Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy.

Gustave Roussy Cancer Campus Villejuif France

Gustave Roussy Cancer Campus Villejuif France; INSERM U1015 CICBT507 Villejuif France

INSERM U1138 Paris France; Equipe 13 Center de Recherche des Cordeliers Paris France; Université Pierre et Marie Curie Paris 6 Paris France

INSERM U1138 Paris France; Gustave Roussy Cancer Campus Villejuif France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer Center de Recherche des Cordeliers Paris France

INSERM U1138 Paris France; Université Pierre et Marie Curie Paris 6 Paris France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer Center de Recherche des Cordeliers Paris France; Université Paris Descartes Paris 5 Sorbonne Paris Cité Paris France; Pôle de Biologie Hôpital Européen Georges Pompidou AP HP Paris France; Metabolomics and Cell Biology Platforms Gustave Roussy Cancer Campus Villejuif France; Department of Women's and Children's Health Karolinska University Hospital Stockholm Sweden

INSERM U1138 Paris France; Université Pierre et Marie Curie Paris 6 Paris France; Gustave Roussy Cancer Campus Villejuif France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer Center de Recherche des Cordeliers Paris France; Université Paris Descartes Paris 5 Sorbonne Paris Cité Paris France

INSERM U1138 Paris France; Université Pierre et Marie Curie Paris 6 Paris France; Laboratory of Integrative Cancer Immunology Center de Recherche des Cordeliers Paris France; Université Paris Descartes Paris 5 Sorbonne Paris Cité Paris France

Sotio Prague Czech Republic; Dept of Immunology 2nd Faculty of Medicine and University Hospital Motol Charles University Prague Czech Republic

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Yang H, Wang H, Ju Z, Ragab AA, Lundback P, Long W, Valdes-Ferrer SI, He M, Pribis JP, Li J 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 PubMed DOI PMC

Nothelfer K, Arena ET, Pinaud L, Neunlist M, Mozeleski B, Belotserkovsky I, Parsot C, Dinadayala P, Burger-Kentischer A, Raqib R 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 PubMed DOI PMC

Mancek-Keber M, Frank-Bertoncelj M, Hafner-Bratkovic I, Smole A, Zorko M, Pirher N, Hayer S, Kralj-Iglič V, Rozman B, Ilc N 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 PubMed DOI

Daniele SG, Beraud D, Davenport C, Cheng K, Yin H, Maguire-Zeiss KA. 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 PubMed DOI PMC

Kolb JP, Casella CR, SenGupta S, Chilton PM, Mitchell TC. 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 PubMed DOI PMC

Chatterjee S, Crozet L, Damotte D, Iribarren K, Schramm C, Alifano M, Lupo A, Cherfils-Vicini J, Goc J, Katsahian S 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 PubMed DOI

Levy HB, Baer G, Baron S, Buckler CE, Gibbs CJ, Iadarola MJ, London WT, Rice J. 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 PubMed DOI

Ming Lim C, Stephenson R, Salazar AM, Ferris RL. 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 PubMed DOI PMC

Ammi R, De Waele J, Willemen Y, Van Brussel I, Schrijvers DM, Lion E, Smits EL. 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 PubMed DOI

Aranda F, Vacchelli E, Eggermont A, Galon J, Sautes-Fridman C, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Peptide vaccines in cancer therapy. Oncoimmunology 2013; 2:e26621; PMID:24498550; http://dx.doi.org/10.4161/onci.26621 PubMed DOI PMC

Bloy N, Pol J, Aranda F, Eggermont A, Cremer I, Fridman WH, Fučíková J, Galon J, Tartour E, Spisek R et al.. Trial Watch: Dendritic cell-based anticancer therapy. Oncoimmunology 2014; 3:e963424; PMID:25941593; http://dx.doi.org/2428602010.4161/21624011.2014.963424 PubMed DOI PMC

Vacchelli E, Vitale I, Eggermont A, Fridman WH, Fucikova J, Cremer I, Galon J, Tartour E, Zitvogel L, Kroemer G 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 PubMed DOI PMC

Mavilio D, Lugli E. Inhibiting the inhibitors: Checkpoints blockade in solid tumors. Oncoimmunology 2013; 2:e26535; PMID:24244910; http://dx.doi.org/10.4161/onci.26535 PubMed DOI PMC

