Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy

OncoImmunology

Volumn 5, Issue 3, 2016, Pages

  Iribarren, Kristina ^a,b,c   Bloy, Norma ^a,b,d   Buqué, Aitziber ^a,b,d   Cremer, Isabelle ^a,b,c   Eggermont, Alexander ^d   Fridman, Wolf Hervé ^a,b,c   Fucikova, Jitka ^e,f   Galon, Jérôme ^a,b,c,g   Špíšek, Radek ^e,f   Zitvogel, Laurence ^a,d   Kroemer, Guido ^{a,b,c,d,g,h,i}   Galluzzi, Lorenzo ^a,b,c,d,g  

^a INSERM   (France)

^b CENTRE DE RECHERCHE DES CORDELIERS   (France)

^c SORBONNE UNIVERSITÉ   (France)

^d INSTITUT GUSTAVE ROUSSY   (France)

^e Sotio   (Czech Republic)

^f UNIVERSITY HOSPITAL MOTOL   (Czech Republic)

^g UNIVERSITÉ PARIS DESCARTES   (France)

^h HÔPITAL EUROPÉEN GEORGES POMPIDOU   (France)

ⁱ KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

Ampligen ; bacillus Calmette Gu rin; G100; Hiltonol ; imiquimod; motolimod

Indexed keywords

AS 15; BEVACIZUMAB; CETUXIMAB; CLOBAZAM; CPG 28; DOXORUBICIN; DUK CPG 001; DURVALUMAB; ENTOLIMOD; ERLOTINIB; FLUOROURACIL; FOLINIC ACID; G100; HYALURONIC ACID; IMIQUIMOD; IMO 2055; INTERLEUKIN 15; IPILIMUMAB; IRINOTECAN; LEFITOLIMOD; MITOMYCIN; MOTOLIMOD; POLYINOSINIC POLYCYTIDYLIC ACID; PREDNISOLONE; RINTATOLIMOD; SD 10; TMX 101; TOLL LIKE RECEPTOR AGONIST; UNCLASSIFIED DRUG; UNINDEXED DRUG; VPM1002BC;

ACTINIC KERATOSIS; BASAL CELL CARCINOMA; BLADDER CANCER; BLADDER CARCINOMA; BREAST CARCINOMA; CANCER THERAPY; COLORECTAL CARCINOMA; CONDYLOMA ACUMINATUM; FOLLICULAR LYMPHOMA; GLIOBLASTOMA; GLIOMA; HEMATOLOGIC MALIGNANCY; HUMAN; IMMUNE RESPONSE; IMMUNOSTIMULATION; LUNG CARCINOMA; LYMPHOMA; MALIGNANT LENTIGO; MELANOMA; MENINGITIS; MERKEL CELL TUMOR; MULTICENTER STUDY (TOPIC); MYCOSIS; NON SMALL CELL LUNG CANCER; NONHUMAN; OVARY CARCINOMA; PAGET SKIN DISEASE; PERITONEUM TUMOR; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PROSTATE CARCINOMA; PROTEIN EXPRESSION; REVIEW; SOFT TISSUE SARCOMA; STOMACH CARCINOMA; SURVIVAL; URINARY TRACT TUMOR; UTERINE CERVIX CARCINOMA; UTERINE CERVIX CARCINOMA IN SITU;

EID: 84961671432     PISSN: 21624011     EISSN: 2162402X     Source Type: Journal    
DOI: 10.1080/2162402X.2015.1088631     Document Type: Review

References (117)

