46152649)
11. Beckhove P, Feuerer M, Dolenc M, et al. Specifically activated memory T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors. J Clin Invest 2004; 114:67-76. (Pubitemid 39071645)
12. Feuerer M, Beckhove P, Bai L, et al. Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nat Med 2001; 7:452-458. (Pubitemid 32298548)
13. Sommerfeldt N, Schutz F, Sohn C, et al. The shaping of a polyvalent and highly individual T-cell repertoire in the bone marrow of breast cancer patients. Cancer Res 2006; 66:8258-8265. (Pubitemid 44299195)
14. Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3:991-998. (Pubitemid 35363648)
15. Koch M, Beckhove P, Op den Winkel J, et al. Tumor infiltrating T lymphocytes in colorectal cancer: Tumor-selective activation and cytotoxic activity in situ. Ann Surg 2006; 244:986-992; discussion 992-1983
16. Schuetz F, Ehlert K, Ge Y, et al. Treatment of advanced metastasized breast cancer with bone marrow-derived tumour-reactive memory T cells: a pilot clinical study. Cancer Immunol Immunother 2009; 58:887-900.
17. Banchereau J, Palucka AK. Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 2005; 5:296-306. (Pubitemid 40516155)
18. Tacken PJ, de Vrles IJ, Torensma R, Figdor CG. Dendritic-cell immunotherapy: from exvivo loading to in vivo targeting. Nat Rev Immunol 2007; 7:790-802. (Pubitemid 47480309)
19. Nagorsen D, Thiel E. Clinical and immunologic responses to active specific cancer vaccines in human colorectal cancer. Clin Cancer Res 2006; 12:3064-3069. (Pubitemid 43837352)
20. Smith FO, Downey SG, Klapper JA, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res 2008; 14:5610-5618.
21. Marchand M, van Baren N, Weynants P, et al. Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1. Int J Cancer 1999; 80:219-230.
22. Appay V, Jandus C, Voelter V, et al. New generation vaccine induces effective melanoma-specific CD8+ T cells in the circulation but not in the tumor site. J Immunol 2006; 177:1670-1678.
23. Zippelius A, Batard P, Rubio-Godoy V, et al. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 2004; 64:2865-2873.
24. Schmitt M, Schmitt A, Rojewski MT, et al. RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses. Blood 2008; 111:1357-1365.
25. Schuster SJ, Neelapu SS, Gause BL, et al. Idiotype vaccine therapy (BlovaxID) in follicular lymphoma in first complete remission: phase III clinical trial results [abstract 2]. J Clin Oncol 2009; 27:18s.
26. Schwartzentruber DJ, Lawson D, Richards J, et al. A phase III multiinstitutional randomized study of immunization with the gp100:209-21 7(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma [abstract CRA9011]. J Clin Oncol 2009; 27:18s.
27. Falk K, Rotzschke O, Stevanovic S, et al. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 1991; 351:290-296. (Pubitemid 21896578)
28. Rammensee H, Bachmann J, Emmerich NP, et al. SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetlcs 1999; 50:213-219. (Pubitemid 30099526)
29. Melief CJ, van der Burg SH. Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nat Rev Cancer 2008; 8:351-360.
30. Faure F, Mantegazza A, Sadaka C, et al. Long-lasting cross-presentation of tumor antigen in human DC. Eur J Immunol 2009; 39:380-390.
31. Bennett SR, Carbone FR, Toy T, et al. B cells directly tolerlze CD8(+) T cells. J Exp Med 1998; 188:1977-1983.
32. Bijker MS, van den Eeden SJ, Franken KL, et al. Superior induction of antitumor CTL immunity by extended peptide vaccines involves prolonged, DC-focused antigen presentation. Eur J Immunol 2008; 38: 1033-1042.
33. Czerniecki BJ, Koski GK, Koldovsky U, et al. Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. Cancer Res 2007; 67:1842-1852.
