Search tips
Search criteria 


Logo of oncoimmunLink to Publisher's site
Oncoimmunology. 2012 September 1; 1(6): 894–907.
PMCID: PMC3489745

Trial watch

FDA-approved Toll-like receptor agonists for cancer therapy
Erika Vacchelli, 1 , 2 , 3 , Lorenzo Galluzzi, 2 , 4 , Alexander Eggermont, 2 Wolf Hervé Fridman, 5 , 6 , 6 , 7 Jerome Galon, 5 , 8 , 6 , 6 , 9 Catherine Sautès-Fridman, 5 , 6 , 9 Eric Tartour, 8 , 6 , 10 Laurence Zitvogel, 2 , 11 and Guido Kroemer 1 , 5 , 6 , 6 , 12 ,*


Toll-like receptors (TLRs) have first been characterized for their capacity to detect conserved microbial components like lipopolysaccharide (LPS) and double-stranded RNA, resulting in the elicitation of potent (innate) immune responses against invading pathogens. More recently, TLRs have also been shown to promote the activation of the cognate immune system against cancer cells. Today, only three TLR agonists are approved by FDA for use in humans: the bacillus Calmette-Guérin (BCG), monophosphoryl lipid A (MPL) and imiquimod. BCG (an attenuated strain of Mycobacterium bovis) is mainly used as a vaccine against tuberculosis, but also for the immunotherapy of in situ bladder carcinoma. MPL (derived from the LPS of Salmonella minnesota) is included in the formulation of Cervarix®, a vaccine against human papillomavirus-16 and -18. Imiquimod (a synthetic imidazoquinoline) is routinely employed for actinic keratosis, superficial basal cell carcinoma, and external genital warts (condylomata acuminata). In this Trial Watch, we will summarize the results of recently completed clinical trials and discuss the progress of ongoing studies that have evaluated/are evaluating FDA-approved TLR agonists as off-label medications for cancer therapy.

Keywords: Coley’s toxin, HPV, MyD88, Mycobacterium bovis, dsRNA, resiquimod


In 1985, the laboratory of Christiane Nüsslein-Volhard characterized for the first time Toll, a gene that regulates the dorsal-ventral embryonic polarity of the fruit fly Drosophila melanogaster.1,2 For her discoveries concerning the genetic control of early embryonic development, Christiane Nüsslein-Volhard shared the 1995 Nobel prize in Medicine or Physiology with her collaborator Eric F. Wieschaus and with Edward B. Lewis, an American geneticist who first characterized the Drosophila bithorax gene cluster.3,4 Besides elucidating (at least in part) the mechanisms that regulate early embryonic development, the work of Christiane Nüsslein-Volhard de facto laid the basis for the discovery and characterization of Toll-like receptors (TLRs), transmembrane proteins that are crucial for the activation of the innate immune system in response to conserved microbial products known as microbe-associated molecular patterns (MAMPs), including bacterial lipopolysaccharide (LPS, also known as endotoxin) and viral double-stranded RNA (dsRNA).5 The discovery that TLRs exert a crucial function in innate immune responses (in a wide range of organisms) granted to the French biologist Jules Hoffmann and the American immunologist Bruce Beutler the 2011 Nobel Prize in Medicine or Physiology.6,7

Today, 13 distinct TLRs are known to be expressed in mammals (of which 10 in humans), and proteins of the TLR family have been identified in evolutionarily distant organisms including fish and plants.8-10 Importantly, TLRs (in particular TLR2 and TLR4) have recently been shown to bind not only MAMPs but also a large panel of damage-associated molecular patterns (DAMPs), i.e., endogenous signals that are dispatched by stressed or dying cells to promote sterile inflammation.11 Thus, TLRs appear to be critical for the activation of innate immunity against pathogens as well as for the orchestration of potentially therapeutic anti-cancer immune responses.12

In line with this notion, long-used (and relatively effective) anticancer preparations including Coley's toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and the bacillus Calmette-Guérin (BCG, an attenuated strain of Mycobacterium bovis initially developed as an anti-tuberculosis vaccine), have recently been shown to potently activate TLR2 and TLR4.13,14 Similarly, imiquimod (a small imidazoquinoline that was originally developed as a topic antiviral agent) has been approved by FDA in 1997 for the treatment of genital and perianal warts, but it was found to function as a TLR7 agonist only five years later.15 While the use of Coley's toxin has been interrupted in the 1960s, mostly due to concerns raised by the thalidomide case,16 both BCG and imiquimod are currently approved by FDA for use in humans, the former for the immunotherapy of in situ bladder carcinoma and the latter against actinic keratosis, superficial basal cell carcinoma, and external genital warts (condylomata acuminata).17 The same holds true for monophosphoryl lipid A (MPL), a derivative of Salmonella minnesota LPS that operates as a potent agonist of TLR4,18 which has been authorized by FDA for use within the formulation of Cervarix®, a vaccine against human papillomavirus type 16 and 18 (HPV16 and HPV18, the causative agents of approximately 70% of cervical carcinoma cases) (Table 1).19

Table thumbnail
Table 1. TLR agonists approved by FDA for use in humans against cancer and cancer-related conditions

In the latest issue of OncoImmunology, we have extensively discussed the biological properties of therapeutically relevant TLRs and portrayed the current status of clinical development of experimental TLR agonists as immunostimulatory agents for oncological indications.20 In this Trial Watch, we will focus on recently completed or ongoing clinical trials that have evaluated/are evaluating FDA-approved TLR agonists as off-label medications for cancer therapy.

Bacillus Calmette-Guérin

In the 19th century, research in the area of infectivology witnessed several milestone achievements. These include the demonstration (by Edward Jenner) that cowpox infection provides immunity against smallpox, as well as the isolation (by Robert Koch) of Mycobacterium tuberculosis (the etiological determinant of human tuberculosis) and of its bovine counterpart M. bovis21,22 At the end of the same century, excited by the success of vaccination campaigns for the prevention of smallpox, scientists hypothesized that a similar principle might apply to tuberculosis, and hence begun to investigate the therapeutic potential of M. bovis.23 Unfortunately, early trials conducted in Italy had disastrous outcomes, as M. bovis was found to be as virulent as M. tuberculosis.24 A couple of decades later, however, the bacteriologist Albert Calmette and the veterinarian Camille Guérin, developed an attenuated strain of M. bovis that - upon prolonged culture in peculiar media (including a glycerin-bile-potato mixture) - was unable to cause overt tuberculosis in research animals. The BGC vaccine had officially been born. Since then, BCG has been used for the prevention of tuberculosis in millions of individuals worldwide.25 According to WHO, today tuberculosis is second only to HIV as the greatest killer due to a single infectious agent, with most tuberculosis-related deaths occurring in low- and middle-income countries (source This said, in high-income countries the introduction of BCG as an obligatory vaccine coupled to highly efficient antibiotic regimens has virtually eradicated tuberculosis. Indeed, while in the late 18th century 1:3–7 deaths in the UK were due to tuberculosis, less than 200 people died in the UK in 2007 for the same cause.26

The anticancer potential of BCG has been intuited as early as in the 1960s, but fully recognized only a few years later, when several authors reported not only that the growth of transplanted and viral cancers can be fully prevented by the co-administration of BGC,27-29 but also that the inoculation of BGC into established tumors leads to tumor regression and prevents the development of metastasis.30 Approximately in the same period, an intense wave of clinical investigation started to evaluate BCG (either as such or subjected to distinct extraction procedures, either alone or combined with radio-, chemo- or immunotherapeutic regimens) for the treatment of neoplasms as diverse as leukemia,31-39 lymphoma,40,41 head and neck squamous cell carcinoma (HNSCC),42,43 breast carcinoma,44-49 lung cancer,50-53 melanoma,54-69 gastric cancer,70,71 colorectal carcinoma,72-77 sarcoma,78,79 prostate cancer,80-82 cervical carcinoma,42 renal carcinoma,83-88 and bladder cancer.89-96 Unfortunately, most of these studies either reported no clinical benefits or relied on small patient cohorts, often being not confirmed by the results of subsequent large trials.97-99 As a standalone exception, the intravesical instillation of BCG was suggested to be safe and highly effective for the therapy of bladder carcinoma as soon as in 1976,85,94 a notion that was subsequently confirmed by dozens of randomized clinical studies.100-103 The clinical development of BCG as an adjuvant for cancer therapy culminated in 1990, when FDA approved BCG for use in humans as an immunotherapeutic intervention against superficial bladder carcinoma.

Since then, the possibility of exploiting the potent immunostimulatory properties of BCG against several types of cancer has continued to foster great expectations, and during the past 20 y BCG has been tested in hundreds of clinical studies. These trials (1) covered previously tested indications for which clear results had not been obtained; (2) investigated variations in dose,104-107 administration route108-111 and schedule;111-113 and (3) evaluated the safety and efficacy of BCG or BCG components in a few previously untested or scarcely tested settings, including lymphoma,114 and ovarian cancer.115-117 These clinical studies led to a remarkable refinement in the dosage and schedule of BCG immunotherapy, thus lowering both the incidence and severity of BCG-associated side effects (mainly consisting of fever, hematuria, bladder irritation/infection and a potentially lethal, but very rare, systemic reaction).118 However, such a great clinical effort de facto failed to identify oncological settings other than bladder cancer in which BCG may be beneficial. Accordingly, the indication for which BCG has been granted FDA approval for use in humans in 1990 has never changed since.

As BCG-based immunotherapy constitutes the gold standard approach for some types of bladder carcinoma, several clinical trials registered at were designed to compare novel therapeutic strategies to intravesical BCG for this indication. Alternatively, a few studies have been initiated to investigate the therapeutic potential - again in the context of bladder carcinoma - of BCG in association with either mitomycin C (a DNA alkylating agent) of interferon α (IFNα)-based immunotherapy, as compared with BCG alone.119,120 Beside these studies, de facto employing BCG as an on-label medication, official sources list 15 studies that have been initiated to evaluate the safety/efficacy of BCG, most often as an adjuvant to other immunotherapeutic interventions,121,122 in off-label indications including breast carcinoma, colorectal cancer, lung cancer, melanoma, neuroblastoma, sarcoma, ovarian carcinoma and prostate cancer. One of these trials has been terminated due to business considerations (NCT00671554) and 6 others are listed as completed (NCT00003023, NCT00003184, NCT00003279, NCT00003386, NCT00016133, NCT00427570), but their results have not yet been released (source

Table 2 summarizes recent clinical trials evaluating the safety and efficacy of BCG as an off-label mediation for cancer therapy.

Table thumbnail
Table 2. Clinical trials evaluating BCG as an off-label medication for cancer therapy.*

Monophosphoryl Lipid A

MPL is a chemically modified derivative of S. minnesota endotoxin that exhibits greatly reduced toxicity but maintains most of the immunostimulatory properties of LPS,123 de facto operating as a potent TLR4 agonist.18 The immunogenic potential of lipid A emerged as early as in the 1950s, thanks to the work of Howard, Rowley and Wardlaw from the Wright-Fleming Institute of Microbiology (London, UK).123,124 During the subsequent couple of decades, the biochemical and biological properties of lipid A from different bacterial strains have been extensively characterized.125-134 A few years after the work of Howard and colleagues, pioneer studies performed in Japan suggested that - similar to LPS - lipid A may exert antitumor activity in vivo.135,136 These findings were rapidly confirmed in a number of preclinical tumor models, in vitro and in vivo, along with the discovery that lipid A potently induce IFNγ and tumor necrosis factor α (TNFα).137-139 Strikingly, in 1973 (when neither Toll nor TLRs were known), Parr and colleagues identified similarities in the antineoplastic effects of LPS, lipid A and dsRNA,140 hence foreseeing (by at least 25 y) the fact that all these MAMPs activate innate immune effector mechanisms by binding to TLRs.7,141,142

During the next few years, great efforts were dedicated to the isolation of natural lipid A analogs, as well as to the identification of chemical and/or structural alterations that would preserve the immunostimulatory potential of lipid A while limiting its side effects.143-148 Thus, in the early 1980s, Qureshi and colleagues were the first to detail a method for the extraction and purification of MPL from the endotoxin of Salmonella spp149-151 The first phase I clinical trial testing the intravenous administration of MPL from Salmonella typhimurium and S. minnesota in cancer patients was concluded in 1984, identifying a maximum tolerated dose of 100 µg/m2 but no clear therapeutic benefits.152 Approximately in the same period, Jirillo and colleagues begun to conduct pilot clinical studies in cancer patients receiving acetic acid-inactivated S. minnesota (strain R595 Re), reporting no severe toxicity at the dose employed (up to 6.5 µg in four consecutive intravenous injections) but a consistent improvement in both innate and cognate immune functions.153,154 Since then, the biological and immunological properties of lipid A and some of its derivatives have been the subject of an intense wave of preclinical investigation.18,155-174 In the meanwhile, some of these compounds including ONO-4007, OM-174 and MPL, the latter within formulations such as DETOX (MPL + Mycobacterium phlei cell wall), AS02B (MPL + QS21, a water soluble saponin extracted from the South American tree Quillaja saponaria Molina),175 AS04 (MPL + aluminum salts) and AS15 (AS02B + CpG oligonucleotides), have also been tested in clinical trials, with mixed results. Indeed, whereas the clinical development of ONO-4007 and OM-174 as adjuvants for anticancer immunotherapy appears to stand at an impasse,20,176,177 AS02B,178-183 AS04184-197 and AS15 (Refs. 198,199 and Annual ASCO Meeting 2008, Abstracts 9045 and 9065) have been shown to potently boost the patient's immune response against viral and tumor-associated antigens by a plethora of independent studies. The clinical development of MPL-based adjuvants culminated in 2009, when FDA approved the AS04-adjuvanted preparation Cervarix® for use in humans as a preventive measure against premalignant and malignant lesions of the cervix causally related to oncogenic HPV subtypes.200 In multiple countries, Cervarix® is nowadays administered to young (7–25 y old) girls as part of national vaccination programs, a measure that - in a few years - will almost certainly lead to a drop in the incidence of HPV-associated cervical cancer.200

As we have discussed in the latest issue of OncoImmunology, the development of AS02B and AS15 as adjuvants for cancer immunotherapy continues.20 On the other hand, most clinical trials involving AS04 that are currently included in official databases not only are listed as completed, but also were designed to investigate Cervarix® as an on-label intervention (source Thus, it appears that the immunostimulatory potential of AS04 has never generated a great interest for the immunotherapy of neoplasms other than HPV-associated cervical carcinoma.