1. L.Galluzzi, L.Senovilla, L.Zitvogel, G.Kroemer. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov 2012; 11:215-33; PMID:22301798; http://dx.doi.org/10.1038/nrd3626
2. L.Galluzzi, E.Vacchelli, J.M.Bravo-San Pedro, A.Buque, L.Senovilla, E.E.Baracco, N.Bloy, F.Castoldi, J.P.Abastado, P.Agostinis et al. Classification of current anticancer immunotherapies. Oncotarget 2014; 5:12472-508; PMID:25537519; http://dx.doi.org/10.18632/oncotarget.2998
3. R.D.Schreiber, L.J.Old, M.J.Smyth. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011; 331:1565-70; PMID:21436444; http://dx.doi.org/10.1126/science.1203486
4. L.Zitvogel, L.Galluzzi, M.J.Smyth, G.Kroemer. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 2013; 39:74-88; PMID:23890065; http://dx.doi.org/10.1016/j.immuni.2013.06.014
5. S.Rakoff-Nahoum, R.Medzhitov. Toll-like receptors and cancer. Nat Rev Cancer 2009; 9:57-63; PMID:19052556; http://dx.doi.org/10.1038/nrc2541
6. C.M.Paulos, A.Kaiser, C.Wrzesinski, C.S.Hinrichs, L.Cassard, A.Boni, P.Muranski, L.Sanchez-Perez, D.C.Palmer, Z.Yu et al. Toll-like receptors in tumor immunotherapy. Clin Cancer Res 2007; 13:5280-9; PMID:17875756; http://dx.doi.org/10.1158/1078-0432.CCR-07-1378
7. E.Vacchelli, A.Eggermont, C.Sautes-Fridman, J.Galon, L.Zitvogel, G.Kroemer, L.Galluzzi. Trial Watch: Toll-like receptor agonists for cancer therapy. Oncoimmunology 2013; 2:e25238; PMID:24083080; http://dx.doi.org/10.4161/onci.25238
8. F.Aranda, E.Vacchelli, F.Obrist, A.Eggermont, J.Galon, C.Sautes-Fridman, I.Cremer, J.Henrik Ter Meulen, L.Zitvogel, G.Kroemer et al. Trial Watch: Toll-like receptor agonists in oncological indications. Oncoimmunology 2014; 3:e29179; PMID:25083332; http://dx.doi.org/10.4161/onci.29179
9. T.Kawai, S.Akira. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011; 34:637-50; PMID:21616434; http://dx.doi.org/10.1016/j.immuni.2011.05.006
10. E.J.Hennessy, A.E.Parker, L.A.O'Neill. Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov 2010; 9:293-307; PMID:20380038; http://dx.doi.org/10.1038/nrd3203
11. W.Y.Song, G.L.Wang, L.L.Chen, H.S.Kim, L.Y.Pi, T.Holsten, J.Gardner, B.Wang, W.X.Zhai, L.H.Zhu et al. A receptor kinase-like protein encoded by the rice disease resistance gene, Xa21. Science 1995; 270:1804-6; PMID:8525370; http://dx.doi.org/10.1126/science.270.5243.1804
12. L.Gomez-Gomez, T.Boller. FLS2: an LRR receptor-like kinase involved in the perception of the bacterial elicitor flagellin in Arabidopsis. Mol Cell 2000; 5:1003-11; PMID:10911994; http://dx.doi.org/10.1016/S1097-2765(00)80265-8
13. J.C.Roach, G.Glusman, L.Rowen, A.Kaur, M.K.Purcell, K.D.Smith, L.E.Hood, A.Aderem. The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A 2005; 102:9577-82; PMID:15976025; http://dx.doi.org/10.1073/pnas.0502272102
14. S.Akira, K.Takeda. Toll-like receptor signalling. Nat Rev Immunol 2004; 4:499-511; PMID:15229469; http://dx.doi.org/10.1038/nri1391
15. N.J.Gay, M.F.Symmons, M.Gangloff, C.E.Bryant. Assembly and localization of Toll-like receptor signalling complexes. Nat Rev Immunol 2014; 14:546-58; PMID:25060580; http://dx.doi.org/10.1038/nri3713
16. J.Wang, D.Lin, H.Peng, J.Shao, J.Gu. Cancer-derived immunoglobulin G promotes LPS-induced proinflammatory cytokine production via binding to TLR4 in cervical cancer cells. Oncotarget 2014; 5:9727-43; PMID:25179302; http://dx.doi.org/10.18632/oncotarget.2359
17. C.Brenner, L.Galluzzi, O.Kepp, G.Kroemer. Decoding cell death signals in liver inflammation. J Hepatol 2013; 59:583-94; PMID:23567086; http://dx.doi.org/10.1016/j.jhep.2013.03.033
18. D.V.Krysko, A.D.Garg, A.Kaczmarek, O.Krysko, P.Agostinis, P.Vandenabeele. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 2012; 12:860-75; PMID:23151605; http://dx.doi.org/10.1038/nrc3380
19. L.Galluzzi, O.Kepp, G.Kroemer. Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol 2012; 13:780-8; PMID:23175281; http://dx.doi.org/10.1038/nrm3479
20. L.Galluzzi, J.M.Bravo-San Pedro, I.Vitale, S.A.Aaronson, J.M.Abrams, D.Adam, E.S.Alnemri, L.Altucci, D.Andrews, M.Annicchiarico-Petruzzelli et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ 2015; 22:58-73; PMID:25236395; http://dx.doi.org/10.1038/cdd.2014.137