34. Janssen EM, Lemmens EE, Wolfe T, et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 2003; 421:852-856.
35. Perez-Diez A, Joncker NT, Choi K, et al. CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood 2007; 109:5346-5354. (Pubitemid 46890556)
36. Hunder NN, Wallen H, Cao J, et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 2008; 358:2698-2703. (Pubitemid 351860862)
37. Mumberg D, Monach PA, Wanderung S, et al. CD4(+) T cells eliminate MHC class II-negatlve cancer cells in vivo by indirect effects of IFN-gamma. Proc Natl Acad Sci U S A 1999; 96:8633-8638. (Pubitemid 29354843)
38. Knutson KL, Schiffman K, Disis ML. Immunization with a HER-2/neu helper peptide vaccine generates HER-2/neu CD8 T-cell immunity in cancer patients. J Clin invest 2001 ; 107:477-484. (Pubitemid 32167994)
39. Salazar LG, Fikes J, Southwood S, et al. Immunization of cancer patients with HER-2/neu-derived peptides demonstrating high-affinity binding to multiple class II alleles. Clin Cancer Res 2003; 9:5559-5565. (Pubitemid 37499475)
40. Disis ML, Goodell V, Schiffman K, Knutson KL Humoral epitope-spreading following immunization with a HER-2/neu peptide based vaccine in cancer patients. J Clin Immunol 2004; 24:571-578. (Pubitemid 39221675)
41. Dang Y, Knutson KL, Goodell V, et al. Tumor antigen-specific T-cell expansion is greatly facilitated by in vivo priming. Clin Cancer Res 2007; 13:1883-1891. (Pubitemid 46952959)
42. Kenter GG, Welters MJ, Valentljn AR, et al. Phase I immunotherapeutic trial with long peptides spanning the E6 and E7 sequences of high-risk human papillomavirus 16 in end-stage cervical cancer patients shows low toxicity and robust immunogenicity. Clin Cancer Res 2008; 14:169-177.
43. Welters MJ, Kenter GG, Plersma SJ, et al. Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine. Clin Cancer Res 2008; 14:178-187.
44. Speetjens FM, Kuppen PJ, Welters MJ, et al. Induction of p53-specific immunity by a p53 synthetic long peptide vaccine in patients treated for metastatic colorectal cancer. Clin Cancer Res 2009; 15:1086-1095.
45. Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 2008; 26:5233-5239.
46. Rosenberg SA, Restifo NP, Yang JC, et al. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008; 8:299-308.
47. Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 2005;65:1089-1096. (Pubitemid 40216472)
48. Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res 2003; 63:6501-6505. (Pubitemid 37255203)
49. Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood 2009; 114:1545-1552.
50. Hamanish J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 2007; 104:3360-3365. (Pubitemid 46364164)
51. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 2007; 13:2151-2157. (Pubitemid 46649885)
52. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 2004; 101:17174-17179.
53. Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A 2008; 105:3005-3010.
54. Yuan J, Gnjatic S, Li H, et al. CTLA-4 blockade enhances polyfunotional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit. Proc Natl Acad Sci U S A 2008; 105:20410-20415.
55. Gray JC, French RR, James S, et al. Optimising antitumour CD8 T-cell responses using combinations of immunomodulatory antibodies. Eur J Immunol 2008; 38:2499-2511.
56. Palena C, Foon KA, Panicali D, et al. Potential approach to immunotherapy of chronic lymphocytic leukemia (CLL): enhanced immunogenicity of CLL cells via infection with vectors encoding for multiple costlmulatory molecules. Blood 2005; 106:3515-3523. (Pubitemid 41609188)
57. Kaufman HL, Deraffele G, Mitcham J, et al. Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma. J Clin Invest 2005; 115:1903-1912. (Pubitemid 40979730)
58. Ganss R, Ryschich E, Klar E, et al. Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res 2002; 62:1462-1470. (Pubitemid 34407808)
59. Zhang B, Bowerman NA, Salama JK, et al. Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med 2007; 204:49-55. (Pubitemid 46148755)
60. Khazaie K, von Boehmer H. The impact of CD4+CD25+ Treg on tumor specific CD8- T cell cytotoxicity and cancer. Semln Cancer Biol 2006; 16:124-136.
