Tumor-Selective Induction of Apoptosis and the Small-Molecule Immune Response Modifier Imiquimod

Schön, Margarete; Bong, Anne B.; Drewniok, Claudia; Herz, Jeannine; Geilen, Christoph C.; Reifenberger, Julia; Benninghoff, Bernd; Slade, Herbert B.; Gollnick, Harald; Schön, Michael P.

doi:10.1093/jnci/djg016

Cited by 241 publications

(231 citation statements)

References 49 publications

Supporting

Mentioning

213

Contrasting

Unclassified

Order By: Relevance

“…TLR7 agonists can eradicate tumor cells both in cell culture and in vivo (Schon et al 2003). Imiquimod, which is used clinically to treat anogenital human papillomavirus (HPV) infections, also demonstrates anti-tumor activity against numerous benign and malignant human skin neoplasms.…”

Section: Toll-like Receptor Agonistsmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

View full text Add to dashboard Cite

Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

show abstract

Section: Toll-like Receptor Agonistsmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

View full text Add to dashboard Cite

show abstract

“…It was shown in vitro that imiquimod can directly induce apoptosis of tumor cells using several skin and bladder cancer cells lines, as well as tumor tissue cultures [97][98][99][100][101]. For the skin cancer cell lines, it was demonstrated that this proapoptotic activity was independent of membrane-bound death receptors.…”

Section: Tumor Cellsmentioning

confidence: 99%

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

et al. 2008

View full text Add to dashboard Cite

After completing this course, the reader should be able to:1. Describe the subtypes of Toll-like receptor 7 and 8 agonists and their effect on the different components of the antitumor immune response.2. Argue why they are used as stand-alone immunotherapeutic agents.3. Evaluate their potential to improve current approaches of active and passive immunotherapy.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACT

show abstract

“…13,[17][18][19][20] Moreover, TLR7/8 ligands have been shown to directly affect some tumor cells by inducing apoptosis and sensitizing tumor cells to killing mediated by CTLs and chemotherapeutic agents. 21,22 However, these effects depend on the kinds of TLR7/8 agonists used and the type of tumor being treated.…”

Section: Discussionmentioning

confidence: 99%

The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice

Zhang

et al. 2010

Cell Mol Immunol

100

View full text Add to dashboard Cite

Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors that are essential for host immune responses. TLR ligands represent a promising class of immunotherapeutics or vaccine adjuvants with the potential to generate an effective antitumor immune response. The TLR7/8 agonists have aroused interest because they not only activate antigen-presenting cells but also promote activation of T and natural killer (NK) cells. However, the exact mechanism by which stimulation of these TLRs promotes immune responses remains unclear, and different TLR7/8 agonists have been found to induce different responses. In this study, we demonstrate that both gardiquimod and imiquimod promote the proliferation of murine splenocytes, stimulate the activation of splenic T, NK and natural killer T (NKT) cells, increase the cytolytic activity of splenocytes against B16 and MCA-38 tumor cell lines, and enhance the expression of costimulatory molecules and IL-12 by macrophages and bone marrow-derived dendritic cells (DCs). In a murine model, both agonists improved the antitumor effects of tumor lysate-loaded DCs, resulting in delayed growth of subcutaneous B16 melanoma tumors and suppression of pulmonary metastasis. Further, we found that gardiquimod demonstrated more potent antitumor activity than imiquimod. These results suggest that TLR7/8 agonists may serve as potent innate and adaptive immune response modifiers in tumor therapy. More importantly, they can be used as vaccine adjuvants to potentiate the efficiency of DC-based tumor immunotherapy.

show abstract

Tumor-Selective Induction of Apoptosis and the Small-Molecule Immune Response Modifier Imiquimod

Abstract: Imiquimod has the potential to induce apoptosis in skin cancer cells, possibly by circumventing mechanisms developed by malignant tumors to resist apoptotic signals.

Cited by 241 publications

References 49 publications

Malignant melanoma: genetics and therapeutics in the genomic era

Malignant melanoma: genetics and therapeutics in the genomic era

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice

Contact Info

Product

Resources

About