Intravesical Immunomodulatory Imiquimod Enhances Bacillus Calmette-Guérin Downregulation of Nonmuscle-invasive Bladder Cancer

Camargo, Juliana Alves de; Passos, Gabriela Reolon; Ferrari, Karen L.; Billis, Athanase; Saad, Mário José Abdalla; Reis, Leonardo Oliveira

doi:10.1016/j.clgc.2017.10.019

Cited by 25 publications

(19 citation statements)

References 23 publications

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“…R848 reduces PDAC tumor burden and alters the tumor microenvironment. TLR agonists are employed for a variety of malignancies to induce anti-tumor immunity 9,[18][19][20] , which we hypothesized could occur in the context of PDAC. Further, we hypothesized this response would depend on neoplastic epithelial cell factors regulating immune cell recruitment and neoantigen quality, both of which are necessary components of CD8 + T-cellmediated anti-tumor immunity.…”

Section: Resultsmentioning

confidence: 99%

“…In some cases, TLR7 stimulation of T cells alone is sufficient for anti-tumor responses: nanoparticle delivery of R848 to CD8 + T cells results in increased anti-tumor immunity and prolonged survival in a murine colorectal cancer model 20 . TLR7 agonists also demonstrate benefit in combination with doxorubicin in Tcell lymphoma 19 , with vaccination in bladder cancer 18 , and with radiotherapy in gastrointestinal tumors 45 .…”

Section: Discussionmentioning

confidence: 99%

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The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer

et al. 2019

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A priority in cancer research is to innovate therapies that are not only effective against tumor progression but also address comorbidities such as cachexia that limit quality and quantity of life. We demonstrate that TLR7/8 agonist R848 induces anti-tumor responses and attenuates cachexia in murine models of pancreatic ductal adenocarcinoma (PDAC). In vivo, tumors from two of three cell lines were R848-sensitive, resulting in smaller tumor mass, increased immune complexity, increased CD8 + T-cell infiltration and activity, and decreased Treg frequency. R848-treated mice demonstrated improvements in behavioral and molecular cachexia manifestations, resulting in a near-doubling of survival duration. Knockout mouse studies revealed that stromal, not neoplastic, TLR7 is requisite for R848-mediated responses. In patient samples, we found Tlr7 is ubiquitously expressed in stroma across all stages of pancreatic neoplasia, but epithelial Tlr7 expression is relatively uncommon. These studies indicate immune-enhancing approaches including R848 may be useful in PDAC and cancerassociated cachexia.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer

et al. 2019

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“…Despite known limitations, such as using exclusively female mice or the variability of tumor cells implanted into the bladder 27 , which could also lead to variability in the immune response generated by mycobacteria treatment, the orthotopic murine BC model is a solid, well-recognized model that provides consistent results to evaluate the immune response triggered by potential new antitumor therapies, such as IL-12 plus chitosan 28 , or the synergy of different treatments 29 . However, one drawback of our study is the low number of mice that survived until day 29 after tumor induction in the non-treated group of animals due to the high mortality rates in this group.…”

Section: Discussionmentioning

confidence: 99%

Intravesical Mycobacterium brumae triggers both local and systemic immunotherapeutic responses against bladder cancer in mice

Noguera-Ortega

Rabanal

Gómez-Mora

et al. 2018

Sci Rep

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The standard treatment for high-risk non-muscle invasive bladder cancer (BC) is the intravesical administration of live Mycobacterium bovis BCG. Previous studies suggest improving this therapy by implementing non-pathogenic mycobacteria, such as Mycobacterium brumae, and/or different vehicles for mycobacteria delivery, such as an olive oil (OO)-in-water emulsion. While it has been established that BCG treatment activates the immune system, the immune effects of altering the mycobacterium and/or the preparation remain unknown. In an orthotopic murine BC model, local immune responses were assessed by measuring immune cells into the bladder and macromolecules in the urine by flow cytometry and multiplexing, respectively. Systemic immune responses were analyzed by quantifying sera anti-mycobacteria antibody levels and recall responses of ex vivo splenocytes cultured with mycobacteria antigens. In both BCG- and M. brumae-treated mice, T, NK, and NKT cell infiltration in the bladder was significantly increased. Notably, T cell infiltration was enhanced in OO-in-water emulsified mycobacteria-treated mice, and urine IL-6 and KC concentrations were elevated. Furthermore, mycobacteria treatment augmented IgG antibody production and splenocyte proliferation, especially in mice receiving OO-in-water emulsified mycobacteria. Our data demonstrate that intravesical mycobacterial treatment triggers local and systemic immune responses, which are most significant when OO-in-water emulsified mycobacteria are used.

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“…Moreover, topical imiquimod might be considered as adjuvant for vaccination [191,196]. Imiquimod was also tested as potent agent against prostate [197], bladder [107,198,199], breast [200e203] cancers and squamous carcinoma [204,205].…”

Section: Pyrimidine and Purine Base Derivativesmentioning

confidence: 99%

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

Patinote

Karroum

Moarbess

et al. 2020

European Journal of Medicinal Chemistry

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a b s t r a c tThe discovery of the TLRs family and more precisely its functions opened a variety of gates to modulate immunological host responses. TLRs 7/8 are located in the endosomal compartment and activate a specific signaling pathway in a MyD88-dependant manner. According to their involvement into various autoimmune, inflammatory and malignant diseases, researchers have designed diverse TLRs 7/8 ligands able to boost or block the inherent signal transduction. These modulators are often small synthetic compounds and most act as agonists and to a much lesser extent as antagonists. Some of them have reached preclinical and clinical trials, and only one has been approved by the FDA and EMA, imiquimod. The key to the success of these modulators probably lies in their combination with other therapies as recently demonstrated. We gather in this review more than 360 scientific publications, reviews and patents, relating the extensive work carried out by researchers on the design of TLRs 7/8 modulators, which are classified firstly by their biological activities (agonist or antagonist) and then by their chemical structures, which total syntheses are not discussed here. This review also reports about 90 clinical cases, thereby showing the biological interest of these modulators in multiple pathologies.

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Intravesical Immunomodulatory Imiquimod Enhances Bacillus Calmette-Guérin Downregulation of Nonmuscle-invasive Bladder Cancer

Cited by 25 publications

References 23 publications

The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer

The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer

Intravesical Mycobacterium brumae triggers both local and systemic immunotherapeutic responses against bladder cancer in mice

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

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