61. Sakaguchi S. Naturally arising CD4- regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22:531-562. (Pubitemid 38680433)
62. Klein L, Emmerich J, d'Cruz L, et al. Selection and behavior of CD4+ CD25+ T cells in vivo: lessons from T cell receptor transgenic models. Curr Top Microbiol Immunol 2005; 293:73-87.
63. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4:330-336.
64. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299:1057-1061. (Pubitemid 36222930)
65. Mempel TR, Pittet MJ, Khazaie K, et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 2006; 25:129-141. (Pubitemid 44066829)
66. Chen ML, Pittet MJ, Gorelik L, et al. Regulatory T cells suppress tumorspecific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA 2005; 102:419-424. (Pubitemid 40116782)
67. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 2006; 12:5423-5434. (Pubitemid 44497257)
68. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10:942-949.
69. Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8-/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 2005; 102:18538-18543.
70. Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 2006; 24:5373-5380. (Pubitemid 46623168)
71. Gao Q, Qiu SJ, Fan J, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25:2586-2593. (Pubitemid 47041232)
72. Kobayashi N, Hiraoka N, Yamagami W, et al. FOXP3+ regulatory T cells affect the development and progression of hepatocarclnogenesis. Clin Cancer Res 2007; 13:902-911. (Pubitemid 46340366)
73. Nummer D, Surl-Payer E, Schmitz-Winnenthal H, et al. Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma. J Natl Cancer Inst 2007; 99:1188-1199. (Pubitemid 47233069)
74. Needham DJ, Lee JX, Beilharz MW. Intra-tumoural regulatory T cells: a potential new target in cancer immunotherapy. Biochem Biophys Res Commun 2006; 343:684-691.
75. Clarke SL, Betts GJ, Plant A, et al. CD4+CD25+FOXP3+ regulatory T cells suppress antitumor immune responses in patients with colorectal cancer. PLoS ONE 2006; 1:e129.
76. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007; 8:191-197.
77. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155:1151-1164.
78. Cao X, Cai SF, Fehniger TA, et al. Granzyme Band perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 2007; 27:635-646. (Pubitemid 47628832)
79. Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007; 450:566-569.
80. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204:1257-1265.
81. Kobie JJ, Shah PR, Yang L, et al. T regulatory and primed uncommitted CD4T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine. J Immunol 2006; 177:6780-6786.
82. Li MO, Wan YY, Flavell RA. T cell-produced transforming growth factorbeta1 controls T cell tolerance and regulates Th1 and Th1 7-cell differentiation. Immunity 2007; 26:579-591.
83. Rubtsov YP, Rasmussen JP, Chi EY, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 2008; 28:546-558.
84. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192:303-310.
85. Awwad M, North RJ. Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamlde-reslstant murine tumor: a consequence of eliminating precursor L3T4- suppressor T-cells. Cancer Res 1989; 49: 1649-1654. (Pubitemid 19108381)
86. North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med 1982; 155:1063-1074.
87. Dannull J, Su Z, Rizzieri D, et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 2005; 115:3623-3633. (Pubitemid 43121851)
88. Larmonier N, Janikashvili N, LaCasse CJ, et al. Imatlnlb mesylate inhibits CD4+ CD25+ regulatory T cell activity and enhances active immunotherapy against BCR-ABL- tumors. J Immunol 2008; 181:6955-6963.
89. Quezada SA, Peggs KS, Simpson TR, et al. Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J Exp Med 2008; 205:2125-2138.
90. Gounaris E, Blatner NR, Denis K, et al. T-regulatory cells shift from a protective anti-inflammatory to a cancer promoting pro-inflammatory phenotype in polyposis. Cancer Res (in press).