21. L.Galluzzi, F.Pietrocola, J.M.Bravo-San Pedro, R.K.Amaravadi, E.H.Baehrecke, F.Cecconi, P.Codogno, J.Debnath, D.A.Gewirtz, V.Karantza et al. Autophagy in malignant transformation and cancer progression. EMBO J 2015; 34:856-80; PMID:25712477; http://dx.doi.org/10.15252/embj.201490784
22. G.Kroemer, L.Galluzzi, O.Kepp, L.Zitvogel. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013; 31:51-72; PMID:23157435; http://dx.doi.org/10.1146/annurev-immunol-032712-100008
23. J.Fucikova, I.Moserova, L.Urbanova, L.Bezu, O.Kepp, I.Cremer, C.Salek, P.Strnad, G.Kroemer, L.Galluzzi et al. Prognostic and predictive value of DAMPs and DAMP-associated processes in cancer. Front Immunol 2015; 6:402; PMID:26300886; http://dx.doi.org/10.3389/fimmu.2015.00402
24. E.S.Hoffman, R.E.Smith, R.C.Renaud, Jr. From the analyst's couch: TLR-targeted therapeutics. Nat Rev Drug Discov 2005; 4:879-80; PMID:16299917; http://dx.doi.org/10.1038/nrd1880
25. J.W.Hsu, P.N.Yin, R.Wood, J.Messing, E.Messing, Y.F.Lee. One α, 25-dihydroxylvitamin D3 promotes Bacillus Calmette-Guerin immunotherapy of bladder cancer. Oncotarget 2013; 4:2397-406; PMID:24353168; http://dx.doi.org/10.18632/oncotarget.1494
26. H.Okamoto, S.Shoin, S.Koshimura, R.Shimizu. Studies on the anticancer and streptolysin S-forming abilities of hemolytic streptococci. Jpn J Microbiol 1967; 11:323-6; PMID:4875331; http://dx.doi.org/10.1111/j.1348-0421.1967.tb00350.x
27. J.Paavonen, P.Naud, J.Salmeron, C.M.Wheeler, S.N.Chow, D.Apter, H.Kitchener, X.Castellsague, J.C.Teixeira, S.R.Skinner et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009; 374:301-14; PMID:19586656; http://dx.doi.org/10.1016/S0140-6736(09)61248-4
28. M.Lehtinen, J.Paavonen. Sound efficacy of prophylactic HPV vaccination: Basics and implications. Oncoimmunology 2012; 1:995-6; PMID:23162784; http://dx.doi.org/10.4161/onci.20011
29. S.W.Huang, J.K.Kao, C.Y.Wu, S.T.Wang, H.C.Lee, S.M.Liang, Y.J.Chen, J.J.Shieh. Targeting aerobic glycolysis and HIF-1alpha expression enhance imiquimod-induced apoptosis in cancer cells. Oncotarget 2014; 5:1363-81; PMID:24658058; http://dx.doi.org/10.18632/oncotarget.1734
30. A.Walter, M.Schafer, V.Cecconi, C.Matter, M.Urosevic-Maiwald, B.Belloni, N.Schönewolf, R.Dummer, W.Bloch, S.Werner et al. Aldara activates TLR7-independent immune defence. Nat Commun 2013; 4:1560; PMID:23463003; http://dx.doi.org/10.1038/ncomms2566
31. L.Zitvogel, O.Kepp, L.Galluzzi, G.Kroemer. Inflammasomes in carcinogenesis and anticancer immune responses. Nat Immunol 2012; 13:343-51; PMID:22430787; http://dx.doi.org/10.1038/ni.2224
32. S.Agrawal, E.R.Kandimalla. Synthetic agonists of Toll-like receptors 7, 8 and 9. Biochem Soc Trans 2007; 35:1461-7; PMID:18031246; http://dx.doi.org/10.1042/BST0351461
33. E.R.Kandimalla, L.Bhagat, Y.Li, D.Yu, D.Wang, Y.P.Cong, S.S.Song, J.X.Tang, T.Sullivan, S.Agrawal. Immunomodulatory oligonucleotides containing a cytosine-phosphate-2′-deoxy-7-deazaguanosine motif as potent toll-like receptor 9 agonists. Proc Natl Acad Sci U S A 2005; 102:6925-30; PMID:15860583; http://dx.doi.org/10.1073/pnas.0501729102
34. J.P.Machiels, M.C.Kaminsky, U.Keller, T.H.Brummendorf, T.Goddemeier, U.Forssmann, J.P.Delord. Phase Ib trial of the Toll-like receptor 9 agonist IMO-2055 in combination with 5-fluorouracil, cisplatin, and cetuximab as first-line palliative treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck. Invest New Drugs 2013; 31(5):1207-16; PMID:23397499; http://dx.doi.org/10.1007/s10637-013-9933-z
35. T.de La Motte Rouge, L.Galluzzi, K.A.Olaussen, Y.Zermati, E.Tasdemir, T.Robert, H.Ripoche, V.Lazar, P.Dessen, F.Harper et al. A novel epidermal growth factor receptor inhibitor promotes apoptosis in non-small cell lung cancer cells resistant to erlotinib. Cancer Res 2007; 67:6253-62; PMID:17616683; http://dx.doi.org/10.1158/0008-5472.CAN-07-0538
36. E.Vacchelli, A.Eggermont, J.Galon, C.Sautes-Fridman, L.Zitvogel, G.Kroemer, L.Galluzzi. Trial watch: Monoclonal antibodies in cancer therapy. Oncoimmunology 2013; 2:e22789; PMID:23482847; http://dx.doi.org/10.4161/onci.22789
37. E.Vacchelli, F.Aranda, A.Eggermont, J.Galon, C.Sautes-Fridman, L.Zitvogel, G.Kroemer, L.Galluzzi. Trial Watch: Tumor-targeting monoclonal antibodies in cancer therapy. Oncoimmunology 2014; 3:e27048; PMID:24605265; http://dx.doi.org/10.4161/onci.27048