Peng W, Lizee G, Hwu P. 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 PubMed DOI PMC

Linch SN, Redmond WL. 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 PubMed DOI PMC

Sandin LC, Eriksson F, Ellmark P, Loskog AS, Totterman TH, Mangsbo SM. 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 PubMed DOI PMC

Thomas LJ, He LZ, Marsh H, Keler T. 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 PubMed DOI PMC

Kandalaft LE, Powell DJ Jr., Chiang CL, Tanyi J, Kim S, Bosch M, Montone K, Mick R, Levine BL, Torigian DA 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 PubMed DOI PMC

Khodadoust MS, Chu MP, Czerwinski D, McDonald K, Long S, Kohrt HE, Hoppe RT, Advani RH, Lowsky R, Levy R. 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

Zhang Y, Lin A, Zhang C, Tian Z, Zhang J. 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 PubMed DOI PMC

Navabi H, Jasani B, Reece A, Clayton A, Tabi Z, Donninger C, Mason M, Adams M. 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 PubMed DOI

Fucikova J, Rozkova D, Ulcova H, Budinsky V, Sochorova K, Pokorna K, Bartůňková J, Špíšek R. 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 PubMed DOI PMC

Cohen PA, Northfelt DW, Weiss GJ, Von Hoff DD, Manjarrez K, Dietsch G, Manjarrez KL, Randall TD, Hershberg RM. 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. DOI

Lu H, Dietsch GN, Matthews MA, Yang Y, Ghanekar S, Inokuma M, Suni M, Maino VC, Henderson KE, Howbert JJ 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 PubMed DOI

Vacchelli E, Aranda F, Eggermont A, Galon J, Sautes-Fridman C, Cremer I, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Chemotherapy with immunogenic cell death inducers. Oncoimmunology 2014; 3:e27878; PMID:24800173; http://dx.doi.org/10.4161/onci.27878 PubMed DOI PMC

Kepp O, Senovilla L, Vitale I, Vacchelli E, Adjemian S, Agostinis P, Apetoh L, Aranda F, Barnaba V, Bloy N 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 PubMed DOI PMC

Kepp O, Senovilla L, Kroemer G. Immunogenic cell death inducers as anticancer agents. Oncotarget 2014; 5:5190-1; PMID:25114034; http://dx.doi.org/10.18632/oncotarget.2266 PubMed DOI PMC

Munir S, Andersen GH, Svane IM, Andersen MH. 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 PubMed DOI PMC

Sunshine J, Taube JM. 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 PubMed DOI PMC

Ibrahim R, Stewart R, Shalabi A. 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 PubMed DOI

Topazio L, Miano R, Maurelli V, Gaziev G, Gacci M, Iacovelli V, Finazzi-Agr∫ E. 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 PubMed DOI PMC

Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautes-Fridman C, Tartour E, Zitvogel L, Kroemer G. 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 PubMed DOI PMC

Vacchelli E, Galluzzi L, Eggermont A, Fridman WH, Galon J, Sautes-Fridman C, Tartour E, Zitvogel L, Kroemer G. 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 PubMed DOI PMC

Ruzsa A, Sen M, Evans M, Lee LW, Hideghety K, Rottey S, Klimak P, Holeckova P, Fayette J, Csoszi T 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 PubMed DOI

Dhodapkar MV, Sznol M, Zhao B, Wang D, Carvajal RD, Keohan ML, Chuang E, Sanborn RE, Lutzky J, Powderly J 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 PubMed DOI PMC

Rapoport AP, Aqui NA, Stadtmauer EA, Vogl DT, Xu YY, Kalos M, Cai L, Fang HB, Weiss BM, Badros A 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 PubMed DOI PMC

Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M 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 PubMed DOI

Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E 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 PubMed DOI

Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K 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 PubMed DOI PMC

Galluzzi L, Kroemer G, Eggermont A. 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 PubMed DOI PMC

Poole RM. Pembrolizumab: first global approval. Drugs 2014; 74:1973-81; PMID:25331768; http://dx.doi.org/10.1007/s40265-014-0314-5 PubMed DOI

Multi-Institutional Evaluation of Pathologists' Assessment Compared to Immunoscore

Trial Watch: Toll-like receptor agonists in cancer immunotherapy