Imiquimod (a small non-nucleoside imidazoquinoline originally known as S-26308 or R-837) has begun to attract attention in the late 1980s, when a few reports demonstrated its therapeutic and prophylactic potential in animal models of cytomegalovirus (CMV) and herpes simplex virus type 2 (HSV-2) infection.201-203 It was clear from the beginning that the biological targets for such an antiviral activity were not infected cells (as imiquimod was inactive against HSV-2 and CMV in vitro),203 but rather components of the immune system.202-206 Indeed, similar to other imidazoquinolines (e.g., S-27609), imiquimod turned out to act in vivo as a potent inducer of immunostimulatory cytokines including IFNα, TNFα, interleukin (IL)-1β and IL-6,207-210 and to exert consistent antitumor effects.211 Following these preclinical results, a phase I clinical trial was conducted with 14 cancer patients to investigate maximum tolerated dose, toxicity, and biological outcome of imiquimod (100–500 mg), given per os either once or twice weekly.212 Unfortunately, although the drug was well tolerated (main side effects being fatigue, malaise, fever, headache, and lymphocytopenia) and exerted immunostimulatory effects in all patients, no clinical responses were observed.212 A few years later, another phase I study testing oral imiquimod in 21 patients with refractory neoplasms was concluded, reporting biological activity (measured in terms of circulating IFNα concentrations and 2–5A synthetase levels in peripheral blood mononuclear cells) but again no clear therapeutic benefit.213

Approximately in the same period, however, imiquimod (and some derivatives) begun to be extensively tested for the topical treatment of actinic keratosis (a precancerous lesion of the skin),214-220 basal cell carcinoma,221-230 and genital and perianal warts (a common sexually transmitted disease caused by HPV).231-240 These studies (and many others that followed whose detailed discussion goes beyond the scope of this Trial Watch) demonstrated that imiquimod (as a 5% cream) is safe, generally well tolerated and highly efficient against multiple skin disorders, de facto leading to its approval by FDA for use in humans as early as in 1997, initially as a countermeasure against genital and perianal warts only. Strikingly, it was not until 2002 that imiquimod was found to exert immunostimulatory and anticancer effects by binding to TLR7,15 a TLR predominantly expressed at the endosomal membrane of monocytes, macrophages, plasmacytoid DCs (one peculiar subset of DCs that operate at the interface between innate and adaptive immunity)241 and mast cells.177 In 2004, FDA granted its approval to imiquimod also for use in humans against actinic keratosis and superficial basal cell carcinoma. Since then, further insights have been gained into the cellular and molecular circuitries whereby imiquimod promotes antitumor immune responses. In particular, imiquimod has been shown to stimulate the production of pro-inflammatory cytokines by acting as an adenosine receptor antagonist,242 as well as to promote the (CCL2-dependent) recruitment of plasmacytoid DCs into the tumor bed and their conversion into tumor-killing effector cells.243

Following the demonstration that imiquimod is exceptionally efficient against actinic keratosis, basal cell carcinoma and warts, its therapeutic potential as an off-label prescription has been intensively investigated. In the vast majority of cases, these approaches (including large, randomized trials as well as case studies) focused on conditions for which the topical application of imiquimod alone would be appropriate, encompassing infantile hemangiomas,244-248 dysplastic nevi and in situ melanoma (lentigo maligna),249-258 in situ squamous cell carcinoma (Bowen's disease)259-264 keratoacanthoma,265-267 non-genital warts,268-272 xeroderma pigmentosum,273 vulvar, vaginal and cervical intraepithelial dysplasia/neoplasia,274-284 extramammary Paget's disease,285-289 Kaposi's sarcoma,290-292 desmoplastic trichoepithelioma (an uncommon adnexal tumor usually found on the face of young women),293 cutaneous T-cell lymphoma,294-296 as well as cutaneous metastases from multiple primary tumors.297-301 In addition, a few groups have evaluated the therapeutic potential of imiquimod as an adjuvant to peptide- or cell-based anticancer vaccines.302-305 Notably, the results of most - if not all - these studies support the contention that topical imiquimod might be beneficial for a very large spectrum of pre-neoplastic and malignant conditions, including primary lesions of the skin (i.e., squamous cell carcinoma, melanoma, Paget's disease), accessible epithelial cancers (i.e., vulvar, vaginal and cervical intraepithelial cancer), tumors that localize to the derma (i.e., cutaneous T-cell lymphoma, Kaposi's sarcoma, hemangioma) as well as cutaneous metastases from unrelated tumors. However, the actual therapeutic potential of imiquimod in all these settings will have to be confirmed by large, randomized studies.

Today, topical imiquimod, most often alone or combined with cryosurgery, continues to be extensively tested as an on-label prescription both in subjects affected by actinic keratosis (2 phase II + 20 phase III/IV trials registered at and in basal cell carcinoma patients (3 phase II + 9 phase III/IV trials registered at These studies are mainly intended to evaluate the safety and efficacy of reduced doses (e.g., 2.5% or 3.75% cream formulations) and/or alternative (i.e., cyclic, very prolonged) administration schedules, and in some cases promising results have already been released.306-310 In off-label settings, imiquimod 5% cream (as a single agent) is being/has recently been evaluated in patients affected by lentigo maligna (NCT00707174, NCT01161888, NCT01088737), cutaneous neurofibromas (NCT00865644), infantile hemangiomas (NCT00601016), HNSCC (NCT00384124), breast cancer (NCT00899574), cervical dysplasia/neoplasia (NCT00031759, NCT00941811, NCT00941252, NCT01283763) and recurrent Paget’s disease (NCT00504023). Topical imiquimod is also under investigation combined with paclitaxel or radiotherapy for the treatment of advanced/metastatic breast cancer (NCT00821964, NCT01421017) as well as combined with laser therapy for the control of (cutaneous) metastases of melanoma (NCT00453050).

In all these studies, imiquimod appears to be employed either as an immunostimulant per se or to exacerbate anticancer immune responses as elicited by chemo-, radio- or laser therapy. In addition to these relatively unspecific approaches, imiquimod 5% cream is being extensively investigated as an adjuvant to tumor-specific (peptide- or cell-based) vaccination strategies, including approaches directed against brain tumors (NCT00626483, NCT01171469, NCT01204684, NCT01400672, NCT01403285), neuroblastoma and sarcoma (NCT00944580, NCT01241162), melanoma (NCT00118313, NCT00142454, NCT00651703, NCT01191034, NCT01264731, NCT01543464), non-small cell lung cancer (NCT01219348), colorectal cancer (NCT00785122), cervical intraepithelial neoplasia (NCT00788164) and tumors of the reproductive tract (NCT00799110). In this case, imiquimod is applied to the vaccination site (which almost invariably consists in a subcutaneous injection) both before (often 24h) and after (often 24h) the injection. Of note, while the majority of clinical trials testing imiquimod as an on-label medication are listed as completed, most studies investigating imiquimod in off-label settings (in particular those in which imiquimod is used to boost anticancer vaccines) are still ongoing.

Table 3 summarizes recent clinical trials evaluating the safety and efficacy of imiquimod as an off-label mediation for cancer therapy.

Table thumbnail
Table 3. Clinical trials evaluating imiquimod as an off-label medication for cancer therapy.*

Concluding Remarks

As we have discussed here and in the latest issue of OncoImmunology,20 there’s a vast amount of preclinical and clinical evidence indicating that TLR agonists exert potent immunostimulatory functions, in vivo. In line with this notion, BCG, MPL and imiquimod constitute - at least for the indications for which they are approved by FDA and the European Medicines Agency - an important clinical reality, being associated with consistent rates of remission and limited side effects. Moreover, whereas the MPL-based adjuvant AS04 is under clinical investigation only as an on-label medication, BCG and imiquimod are currently being tested as off-label prescriptions in a variety of oncological settings, either as single agents or combined with specific anticancer vaccines. Thus, at odds with their experimental counterparts,20 BCG and imiquimod continue to attract great attention as immunostimulatory agents for cancer immunotherapy. We surmise that the results of ongoing clinical studies might induce regulatory agencies to extend the oncological indications for which BCG and imiquimod are approved.


Authors are supported by the Ligue contre le Cancer (équipes labelisées), AXA Chair for Longevity Research, Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Fondation Bettencourt-Schueller, Fondation de France, Fondation pour la Recherche Médicale, Agence National de la Recherche, the European Commission (Apo-Sys, ArtForce, ChemoRes. Death-Train) and the LabEx Immuno-Oncology.



bacillus Calmette-Guérin
damage-associated molecular pattern
double-stranded RNA
glutathione peroxidase 1
head and neck squamous cell carcinoma
human papillomavirus
herpes simplex virus type 2
microbe-associated molecular pattern
monophosphoryl lipid A
natural resistance-associated macrophage protein 1
Toll-like receptor