38. D.A.Smith, P.Conkling, D.A.Richards, J.J.Nemunaitis, T.E.Boyd, A.C.Mita, G.de La Bourdonnaye, D.Wages, A.S.Bexon. Antitumor activity and safety of combination therapy with the Toll-like receptor 9 agonist IMO-2055, erlotinib, and bevacizumab in advanced or metastatic non-small cell lung cancer patients who have progressed following chemotherapy. Cancer Immunol Immunother 2014; 63:787-96; PMID:24770667; http://dx.doi.org/10.1007/s00262-014-1547-6
39. E.Chan, E.L.Kwak, J.Hwang, M.Heiskala, G.de La Bourdonnaye, M.Mita. Open-label phase 1b study of FOLFIRI plus cetuximab plus IMO-2055 in patients with colorectal cancer who have progressed following chemotherapy for advanced or metastatic disease. Cancer Chemother Pharmacol 2015; 75:701-9; PMID:25627002; http://dx.doi.org/10.1007/s00280-015-2682-2
40. J.Falke, R.J.Lammers, H.C.Arentsen, M.Ravic, R.Pozzi, E.B.Cornel, H.Vergunst, T.M.de Reijke, J.A.Witjes. Results of a Phase 1 Dose Escalation Study of Intravesical TMX-101 in Patients with Nonmuscle Invasive Bladder Cancer. J Urol 2013; 189:2077-82; PMID:23206424; http://dx.doi.org/10.1016/j.juro.2012.11.150
41. H.C.Arentsen, C.A.Hulsbergen-Van de Kaa, C.F.Jansen, R.Maj, L.M.Leoni, E.Oosterwijk, J.A.Witjes. Pharmacokinetics and toxicity of intravesical TMX-101: a preclinical study in pigs. BJU Int 2011; 108:1210-4; PMID:21314886; http://dx.doi.org/10.1111/j.1464-410X.2010.10055.x
42. T.J.Arends, R.J.Lammers, J.Falke, A.G.van der Heijden, I.Rustighini, R.Pozzi, M.Ravic, A.Eisenhardt, H.Vergunst, J.A.Witjes. Pharmacokinetic, Pharmacodynamic, and Activity Evaluation of TMX-101 in a Multicenter Phase 1 Study in Patients With Papillary Non-Muscle-Invasive Bladder Cancer. Clin Genitourin Cancer 2015; 13:204-9 e2; PMID:25660383; http://dx.doi.org/10.1016/j.clgc.2014.12.010
43. A.Carpentier, P.Metellus, R.Ursu, S.Zohar, F.Lafitte, M.Barrie, Y.Meng, M.Richard, C.Parizot, F.Laigle-Donadey et al. Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. Neuro Oncol 2010; 12:401-8; PMID:20308317; http://dx.doi.org/10.1093/neuonc/nop047
44. A.Carpentier, F.Laigle-Donadey, S.Zohar, L.Capelle, A.Behin, A.Tibi, N.Martin-Duverneuil, M.Sanson, L.Lacomblez, S.Taillibert et al. Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro Oncol 2006; 8:60-6; PMID:16443949; http://dx.doi.org/10.1215/S1522851705000475
45. Y.Meng, A.F.Carpentier, L.Chen, G.Boisserie, J.M.Simon, J.J.Mazeron, J.Y.Delattre. Successful combination of local CpG-ODN and radiotherapy in malignant glioma. Int J Cancer 2005; 116:992-7; PMID:15856470; http://dx.doi.org/10.1002/ijc.21131
46. R.Ursu, S.Taillibert, C.Banissi, E.Vicaut, O.Bailon, E.Le Rhun, J.S.Guillamo, D.Psimaras, A.Tibi, A.Sacko et al. Immunotherapy with CpG-ODN in neoplastic meningitis: A phase I trial. Cancer Sci 2015; 106:1212-8; PMID:26094710; http://dx.doi.org/10.1111/cas.12724
47. B.Wittig, M.Schmidt, W.Scheithauer, H.J.Schmoll. MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: from bench to bedside. Crit Rev Oncol Hematol 2015; 94:31-44; PMID:25577571; http://dx.doi.org/10.1016/j.critrevonc.2014.12.002
48. M.Tschaika, H.Schmoll, J.Riera-Knorrenschild, D.Nitsche, J.Trojan, H.Kröning, F.Mayer, E.Weith, M.Schroff, M.Krikov et al. IMPACT study: A phase II-III clinical study with the immunomodulator MGN1703 in patients with advanced colorectal carcincoma. J Clin Oncol 2012; 30:abstr 633
49. M.Tschaika, H.Schmoll, W.Scheithauer, F.Mayer, M.Schroff, M.Schmidt, B.Wittig. Preliminary results of an ongoing phase II/III clinical study of the TLR9 agonist MGN1703 in patients with advanced colorectal carcinoma with disease control after first-line induction therapy (IMPACT Study). J Clin Oncol 2011; 29:abstr 618
50. H.J.Schmoll, B.Wittig, D.Arnold, J.Riera-Knorrenschild, D.Nitsche, H.Kroening, F.Mayer, J.Andel, R.Ziebermayr, W.Scheithauer. Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-blind, placebo-controlled trial. J Cancer Res Clin Oncol 2014; 140:1615-24; PMID:24816725; http://dx.doi.org/10.1007/s00432-014-1682-7
51. M.R.Weihrauch, H.Richly, M.S.von Bergwelt-Baildon, H.J.Becker, M.Schmidt, U.T.Hacker, A.Shimabukuro-Vornhagen, U.Holtick, B.Nokay, M.Schroff et al. Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours. Eur J Cancer 2015; 51:146-56; PMID:25480557; http://dx.doi.org/10.1016/j.ejca.2014.11.002
