Development of TLR9 agonists for cancer therapy

被引:334
作者
Krieg, Arthur M. [1 ]
机构
[1] Coley Pharmaceut Grp, Wellesley, MA 02481 USA
关键词
D O I
10.1172/JCI31414
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
In vertebrates, the TLRs are a family of specialized immune receptors that induce protective immune responses when they detect highly conserved pathogen-expressed molecules. Synthetic agonists for several TLRs, including TLR3, TLR4, TLR7, TLR8, and TLR9, have been or are being developed for the treatment of cancer. TLR9 detects the unmethylated CpG dinucleotides prevalent in bacterial and viral DNA but not in vertebrate genomes. As discussed in this Review, short synthetic oligodeoxynucleotides containing these immune stimulatory CpG motifs activate TLR9 in vitro and in vivo, inducing innate and adaptive immunity, and are currently being tested in multiple phase II and phase III human clinical trials as adjuvants to cancer vaccines and in combination with conventional chemotherapy and other therapies.
引用
收藏
页码:1184 / 1194
页数:11
相关论文
共 126 条
[101]   Vaccination with plasmid DNA activates dendritic cells via toll-like receptor 9 (TLR9) but functions in TLR9-deficient mice [J].
Spies, B ;
Hochrein, H ;
Vabulas, M ;
Huster, K ;
Busch, DH ;
Schmitz, F ;
Heit, A ;
Wagner, H .
JOURNAL OF IMMUNOLOGY, 2003, 171 (11) :5908-5912
[102]   Vaccination with tumor peptide in CpG adjuvant protects via IFN-γ-dependent CD4 cell immunity [J].
Stern, BV ;
Boehm, BO ;
Tary-Lehmann, M .
JOURNAL OF IMMUNOLOGY, 2002, 168 (12) :6099-6105
[103]   Recognition of cytosolic DNA activates an IRF3-dependent innate immune response [J].
Stetson, DB ;
Medzhitov, R .
IMMUNITY, 2006, 24 (01) :93-103
[104]   Upon TLR9 signaling, CD5+ B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs [J].
Sun, CM ;
Deriaud, E ;
Leclerc, C ;
Lo-Man, R .
IMMUNITY, 2005, 22 (04) :467-477
[105]   Toll-like receptor 2 controls expansion and function of regulatory T cells [J].
Sutmuller, RPM ;
den Brok, MHMGM ;
Kramer, M ;
Bennink, EJ ;
Toonen, LWJ ;
Kullberg, BJ ;
Joosten, LA ;
Akira, S ;
Netea, MG ;
Adema, GJ .
JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (02) :485-494
[106]   Chemoimmunotherapy of tumors:: Cyclophosphamide synergizes with exosome based vaccines [J].
Taieb, Julien ;
Chaput, Nathalie ;
Schartz, Noel ;
Roux, Stephan ;
Novault, Sophie ;
Menard, Cedric ;
Ghiringhelli, Francois ;
Terme, Magali ;
Carpentier, Antoine F. ;
Darrasse-Jese, Guillaume ;
Lemonnier, Francois ;
Zitvogel, Laurence .
JOURNAL OF IMMUNOLOGY, 2006, 176 (05) :2722-2729
[107]   Toll-like receptors [J].
Takeda, K ;
Kaisho, T ;
Akira, S .
ANNUAL REVIEW OF IMMUNOLOGY, 2003, 21 :335-376
[108]   CD4+ CD25+ T cells regulate vaccine-generated primary and memory CD8+ T-cell responses against herpes simplex virus type 1 [J].
Toka, FN ;
Suvas, S ;
Rouse, BT .
JOURNAL OF VIROLOGY, 2004, 78 (23) :13082-13089
[109]  
TREFZER U, 2002, 2002 AM SOC CLIN ONC, V21, P1902
[110]   Antitumor efficacy of the novel chemotherapeutic agent coramsine is potentiated by cotreatment with CpG-containing oligodeoxynucleotides [J].
van der Most, RG ;
Himbeck, R ;
Aarons, S ;
Carter, SJ ;
Larma, I ;
Robinson, C ;
Currie, A ;
Lake, RA .
JOURNAL OF IMMUNOTHERAPY, 2006, 29 (02) :134-142