1. Anderson KV, Bokla L, Nüsslein-Volhard C. Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell. 1985;42:791–8. doi: 10.1016/0092-8674(85)90275-2. [PubMed] [Cross Ref]
2. Anderson KV, Jürgens G, Nüsslein-Volhard C. Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell. 1985;42:779–89. doi: 10.1016/0092-8674(85)90274-0. [PubMed] [Cross Ref]
3. Lewis EB. A gene complex controlling segmentation in Drosophila. Nature. 1978;276:565–70. doi: 10.1038/276565a0. [PubMed] [Cross Ref]
4. Bender W, Akam M, Karch F, Beachy PA, Peifer M, Spierer P, et al. Molecular genetics of the bithorax complex in Drosophila melanogaster. Science. 1983;221:23–9. doi: 10.1126/science.221.4605.23. [PubMed] [Cross Ref]
5. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–76. doi: 10.1146/annurev.immunol.21.120601.141126. [PubMed] [Cross Ref]
6. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973–83. doi: 10.1016/S0092-8674(00)80172-5. [PubMed] [Cross Ref]
7. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085–8. doi: 10.1126/science.282.5396.2085. [PubMed] [Cross Ref]
8. Song WY, Wang GL, Chen LL, Kim HS, Pi LY, Holsten T, et al. A receptor kinase-like protein encoded by the rice disease resistance gene, Xa21. Science. 1995;270:1804–6. doi: 10.1126/science.270.5243.1804. [PubMed] [Cross Ref]
9. Gómez-Gómez L, Boller T. FLS2: an LRR receptor-like kinase involved in the perception of the bacterial elicitor flagellin in Arabidopsis. Mol Cell. 2000;5:1003–11. [PubMed]
10. Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, et al. The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A. 2005;102:9577–82. doi: 10.1073/pnas.0502272102. [PubMed] [Cross Ref]
11. Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10:826–37. doi: 10.1038/nri2873. [PMC free article] [PubMed] [Cross Ref]
12. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov. 2012;11:215–33. doi: 10.1038/nrd3626. [PubMed] [Cross Ref]
13. Heldwein KA, Liang MD, Andresen TK, Thomas KE, Marty AM, Cuesta N, et al. TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG. J Leukoc Biol. 2003;74:277–86. doi: 10.1189/jlb.0103026. [PubMed] [Cross Ref]
14. Uehori J, Matsumoto M, Tsuji S, Akazawa T, Takeuchi O, Akira S, et al. Simultaneous blocking of human Toll-like receptors 2 and 4 suppresses myeloid dendritic cell activation induced by Mycobacterium bovis bacillus Calmette-Guérin peptidoglycan. Infect Immun. 2003;71:4238–49. doi: 10.1128/IAI.71.8.4238-4249.2003. [PMC free article] [PubMed] [Cross Ref]
15. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002;3:196–200. doi: 10.1038/ni758. [PubMed] [Cross Ref]
16. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327:1345–50. doi: 10.1126/science.1177319. [PubMed] [Cross Ref]
17. Hoffman ES, Smith RE, Renaud RC., Jr. From the analyst’s couch: TLR-targeted therapeutics. Nat Rev Drug Discov. 2005;4:879–80. doi: 10.1038/nrd1880. [PubMed] [Cross Ref]
18. Mata-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, Mitchell TC. The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science. 2007;316:1628–32. doi: 10.1126/science.1138963. [PubMed] [Cross Ref]
19. Agosti JM, Goldie SJ. Introducing HPV vaccine in developing countries--key challenges and issues. N Engl J Med. 2007;356:1908–10. doi: 10.1056/NEJMp078053. [PubMed] [Cross Ref]
20. Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, et al. Trial Watch - Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunol. 2012;1 In press. [PMC free article] [PubMed]
21. Blevins SM, Bronze MS. Robert Koch and the ‘golden age’ of bacteriology. Int J Infect Dis. 2010;14:e744–51. doi: 10.1016/j.ijid.2009.12.003. [PubMed] [Cross Ref]
22. Smith KA. Edward jenner and the small pox vaccine. Front Immunol. 2011;2:21. doi: 10.3389/fimmu.2011.00021. [PMC free article] [PubMed] [Cross Ref]
23. Bolin CA, Whipple DL, Khanna KV, Risdahl JM, Peterson PK, Molitor TW. Infection of swine with Mycobacterium bovis as a model of human tuberculosis. J Infect Dis. 1997;176:1559–66. doi: 10.1086/514155. [PubMed] [Cross Ref]
24. Fritsche A, Engel R, Buhl D, Zellweger JP. Mycobacterium bovis tuberculosis: from animal to man and back. Int J Tuberc Lung Dis. 2004;8:903–4. [PubMed]
25. Partenheimer RC. BCG vaccination. N Engl J Med. 1951;245:496–501. doi: 10.1056/NEJM195109272451305. [PubMed] [Cross Ref]
26. Tuberculosis in the UK. Annual report on tuberculosis surveillance in the UK 2009. London: Health Protection Agency Centre for Infections, 2009.
27. Sjögren HO, Ankerst J. Effect of BCG and allogeneic tumor cells on adenovirus type 12 tumorigenesis in mice. Nature. 1969;221:863–4. doi: 10.1038/221863a0. [PubMed] [Cross Ref]
28. Zbar B, Bernstein I, Tanaka T, Rapp HJ. Tumor immunity produced by the intradermal inoculation of living tumor cells and living Mycobacterium bovis (strain BCG) Science. 1970;170:1217–8. doi: 10.1126/science.170.3963.1217. [PubMed] [Cross Ref]
29. Bekierkunst A, Levij IS, Yarkoni E. Suppression of urethan-induced lung adenomas in mice treated with trehalose-6,6-dimycolate (cord factor) and living bacillus Calmette Guérin. Science. 1971;174:1240–2. doi: 10.1126/science.174.4015.1240. [PubMed] [Cross Ref]
30. Zbar B, Tanaka T. Immunotherapy of cancer: regression of tumors after intralesional injection of living Mycobacterium bovis. Science. 1971;172:271–3. doi: 10.1126/science.172.3980.271. [PubMed] [Cross Ref]
31. Treatment of acute lymphoblastic leukaemia. Comparison of immunotherapy (B.C.G.), intermittent methotrexate, and no therapy after a five-month intensive cytotoxic regimen ((Concord trial). Preliminary report to the Medical Research Council by the Leukaemia Committee and the Working Party on Leukaemia in Childhood. Br Med J. 1971;4:189–94. doi: 10.1136/bmj.4.5781.189. [PMC free article] [PubMed] [Cross Ref]
32. Advani SH, Gulwani B, Ghogale SG, Shetye MR, Gangal SG. Effect of administration of BCG, levamisole and irradiated leukemic cells on immune status and remission status in chronic myelogenous leukemia. Oncology. 1985;42:275–81. doi: 10.1159/000226046. [PubMed] [Cross Ref]
33. Baker MA, Taub RN, Carter WH, Jr., Davidson M, Sutton DM, Kutas G, et al. Immunotherapy for chronic myelogenous leukemia: survival not affected by treatment in the stable phase. Cancer Res. 1984;44:383–5. [PubMed]
34. McCredie KB, Gehan EA, Freireich EJ, Hewlett JS, Coltman CA, Jr., Hussein KK, et al. Management of adult acute leukemia. A Southwest Oncology Group study. Cancer. 1983;52:958–66. doi: 10.1002/1097-0142(19830915)52:6<958::AID-CNCR2820520604>3.0.CO;2-Z. [PubMed] [Cross Ref]
35. Odom LF, Tubergen DG, Githens JH, Heideman RL, Blake MA. Intermittent combination chemotherapy with or without bacillus Calmette-Guérin for treatment of acute lymphoblastic leukemia of childhood. Med Pediatr Oncol. 1983;11:79–90. doi: 10.1002/mpo.2950110204. [PubMed] [Cross Ref]
36. Omura GA, Vogler WR, Lefante J, Silberman H, Knospe W, Gordon D, et al. Treatment of acute myelogenous leukemia: influence of three induction regimens and maintenance with chemotherapy or BCG immunotherapy. Cancer. 1982;49:1530–6. doi: 10.1002/1097-0142(19820415)49:8<1530::AID-CNCR2820490804>3.0.CO;2-1. [PubMed] [Cross Ref]
37. Powles RL, Crowther D, Bateman CJ, Beard ME, McElwain TJ, Russell J, et al. Immunotherapy for acute myelogenous leukaemia. Br J Cancer. 1973;28:365–76. doi: 10.1038/bjc.1973.162. [PMC free article] [PubMed] [Cross Ref]
38. Powles RL, Russell JA, Selby PJ, Prentice HG, Jones DR, McElwain TJ, et al. Maintenance of remission in acute myelogenous leukaemia by a mixture of B.C.G. and irradiated leukaemia cells. Lancet. 1977;2:1107–10. doi: 10.1016/S0140-6736(77)90549-9. [PubMed] [Cross Ref]
39. Stryckmans PA, Otten J, Delbeke MJ, Suciu S, Fière D, Bury J, et al. Comparison of chemotherapy with immunotherapy for maintenance of acute lymphoblastic leukemia in children and adults. Blood. 1983;62:606–15. [PubMed]
40. Jones SE, Grozea PN, Metz EN, Haut A, Stephens RL, Morrison FS, et al. Improved complete remission rates and survival for patients with large cell lymphoma treated with chemoimmunotherapy. A Southwest Oncology Group Study. Cancer. 1983;51:1083–90. doi: 10.1002/1097-0142(19830315)51:6<1083::AID-CNCR2820510619>3.0.CO;2-M. [PubMed] [Cross Ref]
41. Cooper MR, Pajak TF, Nissen NI, Brunner K, Stutzman L, Bank A, et al. Effect of methanol extraction residue of Bacillus Calmette-Guerin in advanced Hodgkin’s disease. Cancer. 1982;49:2226–30. doi: 10.1002/1097-0142(19820601)49:11<2226::AID-CNCR2820491104>3.0.CO;2-R. [PubMed] [Cross Ref]
42. Olkowski ZL, McLaren JR, Skeen MJ. Effects of combined immunotherapy with levamisole and Bacillus Calmette-Guérin on immunocompetence of patients with squamous cell carcinoma of the cervix, head and neck, and lung undergoing radiation therapy. Cancer Treat Rep. 1978;62:1651–61. [PubMed]
43. Papac R, Minor DR, Rudnick S, Solomon LR, Capizzi RL. Controlled trial of methotrexate and Bacillus Calmette-Guérin therapy for advanced head and neck cancer. Cancer Res. 1978;38:3150–3. [PubMed]
44. Buzdar AU, Blumenschein GR, Smith TL, Powell KC, Hortobagyi GN, Yap HY, et al. Adjuvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without Bacillus Calmette-Guerin and with or without irradiation in operable breast cancer. A prospective randomized trial. Cancer. 1984;53:384–9. doi: 10.1002/1097-0142(19840201)53:3<384::AID-CNCR2820530303>3.0.CO;2-G. [PubMed] [Cross Ref]
45. Cohen E, Scanlon EF, Caprini JA, Cunningham MP, Oviedo MA, Robinson B, et al. Follow-up adjuvant chemotherapy and chemoimmunotherapy for stage II and III carcinoma of the breast. Cancer. 1982;49:1754–61. doi: 10.1002/1097-0142(19820501)49:9<1754::AID-CNCR2820490904>3.0.CO;2-O. [PubMed] [Cross Ref]
46. Hortobagyi GN, Yap HY, Blumenschein GR, Gutterman JU, Buzdar AU, Tashima CK, et al. Response of disseminated breast cancer to combined modality treatment with chemotherapy and levamisole with or without Bacillus Calmette-Guérin. Cancer Treat Rep. 1978;62:1685–92. [PubMed]
47. Hubay CA, Pearson OH, Manni A, Gordon NH, McGuire WL. Adjuvant endocrine therapy, cytotoxic chemotherapy and immunotherapy in stage II breast cancer: 6-year result. J Steroid Biochem. 1985;23(6B):1147–50. doi: 10.1016/0022-4731(85)90034-2. [PubMed] [Cross Ref]
48. Marshall JS, Gordon NH, Hubay CA, Pearson OH. Assessment of tamoxifen as adjuvant therapy in stage II breast cancer: a long-term follow-up. J Lab Clin Med. 1987;109:300–7. [PubMed]
49. Pearson OH, Hubay CA, Marshall JS, Gordon NH, McGuire WL, Mansour EG, et al. Adjuvant endocrine therapy, cytotoxic chemotherapy, and immunotherapy in stage-II breast cancer: five-year results. Breast Cancer Res Treat. 1983;3(Suppl):S61–8. doi: 10.1007/BF01855129. [PubMed] [Cross Ref]
50. Nilsson BS, Afeldt PE. A pilot study on the effect of BCG vaccination in patients with bronchial carcinoma. Scand J Respir Dis. 1975;56:84–6. [PubMed]
51. Bjornsson S, Takita H, Kuberka N, Preisler H, Catane H, Higby D, et al. Combination chemotherapy plus methanol extracted residue of bacillus Calmette-Guérin or Corynebacterium parvum in stage III lung cancer. Cancer Treat Rep. 1978;62:505–10. [PubMed]
52. Matthay RA, Mahler DA, Beck GJ, Loke J, Baue AE, Carter DC, et al. Intratumoral Bacillus Calmette-Guérin immunotherapy prior to surgery for carcinoma of the lung: results of a prospective randomized trial. Cancer Res. 1986;46:5963–8. [PubMed]
53. The Ludwig Lung Cancer Study Group (LLCSG) Immunostimulation with intrapleural BCG as adjuvant therapy in resected non-small cell lung cancer. Cancer. 1986;58:2411–6. doi: 10.1002/1097-0142(19861201)58:11<2411::AID-CNCR2820581110>3.0.CO;2-C. [PubMed] [Cross Ref]
54. W.H.O. Collaborating Centres for Evaluation of Methods of Diagnosis and Treatment of Melanoma Controlled study with imidazole carboxamide (DTIC), DTIC + bacillus Calmette-Guérin (BCG), and DTIC + corynebacterium parvum in advanced malignant melanoma. Tumori. 1984;70:41–8. [PubMed]
55. The Prudente Foundation Melanoma Study Group Chemotherapy of disseminated melanoma with bleomycin, vincristine, CCNU, and DTIC (BOLD regimen) Cancer. 1989;63:1676–80. [PubMed]