52. C.B.Fox, M.Moutaftsi, J.Vergara, A.L.Desbien, G.I.Nana, T.S.Vedvick, R.N.Coler, S.G.Reed. TLR4 ligand formulation causes distinct effects on antigen-specific cell-mediated and humoral immune responses. Vaccine 2013; 31:5848-55; PMID:24120675; http://dx.doi.org/10.1016/j.vaccine.2013.09.069
53. L.P.Schneider, A.J.Schoonderwoerd, M.Moutaftsi, R.F.Howard, S.G.Reed, E.C.de Jong, M.B.Teunissen. Intradermally administered TLR4 agonist GLA-SE enhances the capacity of human skin DCs to activate T cells and promotes emigration of Langerhans cells. Vaccine 2012; 30:4216-24; PMID:22542815; http://dx.doi.org/10.1016/j.vaccine.2012.04.051
54. M.T.Orr, M.S.Duthie, H.P.Windish, E.A.Lucas, J.A.Guderian, T.E.Hudson, N.Shaverdian, J.O'Donnell, A.L.Desbien, S.G.Reed et al. MyD88 and TRIF synergistic interaction is required for TH1-cell polarization with a synthetic TLR4 agonist adjuvant. Eur J Immunol 2013; 43:2398-408; PMID:23716300; http://dx.doi.org/10.1002/eji.201243124
55. S.Bertholet, G.C.Ireton, D.J.Ordway, H.P.Windish, S.O.Pine, M.Kahn, T.Phan, I.M.Orme, T.S.Vedvick, S.L.Baldwin et al. A defined tuberculosis vaccine candidate boosts BCG and protects against multidrug-resistant Mycobacterium tuberculosis. Sci Transl Med 2010; 2:53ra74; PMID:20944089; http://dx.doi.org/10.1126/scitranslmed.3001094
56. S.Bhatia, D.Ibrani, N.Vandeven, N.Miller, M.Shinohara, D.Byrd, U.Parvathaneni, E.Shantha, O.K.Afanasiev, M.Donahue et al. Pilot study of intratumoral G100, toll-like receptor-4 (TLR4) agonist, therapy in patients with Merkel cell carcinoma (MCC). ASCO Meeting Abstracts 2015; 33:3083
57. F.Hayashi, K.D.Smith, A.Ozinsky, T.R.Hawn, E.C.Yi, D.R.Goodlett, J.K.Eng, S.Akira, D.M.Underhill, A.Aderem. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001; 410:1099-103; PMID:11323673; http://dx.doi.org/10.1038/35074106
58. B.M.Kojouharov, C.M.Brackett, J.M.Veith, C.P.Johnson, I.I.Gitlin,, I.A.Toshkov, A.S.Gleiberman, A.V.Gudkov, L.G.Burdelya. Toll-like receptor-5 agonist Entolimod broadens the therapeutic window of 5-fluorouracil by reducing its toxicity to normal tissues in mice. Oncotarget 2014; 5:802-14; PMID:24583651; http://dx.doi.org/10.18632/oncotarget.1773
59. L.G.Burdelya, V.I.Krivokrysenko, T.C.Tallant, E.Strom, A.S.Gleiberman, D.Gupta, O.V.Kurnasov, F.L.Fort, A.L.Osterman, J.A.Didonato et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 2008; 320:226-30; PMID:18403709; http://dx.doi.org/10.1126/science.1154986
60. S.I.Yoon, O.Kurnasov, V.Natarajan, M.Hong, A.V.Gudkov, A.L.Osterman, I.A.Wilson. Structural basis of TLR5-flagellin recognition and signaling. Science 2012; 335:859-64; PMID:22344444; http://dx.doi.org/10.1126/science.1215584
61. X.Ding, G.Bian, N.D.Leigh, J.Qiu, P.L.McCarthy, H.Liu, S.Aygun-Sunar, L.G.Burdelya, A.V.Gudkov, X.Cao. A TLR5 agonist enhances CD8(+) T cell-mediated graft-versus-tumor effect without exacerbating graft-versus-host disease. J Immunol 2012; 189:4719-27; PMID:23045613; http://dx.doi.org/10.4049/jimmunol.1201206
62. H.Bakhribah, G.K.Dy, W.W.Ma, Y.Zhao, M.Opyrchal, A.Purmal, S.Gollnick, W.E.Brady, G.J.Fetterly, N.Ngamphaiboon, T.Reungwetwattana et al. A phase I study of the toll-like receptor 5 (TLR5) agonist, entolimod in patients (pts) with advanced cancers. ASCO Meeting Abstracts 2015; 33:3063
63. U.Ohto, T.Shibata, H.Tanji, H.Ishida, E.Krayukhina, S.Uchiyama, K.Miyake, T.Shimizu. Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9. Nature 2015; 520:702-5; PMID:25686612; http://dx.doi.org/10.1038/nature14138
64. J.M.Pickard, C.F.Maurice, M.A.Kinnebrew, M.C.Abt, D.Schenten, T.V.Golovkina, S.R.Bogatyrev, R.F.Ismagilov, E.G.Pamer, P.J.Turnbaugh et al. Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature 2014; 514:638-41; PMID:25274297; http://dx.doi.org/10.1038/nature13823
65. T.Bald, T.Quast, J.Landsberg, M.Rogava, N.Glodde, D.Lopez-Ramos, J.Kohlmeyer, S.Riesenberg, D.van den Boorn-Konijnenberg, C.Hömig-Hölzel et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 2014; 507:109-13; PMID:24572365; http://dx.doi.org/10.1038/nature13111
66. K.Hoebe, X.Du, P.Georgel, E.Janssen, K.Tabeta, S.O.Kim, J.Goode, P.Lin, N.Mann, S.Mudd et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 2003; 424:743-8; PMID:12872135; http://dx.doi.org/10.1038/nature01889
67. M.Yamamoto, S.Sato, H.Hemmi, K.Hoshino, T.Kaisho, H.Sanjo, O.Takeuchi, M.Sugiyama, M.Okabe, K.Takeda et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003; 301:640-3; PMID:12855817; http://dx.doi.org/10.1126/science.1087262