91. Samy ET, Parker LA, Sharp CP, Tung KS. Continuous control of autoimmune disease by antigen-dependent polyclonal CD4-CD25- regulatory T cells in the regional lymph node. J Exp Med 2005; 202:771-781.
92. Tang Q, Adams JY, Tooley AJ, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 2006; 7:83-92. (Pubitemid 41823872)
93. Tarbell KV, Yamazaki S, Olson K, et al. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 2004; 199:1467-1477. (Pubitemid 38780402)
94. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006; 6:295-307.
95. Vence L, Palucka AK, Fay JW, et al. Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. Proc Natl Acad Sci U S A 2007; 104:20884-20889.
96. Wang HY, Lee DA, Peng G, et al. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. immunity 2004; 20:107-118.
97. Wang HY, Peng G, Guo Z, et al. Recognition of a new ARTC1 peptide ligand uniquely expressed in tumor cells by antigen-specific CD4- regulatory T cells. J Immunol 2005; 174:2661-2670.
98. Bonertz A, Pietsch K, Rahbari N, et al. Antigen-specific Treg in colorectal carcinoma control T-cell responses against a limited tumor antigen repertoire. J Clin Investig (in press).
99. Geisse J, Caro I, Lindholm J, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 2004; 50:722-733. (Pubitemid 38580549)
100. Hadley G, Derry S, Moore RA. Imiquimod for actinic keratosis: systematic review and meta-analysis. J Invest Dermatol 2006; 126:1251-1255. (Pubitemid 43997904)
101. Prins RM, Craft N, Bruhn KW, et al. TheTLR-7 agonist, imiquimod, enhances dendritic cell survival and promotes tumor antigen-specific T cell priming: relation to central nervous system antitumor immunity. J Immunol 2006; 176:157-164. (Pubitemid 43023259)
102. Feyerabend S, Stevanovic S, Gouttefangeas C, et al. Novel multipeptide vaccination in Hla-A2- hormone sensitive patients with biochemical relapse of prostate cancer. Prostate 2009; 69:917-927.
103. Pashenkov M, Goess G, Wagner C, et al. Phase II trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma. J Clin Oncol 2006; 24:5716-5724.
104. Wysocka M, Benoit BM, Newton S, et al. Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG ollgodeoxynucleotides and IL-15. Blood 2004; 104:4142-4149. (Pubitemid 39620167)
105. Speiser DE, Lienard D, Rufer N, et al. Rapid and strong human CD8- T cell responses to vaccination with peptide, IFA, and CpG ollgodeoxynucleotide 7909. J Clin Invest 2005; 115:739-746. (Pubitemid 40322250)
106. Speiser DE, Baumgaertner P, Voelter V, et al. Unmodified self antigen triggers human CD8 T cells with stronger tumor reactivity than altered antigen. Proc Natl Acad Sci U S A 2008; 105:3849-3854. (Pubitemid 351723488)
107. Stanford JL, Stanford CA, O'Brien ME, Grange JM. Successful immunotherapy with Mycobacterium vaccae in the treatment of adenocarcinoma of the lung. Eur J Cancer 2008; 44:224-227.
108. Patel PM, Sim S, O'Donnell DO, et al. An evaluation of a preparation of Mycobacterium vaccae (SRL1 72) as an mmunotherapeutic agent in renal cancer. Eur J Cancer 2008; 44:216-223.
109. Harper-Wynne CL, Sumpter K, Ryan C, et al. Addition of SRL 172 to standard chemotherapy in small cell lung cancer (SCLC) improves symptom control. Lung Cancer 2005; 47:289-290. (Pubitemid 40082172)
110. O'Brien ME, Anderson H, Kaukel E, et al. SRL172 (killed Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced nonsmall-cell lung cancer: phase III results. Ann Oncol 2004; 15:906-914.