56. Ariyan S, Kirkwood JM, Mitchell MS, Nordlund JJ, Lerner AB, Papac RJ. Intralymphatic and regional surgical adjuvant immunotherapy in high-risk melanoma of the extremities. Surgery. 1982;92:459–63. [PubMed]
57. Cohen MH, Jessup JM, Felix EL, Weese JL, Herberman RB. Intralesional treatment of recurrent metastatic cutaneous malignant melanoma: a randomized prospective study of intralesional Bacillus Calmette-Guerin versus intralesional dinitrochlorobenzene. Cancer. 1978;41:2456–63. doi: 10.1002/1097-0142(197806)41:6<2456::AID-CNCR2820410654>3.0.CO;2-B. [PubMed] [Cross Ref]
58. Grant RM, Mackie R, Cochran AJ, Murray EL, Hoyle D, Ross C. Results of administering B.C.G. to patients with melanoma. Lancet. 1974;2:1096–100. doi: 10.1016/S0140-6736(74)90867-8. [PubMed] [Cross Ref]
59. Gutterman JU, Mavligit GM, Reed R, Burgess MA, Gottlieb J, Hersh EM. Bacillus Calmette-Guérin immunotherapy in combination with DTIC (NSC-45388) for the treatment of malignant melanoma. Cancer Treat Rep. 1976;60:177–82. [PubMed]
60. Lipton A, Harvey HA, Lawrence B, Gottlieb R, Kukrika M, Dixon R, et al. Corynebacterium parvum versus BCG adjuvant immunotherapy in human malignant melanoma. Cancer. 1983;51:57–60. doi: 10.1002/1097-0142(19830101)51:1<57::AID-CNCR2820510114>3.0.CO;2-V. [PubMed] [Cross Ref]
61. Mastrangelo MJ, Sulit HL, Prehn LM, Bornstein RS, Yarbro JW, Prehn RT. Intralesional BCG in the treatment of metastatic malignant melanoma. Cancer. 1976;37:684–92. doi: 10.1002/1097-0142(197602)37:2<684::AID-CNCR2820370212>3.0.CO;2-Y. [PubMed] [Cross Ref]
62. McCulloch PB, Dent PB, Blajchman M, Muirhead WM, Price RA. Recurrent malignant melanoma: effect of adjuvant immunotherapy on survival. Can Med Assoc J. 1977;117:33–6. [PMC free article] [PubMed]
63. Pinsky CM, Hirshaut Y, Wanebo HJ, Fortner JG, Miké V, Schottenfeld D, et al. Randomized trial of Bacillus Calmette-Guérin (percutaneous administration) as surgical adjuvant immunotherapy for patients with stage-II melanoma. Ann N Y Acad Sci. 1976;277:187–94. doi: 10.1111/j.1749-6632.1976.tb41697.x. [PubMed] [Cross Ref]
64. Plesnicar S, Rudolf Z. Combined BCG and irradiation treatment of skin metastases originating from malignant melanoma. Cancer. 1982;50:1100–6. doi: 10.1002/1097-0142(19820915)50:6<1100::AID-CNCR2820500613>3.0.CO;2-6. [PubMed] [Cross Ref]
65. Ramseur WL, Richards F, 2nd, Muss HB, Rhyne L, Cooper MR, White DR, et al. Chemoimmunotherapy for disseminated malignant melanoma: a prospective randomized study. Cancer Treat Rep. 1978;62:1085–7. [PubMed]
66. Spitler LE, Levin AS, Wybran J. Combined immunotherapy in malignant melanoma. Regression of metastatic lesions in two patients concordant in timing with systemic administration of transfer factor and Bacillus Calmette-Guérin. Cell Immunol. 1976;21:1–19. doi: 10.1016/0008-8749(76)90322-1. [PubMed] [Cross Ref]
67. Sterchi JM, Wells HB, Case LD, Spurr CL, White DR, Richards F, et al. A randomized trial of adjuvant chemotherapy and immunotherapy in Stage I and Stage II cutaneous melanoma. An interim report. Cancer. 1985;55:707–12. doi: 10.1002/1097-0142(19850215)55:4<707::AID-CNCR2820550406>3.0.CO;2-5. [PubMed] [Cross Ref]
68. Varella AD, Bandiera DC, de Amorim AR, Sr., Calvis LA, Santos IO, Escaleira N, et al. Treatment of disseminated malignant melanoma with high-dose oral BCG. Cancer. 1981;48:1353–62. doi: 10.1002/1097-0142(19810915)48:6<1353::AID-CNCR2820480617>3.0.CO;2-N. [PubMed] [Cross Ref]
69. Wood WC, Cosimi AB, Carey RW, Kaufman SD. Randomized trial of adjuvant therapy for “high risk” primary malignant melanoma. Surgery. 1978;83:677–81. [PubMed]
70. Akiyoshi T, Kawaguchi M, Arinaga S, Miyazaki S, Koba F, Wada T, et al. A trial of adjuvant combination chemoimmunotherapy for stage III carcinoma of stomach. J Surg Oncol. 1984;26:86–90. doi: 10.1002/jso.2930260204. [PubMed] [Cross Ref]
71. Ochiai T, Sato H, Hayashi R, Asano T, Sato H, Yamamura Y. Postoperative adjuvant immunotherapy of gastric cancer with BCG-cell wall skeleton. 3- to 6-year follow up of a randomized clinical trial. Cancer Immunol Immunother. 1983;14:167–71. doi: 10.1007/BF00205355. [PubMed] [Cross Ref]
72. Gastrointestinal Tumor Study Group Adjuvant therapy of colon cancer--results of a prospectively randomized trial. N Engl J Med. 1984;310:737–43. doi: 10.1056/NEJM198403223101201. [PubMed] [Cross Ref]
73. Higgins GA, Donaldson RC, Rogers LS, Juler GL, Keehn RJ. Efficacy of MER immunotherapy when added to a regimen of 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. A Veterans Administration Surgical Oncology Group report. Cancer. 1984;54:193–8. doi: 10.1002/1097-0142(19840715)54:2<193::AID-CNCR2820540202>3.0.CO;2-F. [PubMed] [Cross Ref]
74. Hoover HC, Jr., Surdyke MG, Dangel RB, Peters LC, Hanna MG., Jr. Prospectively randomized trial of adjuvant active-specific immunotherapy for human colorectal cancer. Cancer. 1985;55:1236–43. doi: 10.1002/1097-0142(19850315)55:6<1236::AID-CNCR2820550616>3.0.CO;2-#. [PubMed] [Cross Ref]
75. Jessup JM, McBride CM, Ames FC, Guarda L, Ota DM, Romsdahl MM, et al. Active specific immunotherapy of Dukes B2 and C colorectal carcinoma: comparison of two doses of the vaccine. Cancer Immunol Immunother. 1986;21:233–9. doi: 10.1007/BF00199367. [PubMed] [Cross Ref]
76. Mavligit GM, Gutterman JU, Burgess MA, Khankhanian N, Seibert GB, Speer JF, et al. Adjuvant immunotherapy and chemoimmunotherapy in colorectal cancer of the Dukes’ C classification. Preliminary clinical results. Cancer. 1975;36(Suppl):2421–7. doi: 10.1002/1097-0142(197512)36:6<2421::AID-CNCR2820360623>3.0.CO;2-2. [PubMed] [Cross Ref]
77. Valdivieso M, Bedikian A, Burgess MA, Rodriguez V, Hersh EM, Bodey GP, et al. Chemoimmunotherapy of metastatic large bowel cancer: nonspecific stimulation with BCG and levamisole. Cancer. 1977;40(Suppl):2731–9. doi: 10.1002/1097-0142(197711)40:5+<2731::AID-CNCR2820400948>3.0.CO;2-W. [PubMed] [Cross Ref]
78. Townsend CM, Jr., Eilber FR, Morton DL. Skeletal and soft tissue sarcomas. Treatment with adjuvant immunotherapy. JAMA. 1976;236:2187–9. doi: 10.1001/jama.1976.03270200025023. [PubMed] [Cross Ref]
79. Rosenburg SA, Chabner BA, Young RC, Seipp CA, Levine AS, Costa J, et al. Treatment of osteogenic sarcoma. I. Effect of adjuvant high-dose methotrexate after amputation. Cancer Treat Rep. 1979;63:739–51. [PubMed]
80. Guinan P, Toronchi E, Shaw M, Crispin R, Sharifi R. Bacillus calmette-guerin (BCG) adjuvant therapy in stage D prostate cancer. Urology. 1982;20:401–3. doi: 10.1016/0090-4295(82)90464-2. [PubMed] [Cross Ref]
81. Guinan PD, John T, Baumgartner G, Sundar B, Ablin RJ. Adjuvant immunotherapy (BCG) in stage D prostate cancer. Am J Clin Oncol. 1982;5:65–8. [PubMed]
82. Merrin C, Han T, Klein E, Wajsman Z, Murphy GP. Immunotherapy of prostatic carcinoma with bacillus Calmette-Guerin. Cancer Chemother Rep. 1975;59:157–63. [PubMed]
83. Adler A, Gillon G, Lurie H, Shaham J, Loven D, Shachter Y, et al. Active specific immunotherapy of renal cell carcinoma patients: a prospective randomized study of hormono-immuno-versus hormonotherapy. Preliminary report of immunological and clinical aspects. J Biol Response Mod. 1987;6:610–24. [PubMed]
84. Laucius JF, Patel YA, Lusch CJ, Koons LS, Bellet RE, Mastrangelo MJ. The phase II evaluation of Bacillus Calmette-Guerin plus megestrol acetate in patients with metastatic renal adenocarcinoma. Med Pediatr Oncol. 1977;3:237–42. doi: 10.1002/mpo.2950030304. [PubMed] [Cross Ref]
85. Morales A, Eidinger D. Bacillus Calmette-Guerin in the treatment of adenocarcinoma of the kidney. J Urol. 1976;115:377–80. [PubMed]
86. Morales A, Wilson JL, Pater JL, Loeb M. Cytoreductive surgery and systemic bacillus Calmette-Guerin therapy in metastatic renal cancer: a phase II trial. J Urol. 1982;127:230–5. [PubMed]
87. Neidhart JA, Murphy SG, Hennick LA, Wise HA. Active specific immunotherapy of stage IV renal carcinoma with aggregated tumor antigen adjuvant. Cancer. 1980;46:1128–34. doi: 10.1002/1097-0142(19800901)46:5<1128::AID-CNCR2820460509>3.0.CO;2-3. [PubMed] [Cross Ref]
88. Wright KC, Soo CS, Wallace S, McDonald MW, Ayala A. Experimental percutaneous renal embolization using BCG-saturated gelfoam. Cardiovasc Intervent Radiol. 1982;5:260–3. doi: 10.1007/BF02565408. [PubMed] [Cross Ref]
89. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116:180–3. [PubMed]
90. Brosman SA. Experience with bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J Urol. 1982;128:27–30. [PubMed]
91. Brosman SA. The use of bacillus Calmette-Guerin in the therapy of bladder carcinoma in situ. J Urol. 1985;134:36–9. [PubMed]
92. Herr HW, Pinsky CM, Whitmore WF, Jr., Sogani PG, Oettgen HF, Melamed MR. Experience with intravesical bacillus Calmette-Guèrin therapy of superficial bladder tumors. Urology. 1985;25:119–23. doi: 10.1016/0090-4295(85)90525-4. [PubMed] [Cross Ref]
93. Lamm DL. Bacillus Calmette-Guerin immunotherapy for bladder cancer. J Urol. 1985;134:40–7. [PubMed]
94. Lamm DL, Thor DE, Harris SC, Reyna JA, Stogdill VD, Radwin HM. Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. J Urol. 1980;124:38–40. [PubMed]
95. Lamm DL, Thor DE, Stogdill VD, Radwin HM. Bladder cancer immunotherapy. J Urol. 1982;128:931–5. [PubMed]
96. Pinsky CM, Camacho FJ, Kerr D, Geller NL, Klein FA, Herr HA, et al. Intravesical administration of bacillus Calmette-Guérin in patients with recurrent superficial carcinoma of the urinary bladder: report of a prospective, randomized trial. Cancer Treat Rep. 1985;69:47–53. [PubMed]
97. Agarwala SS, Neuberg D, Park Y, Kirkwood JM. Mature results of a phase III randomized trial of bacillus Calmette-Guerin (BCG) versus observation and BCG plus dacarbazine versus BCG in the adjuvant therapy of American Joint Committee on Cancer Stage I-III melanoma (E1673): a trial of the Eastern Oncology Group. Cancer. 2004;100:1692–8. doi: 10.1002/cncr.20166. [PubMed] [Cross Ref]
98. Hoover HC, Jr., Brandhorst JS, Peters LC, Surdyke MG, Takeshita Y, Madariaga J, et al. Adjuvant active specific immunotherapy for human colorectal cancer: 6.5-year median follow-up of a phase III prospectively randomized trial. J Clin Oncol. 1993;11:390–9. [PubMed]
99. Harris JE, Ryan L, Hoover HC, Jr., Stuart RK, Oken MM, Benson AB, 3rd, et al. Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Oncol. 2000;18:148–57. [PubMed]
100. Khanna OP, Son DL, Son K, Mazer H, Read J, Nugent D, et al. Multicenter study of superficial bladder cancer treated with intravesical bacillus Calmette-Guerin or adriamycin. Results of long-term follow-up. Urology. 1991;38:271–9. doi: 10.1016/S0090-4295(91)80362-B. [PubMed] [Cross Ref]
101. Mori K, Lamm DL, Crawford ED. A trial of bacillus Calmette-Guérin versus adriamycin in superficial bladder cancer: a South-West Oncology Group Study. Urol Int. 1986;41:254–9. doi: 10.1159/000281212. [PubMed] [Cross Ref]
102. Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, et al. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991;325:1205–9. doi: 10.1056/NEJM199110243251703. [PubMed] [Cross Ref]
103. Melekos MD. Intravesical Bacillus Calmette-Guérin prophylactic treatment for superficial bladder tumors: results of a controlled prospective study. Urol Int. 1990;45:137–41. doi: 10.1159/000281695. [PubMed] [Cross Ref]
104. Pagano F, Bassi P, Piazza N, Abatangelo G, Drago Ferrante GL, Milani C. Improving the efficacy of BCG immunotherapy by dose reduction. Eur Urol. 1995;27(Suppl 1):19–22. [PubMed]
105. Hurle R, Losa A, Ranieri A, Graziotti P, Lembo A. Low dose Pasteur bacillus Calmette-Guerin regimen in stage T1, grade 3 bladder cancer therapy. J Urol. 1996;156:1602–5. doi: 10.1016/S0022-5347(01)65458-2. [PubMed] [Cross Ref]
106. Losa A, Hurle R, Lembo A. Low dose bacillus Calmette-Guerin for carcinoma in situ of the bladder: long-term results. J Urol. 2000;163:68–71, discussion 71-2. doi: 10.1016/S0022-5347(05)67974-8. [PubMed] [Cross Ref]
107. Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, et al. CUETO Group (Club Urológico Español De Tratamiento Oncológico) A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. Eur Urol. 2007;52:1398–406. doi: 10.1016/j.eururo.2007.04.062. [PubMed] [Cross Ref]