68. K.Honda, H.Yanai, H.Negishi, M.Asagiri, M.Sato, T.Mizutani, N.Shimada, Y.Ohba, A.Takaoka, N.Yoshida et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 2005; 434:772-7; PMID:15800576; http://dx.doi.org/10.1038/nature03464
69. C.C.Lee, A.M.Avalos, H.L.Ploegh. Accessory molecules for Toll-like receptors and their function. Nat Rev Immunol 2012; 12:168-79; PMID:22301850; http://dx.doi.org/10.1038/nri3151
70. S.Liu, X.Cai, J.Wu, Q.Cong, X.Chen, T.Li, F.Du, J.Ren, Y.T.Wu, N.V.Grishin et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 2015; 347:aaa2630; PMID:25636800; http://dx.doi.org/10.1126/science.aaa2630
71. F.A.Scheeren, A.H.Kuo, L.J.van Weele, S.Cai, I.Glykofridis, S.S.Sikandar, M.Zabala, D.Qian, J.S.Lam, D.Johnston et al. A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis. Nat Cell Biol 2014; 16:1238-48; PMID:25362351; http://dx.doi.org/10.1038/ncb3058
72. M.Dominguez-Villar, A.S.Gautron, M.de Marcken, M.J.Keller, D.A.Hafler. TLR7 induces anergy in human CD4(+) T cells. Nat Immunol 2015; 16:118-28; PMID:25401424; http://dx.doi.org/10.1038/ni.3036
73. Y.Skabytska, F.Wolbing, C.Gunther, M.Koberle, S.Kaesler, K.M.Chen, E.Guenova, D.Demircioglu, W.E.Kempf, T.Volz et al. Cutaneous innate immune sensing of Toll-like receptor 2–6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells. Immunity 2014; 41:762-75; PMID:25456159; http://dx.doi.org/10.1016/j.immuni.2014.10.009
74. T.Kobayashi, S.Shimabukuro-Demoto, R.Yoshida-Sugitani, K.Furuyama-Tanaka, H.Karyu, Y.Sugiura, Y.Shimizu, T.Hosaka, M.Goto, N.Kato et al. The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity 2014; 41:375-88; PMID:25238095; http://dx.doi.org/10.1016/j.immuni.2014.08.011
75. P.Nair-Gupta, A.Baccarini, N.Tung, F.Seyffer, O.Florey, Y.Huang, M.Banerjee, M.Overholtzer, P.A.Roche, R.Tampé et al. TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation. Cell 2014; 158:506-21; PMID:25083866; http://dx.doi.org/10.1016/j.cell.2014.04.054
76. M.R.Rutkowski, T.L.Stephen, N.Svoronos, M.J.Allegrezza, A.J.Tesone, A.Perales-Puchalt, E.Brencicova, X.Escovar-Fadul, J.M.Nguyen, M.G.Cadungog et al. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 2015; 27:27-40; PMID:25533336; http://dx.doi.org/10.1016/j.ccell.2014.11.009
77. H.Yang, H.Wang, Z.Ju, A.A.Ragab, P.Lundback, W.Long, S.I.Valdes-Ferrer, M.He, J.P.Pribis, J.Li et al. MD-2 is required for disulfide HMGB1-dependent TLR4 signaling. J Exp Med 2015; 212:5-14; PMID:25559892; http://dx.doi.org/10.1084/jem.20141318
78. K.Nothelfer, E.T.Arena, L.Pinaud, M.Neunlist, B.Mozeleski, I.Belotserkovsky, C.Parsot, P.Dinadayala, A.Burger-Kentischer, R.Raqib et al. B lymphocytes undergo TLR2-dependent apoptosis upon Shigella infection. J Exp Med 2014; 211:1215-29; PMID:24863068; http://dx.doi.org/10.1084/jem.20130914
79. M.Mancek-Keber, M.Frank-Bertoncelj, I.Hafner-Bratkovic, A.Smole, M.Zorko, N.Pirher, S.Hayer, V.Kralj-Iglič, B.Rozman, N.Ilc et al. Toll-like receptor 4 senses oxidative stress mediated by the oxidation of phospholipids in extracellular vesicles. Sci Signal 2015; 8:ra60; PMID:26082436; http://dx.doi.org/10.1126/scisignal.2005860
80. S.G.Daniele, D.Beraud, C.Davenport, K.Cheng, H.Yin, K.A.Maguire-Zeiss. Activation of MyD88-dependent TLR1/2 signaling by misfolded alpha-synuclein, a protein linked to neurodegenerative disorders. Sci Signal 2015; 8:ra45; PMID:25969543; http://dx.doi.org/10.1126/scisignal.2005965
81. J.P.Kolb, C.R.Casella, S.SenGupta, P.M.Chilton, T.C.Mitchell. Type I interferon signaling contributes to the bias that Toll-like receptor 4 exhibits for signaling mediated by the adaptor protein TRIF. Sci Signal 2014; 7:ra108; PMID:25389373; http://dx.doi.org/10.1126/scisignal.2005442
82. S.Chatterjee, L.Crozet, D.Damotte, K.Iribarren, C.Schramm, M.Alifano, A.Lupo, J.Cherfils-Vicini, J.Goc, S.Katsahian et al. TLR7 promotes tumor progression, chemotherapy resistance, and poor clinical outcomes in non-small cell lung cancer. Cancer Res 2014; 74:5008-18; PMID:25074614; http://dx.doi.org/10.1158/0008-5472.CAN-13-2698
83. H.B.Levy, G.Baer, S.Baron, C.E.Buckler, C.J.Gibbs, M.J.Iadarola, W.T.London, J.Rice. A modified polyriboinosinic-polyribocytidylic acid complex that induces interferon in primates. J Infect Dis 1975; 132:434-9; PMID:810520; http://dx.doi.org/10.1093/infdis/132.4.434
84. C.Ming Lim, R.Stephenson, A.M.Salazar, R.L.Ferris. TLR3 agonists improve the immunostimulatory potential of cetuximab against EGFR head and neck cancer cells. Oncoimmunology 2013; 2:e24677; PMID:23894722; http://dx.doi.org/10.4161/onci.23187
85. R.Ammi, J.De Waele, Y.Willemen, I.Van Brussel, D.M.Schrijvers, E.Lion, E.L.Smits. Poly(I:C) as cancer vaccine adjuvant: knocking on the door of medical breakthroughs. Pharmacol Ther 2015; 146:120-31; PMID:25281915; http://dx.doi.org/10.1016/j.pharmthera.2014.09.010
86. F.Aranda, E.Vacchelli, A.Eggermont, J.Galon, C.Sautes-Fridman, E.Tartour, L.Zitvogel, G.Kroemer, L.Galluzzi. Trial Watch: Peptide vaccines in cancer therapy. Oncoimmunology 2013; 2:e26621; PMID:24498550; http://dx.doi.org/10.4161/onci.26621
87. N.Bloy, J.Pol, F.Aranda, A.Eggermont, I.Cremer, W.H.Fridman, J.Fučíková, J.Galon, E.Tartour, R.Spisek et al. Trial Watch: Dendritic cell-based anticancer therapy. Oncoimmunology 2014; 3:e963424; PMID:25941593; http://dx.doi.org/10.4161/21624011.2014.963424
88. E.Vacchelli, I.Vitale, A.Eggermont, W.H.Fridman, J.Fucikova, I.Cremer, J.Galon, E.Tartour, L.Zitvogel, G.Kroemer et al. Trial watch: Dendritic cell-based interventions for cancer therapy. Oncoimmunology 2013; 2:e25771; PMID:24286020; http://dx.doi.org/10.4161/onci.25771
89. D.Mavilio, E.Lugli. Inhibiting the inhibitors: Checkpoints blockade in solid tumors. Oncoimmunology 2013; 2:e26535; PMID:24244910; http://dx.doi.org/10.4161/onci.26535
90. W.Peng, G.Lizee, P.Hwu. Blockade of the PD-1 pathway enhances the efficacy of adoptive cell therapy against cancer. Oncoimmunology 2013; 2:e22691; PMID:23524510; http://dx.doi.org/10.4161/onci.22691
91. S.N.Linch, W.L.Redmond. Combined OX40 ligation plus CTLA-4 blockade: More than the sum of its parts. Oncoimmunology 2014; 3:e28245; PMID:25050194; http://dx.doi.org/10.4161/onci.28245
92. L.C.Sandin, F.Eriksson, P.Ellmark, A.S.Loskog, T.H.Totterman, S.M.Mangsbo. Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo. Oncoimmunology 2014; 3:e27614; PMID:24701377; http://dx.doi.org/10.4161/onci.27614
93. L.J.Thomas, L.Z.He, H.Marsh, T.Keler. Targeting human CD27 with an agonist antibody stimulates T-cell activation and antitumor immunity. Oncoimmunology 2014; 3:e27255; PMID:24605266; http://dx.doi.org/10.4161/onci.27255
94. L.E.Kandalaft, D.J.Powell, Jr., C.L.Chiang, J.Tanyi, S.Kim, M.Bosch, K.Montone, R.Mick, B.L.Levine, D.A.Torigian et al. Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer. Oncoimmunology 2013; 2:e22664; PMID:23482679; http://dx.doi.org/10.4161/onci.22664
95. M.S.Khodadoust, M.P.Chu, D.Czerwinski, K.McDonald, S.Long, H.E.Kohrt, R.T.Hoppe, R.H.Advani, R.Lowsky, R.Levy. Phase I/II study of intratumoral injection of SD-101, an immunostimulatory CpG, and intratumoral injection of ipillumumab, an anti-CTLA-4 monoclonal antibody, in combination with local radiation in low-grade B-cell lymphomas. ASCO Meeting Abstracts 2015; 33:TPS8604
96. Y.Zhang, A.Lin, C.Zhang, Z.Tian, J.Zhang. Phosphorothioate-modified CpG oligodeoxynucleotide (CpG ODN) induces apoptosis of human hepatocellular carcinoma cells independent of TLR9. Cancer Immunol Immunother 2014; 63:357-67; PMID:24452201; http://dx.doi.org/10.1007/s00262-014-1518-y
97. H.Navabi, B.Jasani, A.Reece, A.Clayton, Z.Tabi, C.Donninger, M.Mason, M.Adams. A clinical grade poly I:C-analogue (Ampligen) promotes optimal DC maturation and Th1-type T cell responses of healthy donors and cancer patients in vitro. Vaccine 2009; 27:107-15; PMID:18977262; http://dx.doi.org/10.1016/j.vaccine.2008.10.024
98. J.Fucikova, D.Rozkova, H.Ulcova, V.Budinsky, K.Sochorova, K.Pokorna, J.Bartůňková, R.Špíšek. Poly I: C-activated dendritic cells that were generated in CellGro for use in cancer immunotherapy trials. J Transl Med 2011; 9:223; PMID:22208910; http://dx.doi.org/10.1186/1479-5876-9-223
99. P.A.Cohen, D.W.Northfelt, G.J.Weiss, D.D.Von Hoff, K.Manjarrez, G.Dietsch, K.L.Manjarrez, T.D.Randall, R.M.Hershberg. Phase I clinical trial of VTX-2337, a selective toll-like receptor 8 (TLR8) agonist, in patients with advanced solid tumors. J Clin Oncol 2011; 29:abstr 2537; http://dx.doi.org/10.1200/JCO.2010.34.1693.