108. D’Ancona CA, Netto Júnior NR, Claro JA, Ikari O. Oral or intravesical bacillus Calmette-Guerin immunoprophylaxis in bladder carcinoma. J Urol. 1991;145:498–501. [PubMed]
109. Lamm DL, DeHaven JI, Shriver J, Crispen R, Grau D, Sarosdy MF. A randomized prospective comparison of oral versus intravesical and percutaneous bacillus Calmette-Guerin for superficial bladder cancer. J Urol. 1990;144:65–7. [PubMed]
110. Lüftenegger W, Ackermann DK, Futterlieb A, Kraft R, Minder CE, Nadelhaft P, et al. Intravesical versus intravesical plus intradermal bacillus Calmette-Guerin: a prospective randomized study in patients with recurrent superficial bladder tumors. J Urol. 1996;155:483–7. doi: 10.1016/S0022-5347(01)66427-9. [PubMed] [Cross Ref]
111. Witjes JA, Fransen MP, van der Meijden AP, Doesburg WH, Debruyne FM. Use of maintenance intravesical bacillus Calmette-Guérin (BCG), with or without intradermal BCG, in patients with recurrent superficial bladder cancer. Long-term follow-up of a randomized phase 2 study. Urol Int. 1993;51:67–72. doi: 10.1159/000282516. [PubMed] [Cross Ref]
112. Melekos MD, Chionis H, Pantazakos A, Fokaefs E, Paranychianakis G, Dauaher H. Intravesical bacillus Calmette-Guerin immunoprophylaxis of superficial bladder cancer: results of a controlled prospective trial with modified treatment schedule. J Urol. 1993;149:744–8. [PubMed]
113. Librenjak D, Situm M, Vrdoljak E, Milostić K, Gotovac J. Results of long-term follow-up of patients with superficial bladder carcinoma treated with intravesically applied bacillus Calmette-Guerin vaccine according to the schedule of 6 weekly + 6 monthly instillations. Urol Oncol. 2012;30:259–65. doi: 10.1016/j.urolonc.2010.02.007. [PubMed] [Cross Ref]
114. Ravaud A, Eghbali H, Trojani M, Hoerni-Simon G, Soubeyran P, Hoerni B. Adjuvant bacillus Calmette-Guérin therapy in non-Hodgkin’s malignant lymphomas: long-term results of a randomized trial in a single institution. J Clin Oncol. 1990;8:608–14. [PubMed]
115. Pattillo RA, Komaki R, Reynolds M, Robles J. Bacillus Calmette-Guérin immunotherapy in ovarian cancer. J Reprod Med. 1988;33:41–5. [PubMed]
116. Creasman WT, Omura GA, Brady MF, Yordan E, DiSaia PJ, Beecham J. A randomized trial of cyclophosphamide, doxorubicin, and cisplatin with or without bacillus Calmette-Guerin in patients with suboptimal stage III and IV ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 1990;39:239–43. doi: 10.1016/0090-8258(90)90244-F. [PubMed] [Cross Ref]
117. Hayashi A, Nishida Y, Yoshii S, Kim SY, Uda H, Hamasaki T. Immunotherapy of ovarian cancer with cell wall skeleton of Mycobacterium bovis Bacillus Calmette-Guérin: effect of lymphadenectomy. Cancer Sci. 2009;100:1991–5. doi: 10.1111/j.1349-7006.2009.01271.x. [PubMed] [Cross Ref]
118. Sylvester RJ, van der Meijden AP, Oosterlinck W, Hoeltl W, Bono AV, EORTC Genito-Urinary Tract Cancer Group The side effects of Bacillus Calmette-Guerin in the treatment of Ta T1 bladder cancer do not predict its efficacy: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial. Eur Urol. 2003;44:423–8. doi: 10.1016/S0302-2838(03)00371-3. [PubMed] [Cross Ref]
119. Vacchelli E, Galluzzi L, Eggermont A, Galon J, Tartour E, Zitvogel L, et al. Trial Watch - Immunostimulatory cytokines. Oncoimmunol. 2012;1 In press. [PMC free article] [PubMed]
120. Vacchelli E, Galluzzi L, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, et al. Trial Watch - Chemotherapy with immunogenic cell death inducers. Oncoimmunol. 2012;1:179–88. doi: 10.4161/onci.1.2.19026. [PMC free article] [PubMed] [Cross Ref]
121. Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, et al. Trial Watch - Adoptive cell transfer immunotherapy. Oncoimmunol. 2012;1:306–15. doi: 10.4161/onci.19549. [PMC free article] [PubMed] [Cross Ref]
122. Galluzzi L, Vacchelli E, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, et al. Trial Watch - Monoclonal antibodies in cancer therapy. Oncoimmunol. 2012;1:28–37. doi: 10.4161/onci.1.1.17938. [PMC free article] [PubMed] [Cross Ref]
123. Howard JG, Rowley D, Wardlaw AC. Stimulation of non-specific immunity by the lipid A component of bacterial lipopolysaccharide. Nature. 1957;179:314–5. doi: 10.1038/179314a0. [PubMed] [Cross Ref]
124. Howard JG, Rowley D, Wardlaw AC. Investigations on the mechanism of stimulation of non-specific immunity by bacterial lipopolysaccharides. Immunology. 1958;1:181–203. [PubMed]
125. Burton AJ, Carter HE. Purification and characterization of the lipid A component of the lipopolysaccharides from Escherichia Coli. Biochemistry. 1964;3:411–8. doi: 10.1021/bi00891a018. [PubMed] [Cross Ref]
126. Kasai N, Nowotny A. Endotoxic glycolipid from a heptoseless mutant of Salmonella minnesota. J Bacteriol. 1967;94:1824–36. [PMC free article] [PubMed]
127. Kim YB, Watson DW. Biologically active endotoxins from Salmonella mutants deficient in O- and R-polysaccharides and heptose. J Bacteriol. 1967;94:1320–6. [PMC free article] [PubMed]
128. Gmeiner J, Lüderitz O, Westphal O. Biochemical studies on lipopolysaccharides of Salmonella R mutants. 6. Investigations on the structure of the lipid A component. Eur J Biochem. 1969;7:370–9. doi: 10.1111/j.1432-1033.1969.tb19618.x. [PubMed] [Cross Ref]
129. Adams GA, Singh PP. Structural features of lipid A preparations isolated from Escherichia coli and Shigella flexneri. Biochim Biophys Acta. 1970;202:553–5. [PubMed]
130. Adams GA, Singh PP. The chemical constitution of lipid A from Serratia marcescens. Can J Biochem. 1970;48:55–62. doi: 10.1139/o70-010. [PubMed] [Cross Ref]
131. Kato M. Site of action of lipid A on mitochondria. J Bacteriol. 1972;112:268–75. [PMC free article] [PubMed]
132. Rosenstreich DL, Nowotny A, Chused T, Mergenhagen SE. In vitro transformation of mouse bone-marrow-derived (B) lymphocytes induced by the lipid component of endotoxin. Infect Immun. 1973;8:406–11. [PMC free article] [PubMed]
133. Apte RN, Galanos C, Pluznik DH. Lipid A, the active part of bacterial endotoxins in inducing serum colony stimulating activity and proliferation of splenic granulocyte/macrophage progenitor cells. J Cell Physiol. 1976;87:71–8. doi: 10.1002/jcp.1040870110. [PubMed] [Cross Ref]
134. Ralph P, Broxmeyer HE, Nakoinz I. Immunostimulators induce granulocyte/macrophage colony-stimulating activity and block proliferation in a monocyte tumor cell line. J Exp Med. 1977;146:611–6. doi: 10.1084/jem.146.2.611. [PMC free article] [PubMed] [Cross Ref]
135. Kasai N, Aoki Y, Watanabe T, Odaka T, Yamamoto T. Studies on the anti-tumor effect of the bacterial lipid component, lipid A. I. On some physicochemical properties and antitumor activity of lipid A fraction. Jpn J Microbiol. 1961;5:347–66. [PubMed]
136. Kawanishi N, Aoki Y, Watanabe S, Kodaka K, Yamamoto T. [Study on the antineoplastic action of the bacterial lipid, “lipid A”] Nisshin Igaku Jpn J Med Prog. 1962;49:287–8. [PubMed]
137. Tanamoto K, Abe C, Homma JY, Kojima Y. Regions of the lipopolysaccharide of Pseudomonas aeruginosa essential for antitumor and interferon-inducing activities. Eur J Biochem. 1979;97:623–9. doi: 10.1111/j.1432-1033.1979.tb13152.x. [PubMed] [Cross Ref]
138. Haranaka K, Satomi N, Sakurai A, Kunii O. Role of lipid A in the production of tumor necrosis factor and differences in antitumor activity between tumor necrosis factor and lipopolysaccharide. Tohoku J Exp Med. 1984;144:385–96. doi: 10.1620/tjem.144.385. [PubMed] [Cross Ref]
139. Ha DK, Leung SW, Fung KP, Choy YM, Lee CY. Role of lipid A of endotoxin in the production of tumour necrosis factor. Mol Immunol. 1985;22:291–4. doi: 10.1016/0161-5890(85)90164-6. [PubMed] [Cross Ref]
140. Parr I, Wheeler E, Alexander P. Similarities of the anti-tumour actions of endotoxin, lipid A and double-stranded RNA. Br J Cancer. 1973;27:370–89. doi: 10.1038/bjc.1973.45. [PMC free article] [PubMed] [Cross Ref]
141. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413:732–8. doi: 10.1038/35099560. [PubMed] [Cross Ref]
142. Yang RB, Mark MR, Gray A, Huang A, Xie MH, Zhang M, et al. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature. 1998;395:284–8. doi: 10.1038/26239. [PubMed] [Cross Ref]
143. Takayama K, Ribi E, Cantrell JL. Isolation of a nontoxic lipid A fraction containing tumor regression activity. Cancer Res. 1981;41:2654–7. [PubMed]
144. Kanegasaki S, Kojima Y, Matsuura M, Homma JY, Yamamoto A, Kumazawa Y, et al. Biological activities of analogues of lipid A based chemically on the revised structural model. Comparison of mediator-inducing, immunomodulating and endotoxic activities. Eur J Biochem. 1984;143:237–42. doi: 10.1111/j.1432-1033.1984.tb08364.x. [PubMed] [Cross Ref]
145. Matsuura M, Kojima Y, Homma JY, Kubota Y, Yamamoto A, Kiso M, et al. Biological activities of chemically synthesized analogues of the nonreducing sugar moiety of lipid A. FEBS Lett. 1984;167:226–30. doi: 10.1016/0014-5793(84)80131-3. [PubMed] [Cross Ref]
146. Kotani S, Takada H, Tsujimoto M, Ogawa T, Takahashi I, Ikeda T, et al. Synthetic lipid A with endotoxic and related biological activities comparable to those of a natural lipid A from an Escherichia coli re-mutant. Infect Immun. 1985;49:225–37. [PMC free article] [PubMed]
147. Matsuura M, Yamamoto A, Kojima Y, Homma JY, Kiso M, Hasegawa A. Biological activities of chemically synthesized partial structure analogues of lipid A. J Biochem. 1985;98:1229–37. [PubMed]
148. Nakatsuka M, Kumazawa Y, Ikeda S, Yamamoto A, Nishimura C, Homma JY, et al. Antitumor and antimicrobial activities of lipid A-subunit analogue GLA-27. J Clin Lab Immunol. 1988;26:43–7. [PubMed]
149. Qureshi N, Takayama K, Ribi E. Purification and structural determination of nontoxic lipid A obtained from the lipopolysaccharide of Salmonella typhimurium. J Biol Chem. 1982;257:11808–15. [PubMed]
150. Qureshi N, Mascagni P, Ribi E, Takayama K. Monophosphoryl lipid A obtained from lipopolysaccharides of Salmonella minnesota R595. Purification of the dimethyl derivative by high performance liquid chromatography and complete structural determination. J Biol Chem. 1985;260:5271–8. [PubMed]
151. Ribi E, Cantrell JL, Takayama K, Qureshi N, Peterson J, Ribi HO. Lipid A and immunotherapy. Rev Infect Dis. 1984;6:567–72. doi: 10.1093/clinids/6.4.567. [PubMed] [Cross Ref]
152. Vosika GJ, Barr C, Gilbertson D. Phase-I study of intravenous modified lipid A. Cancer Immunol Immunother. 1984;18:107–12. doi: 10.1007/BF00205743. [PubMed] [Cross Ref]
153. Jirillo E, Miragliotta G, Caretto G, Cedola MC, Nappi R, Sansone LA, et al. Relationship between immune system and gram-negative bacteria. Acid-treated Salmonella minnesota R595 (Re) enhances immune responsiveness in patients with gynecologic malignancies. Int J Immunopharmacol. 1986;8:881–6. doi: 10.1016/0192-0561(86)90088-3. [PubMed] [Cross Ref]
154. Jirillo A, Disperati A, Balli M, Bonciarelli G, Demicheli R, Antonaci S, et al. Pilot study of intravenous administration of the acid-treated Salmonella minnesota R595 (Re) in cancer patients. Tumori. 1987;73:481–6. [PubMed]
155. Jeannin JF, Onier N, Lagadec P, von Jeney N, Stütz P, Liehl E. Antitumor effect of synthetic derivatives of lipid A in an experimental model of colon cancer in the rat. Gastroenterology. 1991;101:726–33. [PubMed]
156. Johnston D, Bystryn JC. Effect of cell wall skeleton and monophosphoryl lipid A adjuvant on the immunogenicity of a murine B16 melanoma vaccine. J Natl Cancer Inst. 1991;83:1240–5. doi: 10.1093/jnci/83.17.1240. [PubMed] [Cross Ref]
157. Shimizu T, Ohtsuka Y, Yanagihara Y, Itoh H, Nakamoto S, Achiwa K. Combined effects of synthetic lipid A analogs and muramyl dipeptide on antitumor activity against Meth A fibrosarcoma in mice. Int J Immunopharmacol. 1991;13:605–11. doi: 10.1016/0192-0561(91)90083-J. [PubMed] [Cross Ref]
158. Akimoto T, Kumazawa E, Jimbo T, Joto N, Tohgo A. Antitumor effect of DT-5461a, a synthetic low-toxicity lipid A analog, involves endogenous tumor necrosis factor induction subsequent to macrophage activation. Int J Immunopharmacol. 1994;16:887–93. doi: 10.1016/0192-0561(94)90043-4. [PubMed] [Cross Ref]
159. Yang D, Satoh M, Ueda H, Tsukagoshi S, Yamazaki M. Activation of tumor-infiltrating macrophages by a synthetic lipid A analog (ONO-4007) and its implication in antitumor effects. Cancer Immunol Immunother. 1994;38:287–93. doi: 10.1007/BF01525505. [PubMed] [Cross Ref]
160. Satake K, Yokomatsu H, Hiura A. Effects of a new synthetic lipid A on endogenous tumor necrosis factor production and antitumor activity against human pancreatic cancer cells. Pancreas. 1996;12:260–6. doi: 10.1097/00006676-199604000-00008. [PubMed] [Cross Ref]
161. Kumazawa E, Jimbo T, Akimoto T, Joto N, Tohgo A. Antitumor effect of DT-5461, a lipid A derivative, against human tumor xenografts is mediated by intratumoral production of tumor necrosis factor and affected by host immunosuppressive factors in nude mice. Cancer Invest. 1997;15:522–30. doi: 10.3109/07357909709047593. [PubMed] [Cross Ref]
162. Kuramitsu Y, Nishibe M, Ohiro Y, Matsushita K, Yuan L, Obara M, et al. A new synthetic lipid A analog, ONO-4007, stimulates the production of tumor necrosis factor-alpha in tumor tissues, resulting in the rejection of transplanted rat hepatoma cells. Anticancer Drugs. 1997;8:500–8. doi: 10.1097/00001813-199706000-00013. [PubMed] [Cross Ref]
163. Matsumoto N, Oida H, Aze Y, Akimoto A, Fujita T. Intratumoral tumor necrosis factor induction and tumor growth suppression by ONO-4007, a low-toxicity lipid A analog. Anticancer Res. 1998;18(6A):4283–9. [PubMed]
164. Mizushima Y, Sassa K, Fujishita T, Oosaki R, Kobayashi M. Therapeutic effect of a new synthetic lipid A analog (ONO-4007) on a tumor implanted at different sites in rats. J Immunother. 1999;22:401–6. doi: 10.1097/00002371-199909000-00003. [PubMed] [Cross Ref]
165. Silla S, Fallarino F, Boon T, Uyttenhove C. Enhancement by IL-12 of the cytolytic T lymphocyte (CTL) response of mice immunized with tumor-specific peptides in an adjuvant containing QS21 and MPL. Eur Cytokine Netw. 1999;10:181–90. [PubMed]
166. Staib L, Harel W, Mitchell MS. Optimization of intracerebral tumour protection by active-specific immunization against murine melanoma B16/G3.12. Melanoma Res. 2001;11:325–35. doi: 10.1097/00008390-200108000-00002. [PubMed] [Cross Ref]
167. Kirman I, Asi Z, Carter J, Fowler R, Whelan RL. Combined whole tumor cell and monophosphoryl lipid A vaccine improved by encapsulation in murine colorectal cancer. Surg Endosc. 2002;16:654–8. doi: 10.1007/s00464-001-8187-6. [PubMed] [Cross Ref]
168. Satoh M, Tsurumaki K, Kagehara H, Yamazaki M. Induction of intratumoral tumor necrosis factor by a synthetic lipid A analog, ONO-4007, with less tolerance in repeated administration and its implication in potent antitumor effects with low toxicity. Cancer Immunol Immunother. 2002;50:653–62. doi: 10.1007/s00262-001-0241-7. [PubMed] [Cross Ref]
169. Evans JT, Cluff CW, Johnson DA, Lacy MJ, Persing DH, Baldridge JR. Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529. Expert Rev Vaccines. 2003;2:219–29. doi: 10.1586/14760584.2.2.219. [PubMed] [Cross Ref]
170. Larmonier CB, Arnould L, Larmonier N, Baumann S, Moutet M, Saint-Giorgio V, et al. Kinetics of tumor cell apoptosis and immune cell activation during the regression of tumors induced by lipid A in a rat model of colon cancer. Int J Mol Med. 2004;13:355–61. [PubMed]
171. D’Agostini C, Pica F, Febbraro G, Grelli S, Chiavaroli C, Garaci E. Antitumour effect of OM-174 and cyclophosphamide on murine B16 melanoma in different experimental conditions. Int Immunopharmacol. 2005;5:1205–12. doi: 10.1016/j.intimp.2005.02.013. [PubMed] [Cross Ref]
172. Hermans IF, Silk JD, Gileadi U, Masri SH, Shepherd D, Farrand KJ, et al. Dendritic cell function can be modulated through cooperative actions of TLR ligands and invariant NKT cells. J Immunol. 2007;178:2721–9. [PubMed]
173. Andreani V, Gatti G, Simonella L, Rivero V, Maccioni M. Activation of Toll-like receptor 4 on tumor cells in vitro inhibits subsequent tumor growth in vivo. Cancer Res. 2007;67:10519–27. doi: 10.1158/0008-5472.CAN-07-0079. [PubMed] [Cross Ref]
174. ten Brinke A, van Schijndel G, Visser R, de Gruijl TD, Zwaginga JJ, van Ham SM. Monophosphoryl lipid A plus IFNgamma maturation of dendritic cells induces antigen-specific CD8+ cytotoxic T cells with high cytolytic potential. Cancer Immunol Immunother. 2010;59:1185–95. doi: 10.1007/s00262-010-0843-z. [PubMed] [Cross Ref]
175. Kensil CR, Kammer R. QS-21: a water-soluble triterpene glycoside adjuvant. Expert Opin Investig Drugs. 1998;7:1475–82. doi: 10.1517/13543784.7.9.1475. [PubMed] [Cross Ref]
176. de Bono JS, Dalgleish AG, Carmichael J, Diffley J, Lofts FJ, Fyffe D, et al. Phase I study of ONO-4007, a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide. Clin Cancer Res. 2000;6:397–405. [PubMed]
177. Hennessy EJ, Parker AE, O’Neill LA. Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov. 2010;9:293–307. doi: 10.1038/nrd3203. [PubMed] [Cross Ref]
178. Atanackovic D, Altorki NK, Stockert E, Williamson B, Jungbluth AA, Ritter E, et al. Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J Immunol. 2004;172:3289–96. [PubMed]
179. Hallez S, Simon P, Maudoux F, Doyen J, Noël JC, Beliard A, et al. Phase I/II trial of immunogenicity of a human papillomavirus (HPV) type 16 E7 protein-based vaccine in women with oncogenic HPV-positive cervical intraepithelial neoplasia. Cancer Immunol Immunother. 2004;53:642–50. doi: 10.1007/s00262-004-0501-4. [PubMed] [Cross Ref]
180. Liénard D, Rimoldi D, Marchand M, Dietrich PY, van Baren N, Geldhof C, et al. Ex vivo detectable activation of Melan-A-specific T cells correlating with inflammatory skin reactions in melanoma patients vaccinated with peptides in IFA. Cancer Immun. 2004;4:4. [PubMed]
181. Vantomme V, Dantinne C, Amrani N, Permanne P, Gheysen D, Bruck C, et al. Immunologic analysis of a phase I/II study of vaccination with MAGE-3 protein combined with the AS02B adjuvant in patients with MAGE-3-positive tumors. J Immunother. 2004;27:124–35. doi: 10.1097/00002371-200403000-00006. [PubMed] [Cross Ref]
182. Atanackovic D, Altorki NK, Cao Y, Ritter E, Ferrara CA, Ritter G, et al. Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming. Proc Natl Acad Sci U S A. 2008;105:1650–5. doi: 10.1073/pnas.0707140104. [PubMed] [Cross Ref]
183. Cluff CW. Monophosphoryl lipid A (MPL) as an adjuvant for anti-cancer vaccines: clinical results. Adv Exp Med Biol. 2010;667:111–23. doi: 10.1007/978-1-4419-1603-7_10. [PubMed] [Cross Ref]
184. Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, et al. GlaxoSmithKline HPV Vaccine Study Group Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. 2004;364:1757–65. doi: 10.1016/S0140-6736(04)17398-4. [PubMed] [Cross Ref]
185. Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM, et al. HPV Vaccine Study group Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006;367:1247–55. doi: 10.1016/S0140-6736(06)68439-0. [PubMed] [Cross Ref]
186. Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC, et al. Costa Rican HPV Vaccine Trial Group Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA. 2007;298:743–53. doi: 10.1001/jama.298.7.743. [PubMed] [Cross Ref]
187. Paavonen J, Jenkins D, Bosch FX, Naud P, Salmerón J, Wheeler CM, et al. HPV PATRICIA study group Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007;369:2161–70. doi: 10.1016/S0140-6736(07)60946-5. [PubMed] [Cross Ref]
188. Paavonen J, Naud P, Salmerón J, Wheeler CM, Chow SN, Apter D, et al. HPV PATRICIA Study Group 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. doi: 10.1016/S0140-6736(09)61248-4. [PubMed] [Cross Ref]
189. Romanowski B, de Borba PC, Naud PS, Roteli-Martins CM, De Carvalho NS, Teixeira JC, et al. GlaxoSmithKline Vaccine HPV-007 Study Group Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet. 2009;374:1975–85. doi: 10.1016/S0140-6736(09)61567-1. [PubMed] [Cross Ref]
190. Schwarz TF. Clinical update of the AS04-adjuvanted human papillomavirus-16/18 cervical cancer vaccine, Cervarix. Adv Ther. 2009;26:983–98. doi: 10.1007/s12325-009-0079-5. [PubMed] [Cross Ref]
191. De Carvalho N, Teixeira J, Roteli-Martins CM, Naud P, De Borba P, Zahaf T, et al. Sustained efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine up to 7.3 years in young adult women. Vaccine. 2010;28:6247–55. doi: 10.1016/j.vaccine.2010.07.007. [PubMed] [Cross Ref]
192. Kim YJ, Kim KT, Kim JH, Cha SD, Kim JW, Bae DS, et al. Vaccination with a human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in Korean girls aged 10-14 years. J Korean Med Sci. 2010;25:1197–204. doi: 10.3346/jkms.2010.25.8.1197. [PMC free article] [PubMed] [Cross Ref]
193. Kreimer AR, González P, Katki HA, Porras C, Schiffman M, Rodriguez AC, et al. CVT Vaccine Group Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial. Lancet Oncol. 2011;12:862–70. doi: 10.1016/S1470-2045(11)70213-3. [PMC free article] [PubMed] [Cross Ref]
194. Romanowski B, Schwarz TF, Ferguson LM, Peters K, Dionne M, Schulze K, et al. Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study. Hum Vaccin. 2011;7:1374–86. doi: 10.4161/hv.7.12.18322. [PMC free article] [PubMed] [Cross Ref]
195. Schmeink CE, Bekkers RL, Josefsson A, Richardus JH, Berndtsson Blom K, David MP, et al. Co-administration of human papillomavirus-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine: randomized study in healthy girls. Vaccine. 2011;29:9276–83. doi: 10.1016/j.vaccine.2011.08.037. [PubMed] [Cross Ref]
196. Lehtinen M, Paavonen J, Wheeler CM, Jaisamrarn U, Garland SM, Castellsagué X, et al. HPV PATRICIA Study Group Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012;13:89–99. doi: 10.1016/S1470-2045(11)70286-8. [PubMed] [Cross Ref]
197. Wheeler CM, Castellsagué X, Garland SM, Szarewski A, Paavonen J, Naud P, et al. HPV PATRICIA Study Group Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012;13:100–10. doi: 10.1016/S1470-2045(11)70287-X. [PubMed] [Cross Ref]
198. Kruit WH, Suciu S, Dreno B, Chiarion-Sileni V, Mortier L, Robert C, et al. Immunization with recombinant MAGE-A3 protein combined with adjuvant systems AS15 or AS02B in patients with unresectable and progressive metastatic cutaneous melanoma: A randomized open-label phase II study of the EORTC Melanoma Group (16032- 18031) J Clin Oncol. 2008;26(Suppl):abstr 9065. [PubMed]
199. Louhaed J, Gruselle O, Gaulis S, Coche T, Eggermont AM, Kruit WH, et al. Expression of defined genes identified by pretreatment tumor profiling: Association with clinical responses to the GSK MAGE-A3 immunotherapeutic in metastatic melanoma patients (EORTC 16032-18031) J Clin Oncol. 2008;26(Suppl):abstr 9045. [PubMed]
200. Schiffman M, Wacholder S. Success of HPV vaccination is now a matter of coverage. Lancet Oncol. 2012;13:10–2. doi: 10.1016/S1470-2045(11)70324-2. [PubMed] [Cross Ref]
201. Chen M, Griffith BP, Lucia HL, Hsiung GD. Efficacy of S26308 against guinea pig cytomegalovirus infection. Antimicrob Agents Chemother. 1988;32:678–83. [PMC free article] [PubMed]
202. Harrison CJ, Jenski L, Voychehovski T, Bernstein DI. Modification of immunological responses and clinical disease during topical R-837 treatment of genital HSV-2 infection. Antiviral Res. 1988;10:209–23. doi: 10.1016/0166-3542(88)90032-0. [PubMed] [Cross Ref]
203. Bernstein DI, Harrison CJ. Effects of the immunomodulating agent R837 on acute and latent herpes simplex virus type 2 infections. Antimicrob Agents Chemother. 1989;33:1511–5. [PMC free article] [PubMed]
204. Harrison CJ, Stanberry LR, Bernstein DI. Effects of cytokines and R-837, a cytokine inducer, on UV-irradiation augmented recurrent genital herpes in guinea pigs. Antiviral Res. 1991;15:315–22. doi: 10.1016/0166-3542(91)90012-G. [PubMed] [Cross Ref]
205. Bernstein DI, Miller RL, Harrison CJ. Adjuvant effects of imiquimod on a herpes simplex virus type 2 glycoprotein vaccine in guinea pigs. J Infect Dis. 1993;167:731–5. doi: 10.1093/infdis/167.3.731. [PubMed] [Cross Ref]
206. Bernstein DI, Miller RL, Harrison CJ. Effects of therapy with an immunomodulator (imiquimod, R-837) alone and with acyclovir on genital HSV-2 infection in guinea-pigs when begun after lesion development. Antiviral Res. 1993;20:45–55. doi: 10.1016/0166-3542(93)90058-Q. [PubMed] [Cross Ref]