100. H.Lu, G.N.Dietsch, M.A.Matthews, Y.Yang, S.Ghanekar, M.Inokuma, M.Suni, V.C.Maino, K.E.Henderson, J.J.Howbert et al. VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin Cancer Res 2012; 18:499-509; PMID:22128302; http://dx.doi.org/10.1158/1078-0432.CCR-11-1625
101. E.Vacchelli, F.Aranda, A.Eggermont, J.Galon, C.Sautes-Fridman, I.Cremer, L.Zitvogel, G.Kroemer, L.Galluzzi. Trial Watch: Chemotherapy with immunogenic cell death inducers. Oncoimmunology 2014; 3:e27878; PMID:24800173; http://dx.doi.org/10.4161/onci.27878
102. O.Kepp, L.Senovilla, I.Vitale, E.Vacchelli, S.Adjemian, P.Agostinis, L.Apetoh, F.Aranda, V.Barnaba, N.Bloy et al. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 2014; 3:e955691; PMID:25941621; http://dx.doi.org/10.4161/21624011.2014.955691
103. O.Kepp, L.Senovilla, G.Kroemer. Immunogenic cell death inducers as anticancer agents. Oncotarget 2014; 5:5190-1; PMID:25114034; http://dx.doi.org/10.18632/oncotarget.2266
104. S.Munir, G.H.Andersen, I.M.Svane, M.H.Andersen. The immune checkpoint regulator PD-L1 is a specific target for naturally occurring CD4 T cells. Oncoimmunology 2013; 2:e23991; PMID:23734334; http://dx.doi.org/10.4161/onci.23991
105. J.Sunshine, J.M.Taube. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol 2015; 23:32-8; PMID:26047524; http://dx.doi.org/10.1016/j.coph.2015.05.011
106. R.Ibrahim, R.Stewart, A.Shalabi. PD-L1 blockade for cancer treatment: MEDI4736. Semin Oncol 2015; 42:474-83; PMID:25965366; http://dx.doi.org/10.1053/j.seminoncol.2015.02.007
107. L.Topazio, R.Miano, V.Maurelli, G.Gaziev, M.Gacci, V.Iacovelli, E.Finazzi-Agr∫. Could hyaluronic acid (HA) reduce Bacillus Calmette-Guerin (BCG) local side effects? Results of a pilot study. BMC Urol 2014; 14:64; PMID:25123116; http://dx.doi.org/10.1186/1471-2490-14-64
108. L.Galluzzi, E.Vacchelli, A.Eggermont, W.H.Fridman, J.Galon, C.Sautes-Fridman, E.Tartour, L.Zitvogel, G.Kroemer. Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology 2012; 1:699-716; PMID:22934262; http://dx.doi.org/10.4161/onci.20696
109. E.Vacchelli, L.Galluzzi, A.Eggermont, W.H.Fridman, J.Galon, C.Sautes-Fridman, E.Tartour, L.Zitvogel, G.Kroemer. Trial watch: FDA-approved Toll-like receptor agonists for cancer therapy. Oncoimmunology 2012; 1:894-907; PMID:23162757; http://dx.doi.org/10.4161/onci.20931
110. A.Ruzsa, M.Sen, M.Evans, L.W.Lee, K.Hideghety, S.Rottey, P.Klimak, P.Holeckova, J.Fayette, T.Csoszi et al. Phase 2, open-label, 1:1 randomized controlled trial exploring the efficacy of EMD 1201081 in combination with cetuximab in second-line cetuximab-naive patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Invest New Drugs 2014; 32:1278-84; PMID:24894651; http://dx.doi.org/10.1007/s10637-014-0117-2
111. M.V.Dhodapkar, M.Sznol, B.Zhao, D.Wang, R.D.Carvajal, M.L.Keohan, E.Chuang, R.E.Sanborn, J.Lutzky, J.Powderly et al. Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205. Sci Transl Med 2014; 6:232ra51; PMID:24739759; http://dx.doi.org/10.1126/scitranslmed.3008068
112. A.P.Rapoport, N.A.Aqui, E.A.Stadtmauer, D.T.Vogl, Y.Y.Xu, M.Kalos, L.Cai, H.B.Fang, B.M.Weiss, A.Badros et al. Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/Poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells. Clin Cancer Res 2014; 20:1355-65; PMID:24520093; http://dx.doi.org/10.1158/1078-0432.CCR-13-2817
113. C.Robert, J.Schachter, G.V.Long, A.Arance, J.J.Grob, L.Mortier, A.Daud, M.S.Carlino, C.McNeil, M.Lotem et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015; 372:2521-32; PMID:25891173; http://dx.doi.org/10.1056/NEJMoa1503093
114. C.Robert, G.V.Long, B.Brady, C.Dutriaux, M.Maio, L.Mortier, J.C.Hassel, P.Rutkowski, C.McNeil, E.Kalinka-Warzocha et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372:320-30; PMID:25399552; http://dx.doi.org/10.1056/NEJMoa1412082
115. J.D.Wolchok, H.Kluger, M.K.Callahan, M.A.Postow, N.A.Rizvi, A.M.Lesokhin, N.H.Segal, C.E.Ariyan, R.A.Gordon, K.Reed et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369:122-33; PMID:23724867; http://dx.doi.org/10.1056/NEJMoa1302369
116. L.Galluzzi, G.Kroemer, A.Eggermont. Novel immune checkpoint blocker approved for the treatment of advanced melanoma. Oncoimmunology 2014; 3:e967147; PMID:25941597; http://dx.doi.org/10.4161/21624011.2014.967147
117. R.M.Poole. Pembrolizumab: first global approval. Drugs 2014; 74:1973-81; PMID:25331768; http://dx.doi.org/10.1007/s40265-014-0314-5