207. Reiter MJ, Testerman TL, Miller RL, Weeks CE, Tomai MA. Cytokine induction in mice by the immunomodulator imiquimod. J Leukoc Biol. 1994;55:234–40. [PubMed]
208. Gibson SJ, Imbertson LM, Wagner TL, Testerman TL, Reiter MJ, Miller RL, et al. Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609. J Interferon Cytokine Res. 1995;15:537–45. doi: 10.1089/jir.1995.15.537. [PubMed] [Cross Ref]
209. Megyeri K, Au WC, Rosztoczy I, Raj NB, Miller RL, Tomai MA, et al. Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways. Mol Cell Biol. 1995;15:2207–18. [PMC free article] [PubMed]
210. Testerman TL, Gerster JF, Imbertson LM, Reiter MJ, Miller RL, Gibson SJ, et al. Cytokine induction by the immunomodulators imiquimod and S-27609. J Leukoc Biol. 1995;58:365–72. [PubMed]
211. Sidky YA, Borden EC, Weeks CE, Reiter MJ, Hatcher JF, Bryan GT. Inhibition of murine tumor growth by an interferon-inducing imidazoquinolinamine. Cancer Res. 1992;52:3528–33. [PubMed]
212. Witt PL, Ritch PS, Reding D, McAuliffe TL, Westrick L, Grossberg SE, et al. Phase I trial of an oral immunomodulator and interferon inducer in cancer patients. Cancer Res. 1993;53:5176–80. [PubMed]
213. Savage P, Horton V, Moore J, Owens M, Witt P, Gore ME. A phase I clinical trial of imiquimod, an oral interferon inducer, administered daily. Br J Cancer. 1996;74:1482–6. doi: 10.1038/bjc.1996.569. [PMC free article] [PubMed] [Cross Ref]
214. Persaud AN, Shamuelova E, Sherer D, Lou W, Singer G, Cervera C, et al. Clinical effect of imiquimod 5% cream in the treatment of actinic keratosis. J Am Acad Dermatol. 2002;47:553–6. doi: 10.1067/mjd.2002.123492. [PubMed] [Cross Ref]
215. Salasche SJ, Levine N, Morrison L. Cycle therapy of actinic keratoses of the face and scalp with 5% topical imiquimod cream: An open-label trial. J Am Acad Dermatol. 2002;47:571–7. doi: 10.1067/mjd.2002.126257. [PubMed] [Cross Ref]
216. Harrison LI, Skinner SL, Marbury TC, Owens ML, Kurup S, McKane S, et al. Pharmacokinetics and safety of imiquimod 5% cream in the treatment of actinic keratoses of the face, scalp, or hands and arms. Arch Dermatol Res. 2004;296:6–11. doi: 10.1007/s00403-004-0465-4. [PubMed] [Cross Ref]
217. Lebwohl M, Dinehart S, Whiting D, Lee PK, Tawfik N, Jorizzo J, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol. 2004;50:714–21. doi: 10.1016/j.jaad.2003.12.010. [PubMed] [Cross Ref]
218. Stockfleth E, Christophers E, Benninghoff B, Sterry W. Low incidence of new actinic keratoses after topical 5% imiquimod cream treatment: a long-term follow-up study. Arch Dermatol. 2004;140:1542. doi: 10.1001/archderm.140.12.1542-a. [PubMed] [Cross Ref]
219. Szeimies RM, Gerritsen MJ, Gupta G, Ortonne JP, Serresi S, Bichel J, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol. 2004;51:547–55. doi: 10.1016/j.jaad.2004.02.022. [PubMed] [Cross Ref]
220. Korman N, Moy R, Ling M, Matheson R, Smith S, McKane S, et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol. 2005;141:467–73. doi: 10.1001/archderm.141.4.467. [PubMed] [Cross Ref]
221. Beutner KR, Geisse JK, Helman D, Fox TL, Ginkel A, Owens ML. Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol. 1999;41:1002–7. doi: 10.1016/S0190-9622(99)70261-6. [PubMed] [Cross Ref]
222. Marks R, Gebauer K, Shumack S, Amies M, Bryden J, Fox TL, et al. Australasian Multicentre Trial Group Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J Am Acad Dermatol. 2001;44:807–13. doi: 10.1067/mjd.2001.113689. [PubMed] [Cross Ref]
223. Geisse JK, Rich P, Pandya A, Gross K, Andres K, Ginkel A, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study. J Am Acad Dermatol. 2002;47:390–8. doi: 10.1067/mjd.2002.126215. [PubMed] [Cross Ref]
224. Shumack S, Robinson J, Kossard S, Golitz L, Greenway H, Schroeter A, et al. Efficacy of topical 5% imiquimod cream for the treatment of nodular basal cell carcinoma: comparison of dosing regimens. Arch Dermatol. 2002;138:1165–71. doi: 10.1001/archderm.138.9.1165. [PubMed] [Cross Ref]
225. Sterry W, Ruzicka T, Herrera E, Takwale A, Bichel J, Andres K, et al. Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: randomized studies comparing low-frequency dosing with and without occlusion. Br J Dermatol. 2002;147:1227–36. doi: 10.1046/j.1365-2133.2002.05069.x. [PubMed] [Cross Ref]
226. Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. 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;50:722–33. doi: 10.1016/j.jaad.2003.11.066. [PubMed] [Cross Ref]
227. Huber A, Huber JD, Skinner RB, Jr., Kuwahara RT, Haque R, Amonette RA. Topical imiquimod treatment for nodular basal cell carcinomas: an open-label series. Dermatol Surg. 2004;30:429–30. doi: 10.1111/j.1524-4725.2004.30116.x. [PubMed] [Cross Ref]
228. Marks R, Owens M, Walters SA, Australian Multi-Centre Trial Group Efficacy and safety of 5% imiquimod cream in treating patients with multiple superficial basal cell carcinomas. Arch Dermatol. 2004;140:1284–5. doi: 10.1001/archderm.140.10.1284-b. [PubMed] [Cross Ref]
229. Vidal D, Alomar A. Efficacy of imiquimod 5% cream for basal cell carcinoma in transplant patients. Clin Exp Dermatol. 2004;29:237–9. doi: 10.1111/j.1365-2230.2004.01456.x. [PubMed] [Cross Ref]
230. Vidal D, Matías-Guiu X, Alomar A. Open study of the efficacy and mechanism of action of topical imiquimod in basal cell carcinoma. Clin Exp Dermatol. 2004;29:518–25. doi: 10.1111/j.1365-2230.2004.01601.x. [PubMed] [Cross Ref]
231. Beutner KR, Ferenczy A. Therapeutic approaches to genital warts. Am J Med. 1997;102(5A):28–37. doi: 10.1016/S0002-9343(97)00181-2. [PubMed] [Cross Ref]
232. Beutner KR, Spruance SL, Hougham AJ, Fox TL, Owens ML, Douglas JM., Jr. Treatment of genital warts with an immune-response modifier (imiquimod) J Am Acad Dermatol. 1998;38:230–9. doi: 10.1016/S0190-9622(98)70243-9. [PubMed] [Cross Ref]
233. Beutner KR, Tyring SK, Trofatter KF, Jr., Douglas JM, Jr., Spruance S, Owens ML, et al. Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts. Antimicrob Agents Chemother. 1998;42:789–94. [PMC free article] [PubMed]
234. Edwards L. Imiquimod in clinical practice. Australas J Dermatol. 1998;39(Suppl 1):S14–6. [PubMed]
235. Edwards L, Ferenczy A, Eron L, Baker D, Owens ML, Fox TL, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human PapillomaVirus. Arch Dermatol. 1998;134:25–30. doi: 10.1001/archderm.134.1.25. [PubMed] [Cross Ref]
236. Syed TA, Ahmadpour OA, Ahmad SA, Ahmad SH. Management of female genital warts with an analog of imiquimod 2% in cream: a randomized, double-blind, placebo-controlled study. J Dermatol. 1998;25:429–33. [PubMed]
237. Tyring SK, Arany I, Stanley MA, Tomai MA, Miller RL, Smith MH, et al. A randomized, controlled, molecular study of condylomata acuminata clearance during treatment with imiquimod. J Infect Dis. 1998;178:551–5. doi: 10.1086/517472. [PubMed] [Cross Ref]
238. Gilson RJ, Shupack JL, Friedman-Kien AE, Conant MA, Weber JN, Nayagam AT, et al. Imiquimod Study Group A randomized, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIV-infected patients. AIDS. 1999;13:2397–404. doi: 10.1097/00002030-199912030-00011. [PubMed] [Cross Ref]
239. Hengge UR, Esser S, Schultewolter T, Behrendt C, Meyer T, Stockfleth E, et al. Self-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum. Br J Dermatol. 2000;143:1026–31. doi: 10.1046/j.1365-2133.2000.03777.x. [PubMed] [Cross Ref]
240. Syed TA, Hadi SM, Qureshi ZA, Ali SM, Kwah MS. Treatment of external genital warts in men with imiquimod 2% in cream. A placebo-controlled, double-blind study. J Infect. 2000;41:148–51. doi: 10.1053/jinf.2000.0709. [PubMed] [Cross Ref]
241. Reizis B, Colonna M, Trinchieri G, Barrat F, Gilliet M. Plasmacytoid dendritic cells: one-trick ponies or workhorses of the immune system? Nat Rev Immunol. 2011;11:558–65. doi: 10.1038/nri3027. [PubMed] [Cross Ref]
242. Schön MP, Schön M, Klotz KN. The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion. J Invest Dermatol. 2006;126:1338–47. doi: 10.1038/sj.jid.5700286. [PubMed] [Cross Ref]
243. Drobits B, Holcmann M, Amberg N, Swiecki M, Grundtner R, Hammer M, et al. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest. 2012;122:575–85. doi: 10.1172/JCI61034. [PMC free article] [PubMed] [Cross Ref]
244. Welsh O, Olazarán Z, Gómez M, Salas J, Berman B. Treatment of infantile hemangiomas with short-term application of imiquimod 5% cream. J Am Acad Dermatol. 2004;51:639–42. doi: 10.1016/j.jaad.2004.04.022. [PubMed] [Cross Ref]
245. Ho NT, Lansang P, Pope E. Topical imiquimod in the treatment of infantile hemangiomas: a retrospective study. J Am Acad Dermatol. 2007;56:63–8. doi: 10.1016/j.jaad.2006.06.011. [PubMed] [Cross Ref]
246. Barry RB, Hughes BR, Cook LJ. Involution of infantile haemangiomas after imiquimod 5% cream. Clin Exp Dermatol. 2008;33:446–9. doi: 10.1111/j.1365-2230.2007.02676.x. [PubMed] [Cross Ref]
247. Senchak AJ, Dann M, Cable B, Bessinger G. Successful treatment of cutaneous hemangioma of infancy with topical imiquimod 5%: a report of 3 cases. Ear Nose Throat J. 2010;89:E21–5. [PubMed]
248. Jiang C, Hu X, Ma G, Chen D, Jin Y, Chen H, et al. A prospective self-controlled phase II study of imiquimod 5% cream in the treatment of infantile hemangioma. Pediatr Dermatol. 2011;28:259–66. doi: 10.1111/j.1525-1470.2011.01520.x. [PubMed] [Cross Ref]
249. Ahmed I, Berth-Jones J. Imiquimod: a novel treatment for lentigo maligna. Br J Dermatol. 2000;143:843–5. doi: 10.1046/j.1365-2133.2000.03787.x. [PubMed] [Cross Ref]
250. Naylor MF, Crowson N, Kuwahara R, Teague K, Garcia C, Mackinnis C, et al. Treatment of lentigo maligna with topical imiquimod. Br J Dermatol. 2003;149(Suppl 66):66–70. doi: 10.1046/j.0366-077X.2003.05637.x. [PubMed] [Cross Ref]
251. Fleming CJ, Bryden AM, Evans A, Dawe RS, Ibbotson SH. A pilot study of treatment of lentigo maligna with 5% imiquimod cream. Br J Dermatol. 2004;151:485–8. doi: 10.1111/j.1365-2133.2004.05983.x. [PubMed] [Cross Ref]
252. Wolf IH, Cerroni L, Kodama K, Kerl H. Treatment of lentigo maligna (melanoma in situ) with the immune response modifier imiquimod. Arch Dermatol. 2005;141:510–4. doi: 10.1001/archderm.141.4.510. [PubMed] [Cross Ref]
253. Ray CM, Kluk M, Grin CM, Grant-Kels JM. Successful treatment of malignant melanoma in situ with topical 5% imiquimod cream. Int J Dermatol. 2005;44:428–34. doi: 10.1111/j.1365-4632.2005.02582.x. [PubMed] [Cross Ref]
254. Bassukas ID, Gamvroulia C, Zioga A, Nomikos K, Fotika C. Cryosurgery during topical imiquimod: a successful combination modality for lentigo maligna. Int J Dermatol. 2008;47:519–21. doi: 10.1111/j.1365-4632.2008.03562.x. [PubMed] [Cross Ref]
255. Dusza SW, Delgado R, Busam KJ, Marghoob AA, Halpern AC. Treatment of dysplastic nevi with 5% imiquimod cream, a pilot study. J Drugs Dermatol. 2006;5:56–62. [PubMed]
256. Cotter MA, McKenna JK, Bowen GM. Treatment of lentigo maligna with imiquimod before staged excision. Dermatol Surg. 2008;34:147–51. doi: 10.1111/j.1524-4725.2007.34031.x. [PubMed] [Cross Ref]
257. Ly L, Kelly JW, O’Keefe R, Sutton T, Dowling JP, Swain S, et al. Efficacy of imiquimod cream, 5%, for lentigo maligna after complete excision: a study of 43 patients. Arch Dermatol. 2011;147:1191–5. doi: 10.1001/archdermatol.2011.260. [PubMed] [Cross Ref]
258. Hyde MA, Hadley ML, Tristani-Firouzi P, Goldgar D, Bowen GM. A randomized trial of the off-label use of imiquimod, 5%, cream with vs without tazarotene, 0.1%, gel for the treatment of lentigo maligna, followed by conservative staged excisions. Arch Dermatol. 2012 [PubMed]
259. Mackenzie-Wood A, Kossard S, de Launey J, Wilkinson B, Owens ML. Imiquimod 5% cream in the treatment of Bowen’s disease. J Am Acad Dermatol. 2001;44:462–70. doi: 10.1067/mjd.2001.111335. [PubMed] [Cross Ref]
260. Smith KJ, Germain M, Skelton H. Bowen’s disease (squamous cell carcinoma in situ) in immunosuppressed patients treated with imiquimod 5% cream and a cox inhibitor, sulindac: potential applications for this combination of immunotherapy. Dermatol Surg. 2001;27:143–6. doi: 10.1046/j.1524-4725.2001.00199.x. [PubMed] [Cross Ref]
261. Chen K, Shumack S. Treatment of Bowen’s disease using a cycle regimen of imiquimod 5% cream. Clin Exp Dermatol. 2003;28(Suppl 1):10–2. doi: 10.1046/j.1365-2230.28.s1.4.x. [PubMed] [Cross Ref]
262. Ondo AL, Mings SM, Pestak RM, Shanler SD. Topical combination therapy for cutaneous squamous cell carcinoma in situ with 5-fluorouracil cream and imiquimod cream in patients who have failed topical monotherapy. J Am Acad Dermatol. 2006;55:1092–4. doi: 10.1016/j.jaad.2006.06.031. [PubMed] [Cross Ref]
263. Peris K, Micantonio T, Fargnoli MC, Lozzi GP, Chimenti S. Imiquimod 5% cream in the treatment of Bowen’s disease and invasive squamous cell carcinoma. J Am Acad Dermatol. 2006;55:324–7. doi: 10.1016/j.jaad.2006.04.004. [PubMed] [Cross Ref]
264. Kaushal S, Merideth M, Kopparthy P, Pulanic TK, Stratton P. Treatment of multifocal Bowen’s disease in immunocompromised women with surgery and topical imiquimod. Obstet Gynecol. 2012;119:442–4. doi: 10.1097/AOG.0b013e318236f1a0. [PMC free article] [PubMed] [Cross Ref]
265. Dendorfer M, Oppel T, Wollenberg A, Prinz JC. Topical treatment with imiquimod may induce regression of facial keratoacanthoma. Eur J Dermatol. 2003;13:80–2. [PubMed]
266. Bhatia N. Imiquimod as a possible treatment for keratoacanthoma. J Drugs Dermatol. 2004;3:71–4. [PubMed]
267. Di Lernia V, Ricci C, Albertini G. Spontaneous regression of keratoacanthoma can be promoted by topical treatment with imiquimod cream. J Eur Acad Dermatol Venereol. 2004;18:626–9. doi: 10.1111/j.1468-3083.2004.01025.x. [PubMed] [Cross Ref]
268. Muzio G, Massone C, Rebora A. Treatment of non-genital warts with topical imiquimod 5% cream. Eur J Dermatol. 2002;12:347–9. [PubMed]
269. Hagman JH, Bianchi L, Marulli GC, Soda R, Chimenti S. Successful treatment of multiple filiform facial warts with imiquimod 5% cream in a patient infected by human immunodeficiency virus. Clin Exp Dermatol. 2003;28:260–1. doi: 10.1046/j.1365-2230.2003.01213.x. [PubMed] [Cross Ref]
270. Caversaccio M, Aebi S. Medical treatment of nasal squamous papilloma with imiquimod cream. J Laryngol Otol. 2003;117:720–2. doi: 10.1258/002221503322334576. [PubMed] [Cross Ref]
271. Micali G, Dall’Oglio F, Nasca MR. An open label evaluation of the efficacy of imiquimod 5% cream in the treatment of recalcitrant subungual and periungual cutaneous warts. J Dermatolog Treat. 2003;14:233–6. doi: 10.1080/09546630310016763. [PubMed] [Cross Ref]
272. Fernández-Casado A, Pujol RM, Amat M, Gallardo F. Successful treatment of intranasal papillomata with imiquimod cream in a human immunodeficiency virus positive patient. J Laryngol Otol. 2009;123:240–2. doi: 10.1017/S0022215108002570. [PubMed] [Cross Ref]
273. Weisberg NK, Varghese M. Therapeutic response of a brother and sister with xeroderma pigmentosum to imiquimod 5% cream. Dermatol Surg. 2002;28:518–23. doi: 10.1046/j.1524-4725.2002.01196.x. [PubMed] [Cross Ref]
274. Diaz-Arrastia C, Arany I, Robazetti SC, Dinh TV, Gatalica Z, Tyring SK, et al. Clinical and molecular responses in high-grade intraepithelial neoplasia treated with topical imiquimod 5% Clin Cancer Res. 2001;7:3031–3. [PubMed]
275. Todd RW, Etherington IJ, Luesley DM. The effects of 5% imiquimod cream on high-grade vulval intraepithelial neoplasia. Gynecol Oncol. 2002;85:67–70. doi: 10.1006/gyno.2001.6539. [PubMed] [Cross Ref]
276. Todd RW, Steele JC, Etherington I, Luesley DM. Detection of CD8+ T cell responses to human papillomavirus type 16 antigens in women using imiquimod as a treatment for high-grade vulval intraepithelial neoplasia. Gynecol Oncol. 2004;92:167–74. doi: 10.1016/j.ygyno.2003.09.013. [PubMed] [Cross Ref]
277. Wendling J, Saiag P, Berville-Levy S, Bourgault-Villada I, Clerici T, Moyal-Barracco M. Treatment of undifferentiated vulvar intraepithelial neoplasia with 5% imiquimod cream: a prospective study of 12 cases. Arch Dermatol. 2004;140:1220–4. doi: 10.1001/archderm.140.10.1220. [PubMed] [Cross Ref]
278. Le T, Hicks W, Menard C, Hopkins L, Fung MF. Preliminary results of 5% imiquimod cream in the primary treatment of vulva intraepithelial neoplasia grade 2/3. Am J Obstet Gynecol. 2006;194:377–80. doi: 10.1016/j.ajog.2005.08.022. [PubMed] [Cross Ref]
279. Mathiesen O, Buus SK, Cramers M. Topical imiquimod can reverse vulvar intraepithelial neoplasia: a randomised, double-blinded study. Gynecol Oncol. 2007;107:219–22. doi: 10.1016/j.ygyno.2007.06.003. [PubMed] [Cross Ref]
280. van Seters M, van Beurden M, ten Kate FJ, Beckmann I, Ewing PC, Eijkemans MJ, et al. Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Engl J Med. 2008;358:1465–73. doi: 10.1056/NEJMoa072685. [PubMed] [Cross Ref]
281. Daayana S, Elkord E, Winters U, Pawlita M, Roden R, Stern PL, et al. Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia. Br J Cancer. 2010;102:1129–36. doi: 10.1038/sj.bjc.6605611. [PMC free article] [PubMed] [Cross Ref]
282. Fox PA, Nathan M, Francis N, Singh N, Weir J, Dixon G, et al. A double-blind, randomized controlled trial of the use of imiquimod cream for the treatment of anal canal high-grade anal intraepithelial neoplasia in HIV-positive MSM on HAART, with long-term follow-up data including the use of open-label imiquimod. AIDS. 2010;24:2331–5. [PubMed]
283. Terlou A, van Seters M, Ewing PC, Aaronson NK, Gundy CM, Heijmans-Antonissen C, et al. Treatment of vulvar intraepithelial neoplasia with topical imiquimod: seven years median follow-up of a randomized clinical trial. Gynecol Oncol. 2011;121:157–62. doi: 10.1016/j.ygyno.2010.12.340. [PubMed] [Cross Ref]
284. Pachman DR, Barton DL, Clayton AC, McGovern RM, Jefferies JA, Novotny PJ, et al. Randomized clinical trial of imiquimod: an adjunct to treating cervical dysplasia. Am J Obstet Gynecol. 2012;206:42–, e1-7. doi: 10.1016/j.ajog.2011.06.105. [PMC free article] [PubMed] [Cross Ref]
285. Cohen PR, Schulze KE, Tschen JA, Hetherington GW, Nelson BR. Treatment of extramammary Paget disease with topical imiquimod cream: case report and literature review. South Med J. 2006;99:396–402. doi: 10.1097/01.smj.0000209223.68763.b1. [PubMed] [Cross Ref]
286. Geisler JP, Manahan KJ. Imiquimod in vulvar Paget’s disease: a case report. J Reprod Med. 2008;53:811–2. [PubMed]
287. Hatch KD, Davis JR. Complete resolution of Paget disease of the vulva with imiquimod cream. J Low Genit Tract Dis. 2008;12:90–4. doi: 10.1097/LGT.0b013e31815a58a5. [PubMed] [Cross Ref]
288. Sendagorta E, Herranz P, Feito M, Ramírez P, Floristán U, Feltes R, et al. Successful treatment of three cases of primary extramammary Paget’s disease of the vulva with Imiquimod--proposal of a therapeutic schedule. J Eur Acad Dermatol Venereol. 2010;24:490–2. doi: 10.1111/j.1468-3083.2009.03451.x. [PubMed] [Cross Ref]
289. Baiocchi G, Begnami MD, Fukazawa EM, Surima WS, Badiglian-Filho L, Costa FD, et al. Conservative management of extramammary paget disease with imiquimod. J Low Genit Tract Dis. 2012;16:59–63. doi: 10.1097/LGT.0b013e31822d2484. [PubMed] [Cross Ref]
290. Babel N, Eibl N, Ulrich C, Bold G, Sefrin A, Hammer MH, et al. Development of Kaposi’s sarcoma under sirolimus-based immunosuppression and successful treatment with imiquimod. Transpl Infect Dis. 2008;10:59–62. doi: 10.1111/j.1399-3062.2007.00239.x. [PubMed] [Cross Ref]
291. Célestin Schartz NE, Chevret S, Paz C, Kerob D, Verola O, Morel P, et al. Imiquimod 5% cream for treatment of HIV-negative Kaposi’s sarcoma skin lesions: A phase I to II, open-label trial in 17 patients. J Am Acad Dermatol. 2008;58:585–91. doi: 10.1016/j.jaad.2007.11.005. [PubMed] [Cross Ref]
292. Prinz Vavricka BM, Hofbauer GF, Dummer R, French LE, Kempf W. Topical treatment of cutaneous Kaposi sarcoma with imiquimod 5% in renal-transplant recipients: a clinicopathological observation. Clin Exp Dermatol. 2012 doi: 10.1111/j.1365-2230.2011.04278.x. [PubMed] [Cross Ref]
293. Seo SH, Kim GW, Sung HW. Imiquimod as an adjuvant treatment measure for desmoplastic trichoepithelioma. Ann Dermatol. 2011;23:229–31. doi: 10.5021/ad.2011.23.2.229. [PMC free article] [PubMed] [Cross Ref]
294. Didona B, Benucci R, Amerio P, Canzona F, Rienzo O, Cavalieri R. Primary cutaneous CD30+ T-cell lymphoma responsive to topical imiquimod (Aldara) Br J Dermatol. 2004;150:1198–201. doi: 10.1111/j.1365-2133.2004.05993.x. [PubMed] [Cross Ref]
295. Coors EA, Schuler G, Von Den Driesch P. Topical imiquimod as treatment for different kinds of cutaneous lymphoma. Eur J Dermatol. 2006;16:391–3. [PubMed]
296. Huber MA, Staib G, Pehamberger H, Scharffetter-Kochanek K. Management of refractory early-stage cutaneous T-cell lymphoma. Am J Clin Dermatol. 2006;7:155–69. doi: 10.2165/00128071-200607030-00002. [PubMed] [Cross Ref]
297. Bong AB, Bonnekoh B, Franke I, Schön MP, Ulrich J, Gollnick H. Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma. Dermatology. 2002;205:135–8. doi: 10.1159/000063904. [PubMed] [Cross Ref]
298. Green DS, Bodman-Smith MD, Dalgleish AG, Fischer MD. Phase I/II study of topical imiquimod and intralesional interleukin-2 in the treatment of accessible metastases in malignant melanoma. Br J Dermatol. 2007;156:337–45. doi: 10.1111/j.1365-2133.2006.07664.x. [PubMed] [Cross Ref]
299. Green DS, Dalgleish AG, Belonwu N, Fischer MD, Bodman-Smith MD. Topical imiquimod and intralesional interleukin-2 increase activated lymphocytes and restore the Th1/Th2 balance in patients with metastatic melanoma. Br J Dermatol. 2008;159:606–14. doi: 10.1111/j.1365-2133.2008.08709.x. [PubMed] [Cross Ref]
300. Asakura M, Miura H. Imiquimod 5% cream for the treatment of nasal lesion of metastatic renal cell carcinoma. Dermatol Ther. 2011;24:375–7. doi: 10.1111/j.1529-8019.2011.01423.x. [PubMed] [Cross Ref]
301. Garcia MS, Ono Y, Martinez SR, Chen SL, Goodarzi H, Phan T, et al. Complete regression of subcutaneous and cutaneous metastatic melanoma with high-dose intralesional interleukin 2 in combination with topical imiquimod and retinoid cream. Melanoma Res. 2011;21:235–43. doi: 10.1097/CMR.0b013e328345e95e. [PubMed] [Cross Ref]
302. Adams S, O’Neill DW, Nonaka D, Hardin E, Chiriboga L, Siu K, et al. Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant. J Immunol. 2008;181:776–84. [PMC free article] [PubMed]
303. Feyerabend S, Stevanovic S, Gouttefangeas C, Wernet D, Hennenlotter J, Bedke J, et al. Novel multi-peptide vaccination in Hla-A2+ hormone sensitive patients with biochemical relapse of prostate cancer. Prostate. 2009;69:917–27. doi: 10.1002/pros.20941. [PubMed] [Cross Ref]
304. Hibbitts STA-CIN. TA-CIN, a vaccine incorporating a recombinant HPV fusion protein (HPV16 L2E6E7) for the potential treatment of HPV16-associated genital diseases. Curr Opin Mol Ther. 2010;12:598–606. [PubMed]
305. Smith BD, Kasamon YL, Kowalski J, Gocke C, Murphy K, Miller CB, et al. K562/GM-CSF immunotherapy reduces tumor burden in chronic myeloid leukemia patients with residual disease on imatinib mesylate. Clin Cancer Res. 2010;16:338–47. doi: 10.1158/1078-0432.CCR-09-2046. [PMC free article] [PubMed] [Cross Ref]
306. Del Rosso JQ, Sofen H, Leshin B, Meng T, Kulp J, Levy S. Safety and efficacy of multiple 16-week courses of topical imiquimod for the treatment of large areas of skin involved with actinic keratoses. J Clin Aesthet Dermatol. 2009;2:20–8. [PMC free article] [PubMed]
307. Hanke CW, Beer KR, Stockfleth E, Wu J, Rosen T, Levy S. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles. J Am Acad Dermatol. 2010;62:573–81. doi: 10.1016/j.jaad.2009.06.020. [PubMed] [Cross Ref]
308. Ozolins M, Williams HC, Armstrong SJ, Bath-Hextall FJ. The SINS trial: a randomised controlled trial of excisional surgery versus imiquimod 5% cream for nodular and superficial basal cell carcinoma. Trials. 2010;11:42. doi: 10.1186/1745-6215-11-42. [PMC free article] [PubMed] [Cross Ref]
309. Quirk C, Gebauer K, De’Ambrosis B, Slade HB, Meng TC. Sustained clearance of superficial basal cell carcinomas treated with imiquimod cream 5%: results of a prospective 5-year study. Cutis. 2010;85:318–24. [PubMed]
310. Swanson N, Abramovits W, Berman B, Kulp J, Rigel DS, Levy S. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol. 2010;62:582–90. doi: 10.1016/j.jaad.2009.07.004. [PubMed] [Cross Ref]

Articles from Oncoimmunology are provided here courtesy of Taylor & Francis