Phase II Trial of a Toll-Like Receptor 9–Activating Oligonucleotide in Patients With Metastatic Melanoma

Pashenkov, Мikhail; Goess, G.; Wagner, Christine; Hörmann, Markus; Jandl, Tamara; Moser, Anna; Britten, Cedrik M.; Smolle, Josef; Koller, Sílvia Helena; Mauch, Cornelia; Tantcheva‐Poór, Iliana; Grabbe, Stephan; Loquai, Carmen; Eßer, Stefan; Franckson, Tom; Schneeberger, Achim; Haarmann, Cäcilia; Krieg, Arthur Μ.; Stingl, Georg; Wagner, Stephan N.

doi:10.1200/jco.2006.07.9129

Cited by 198 publications

(111 citation statements)

References 28 publications

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“…Most likely, pDCs are not properly activated on uptake of tumor-derived substances because of the lack of danger signals (12). Recent studies have shown that in vivo TLR triggering with TLR-Ls, such as CpG, induced pDC activation, resulting in antitumor immunity and partial tumor regression (42)(43)(44). Furthermore, activated human pDCs pulsed with a tumor Ag primed IFN-g secreting Ag-specific CTLs (45).…”

Section: Discussionmentioning

confidence: 99%

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

Tel

Lambeck

Cruz

et al. 2010

The Journal of Immunology

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Section: Discussionmentioning

confidence: 99%

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

Tel

Lambeck

Cruz

et al. 2010

The Journal of Immunology

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“…Furthermore, both myeloid and pDCs were activated (Molenkamp et al, 2007), indicating that PF-3512676 clearly has immunomodulatory activity. In a different phase II study in patients (N ¼ 20) with metastatic melanoma treated with s.c. PF-3512676, two (10%) patients had a PR and three (15%) patients had stable disease (SD) (Pashenkov et al, 2006). These patients with possible clinical benefit from PF-3512676 therapy tended to have increased levels of NK cell activity compared to the patients with progressive disease.…”

Section: Skin Cancersmentioning

confidence: 99%

Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

2008

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Although still early in clinical development, agonists of Tolllike receptor 9 (TLR9) have demonstrated potential for the treatment of cancer. TLR9 agonists directly induce activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. Preclinical and early clinical data support the use of TLR9 agonists in patients with solid tumors and hematologic malignancies. In preclinical studies, TLR9 agonists have shown activity not only as monotherapy, but also in combination with multiple other therapies, including vaccines, antibodies, cellular therapies, other immunotherapies, antiangiogenic agents, radiotherapy, cryotherapy and some chemotherapies. Phase I and II clinical trials have indicated that these agents have antitumor activity as single agents and enhance the development of antitumor T-cell responses when used as therapeutic vaccine adjuvants. The activity and safety of these novel anticancer agents are being explored in a wide range of tumor types as part of a variety of therapeutic strategies with the goal of harnessing the immune response to fight cancer.

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“…Three patients experienced stabilization of the disease, although all presented with progression at week 24. The markers of immunological activation showed increased DC activation with elevated levels of type I IFN, and induction of NK cell cytotoxicity [126]. A phase I/II trial was designed to assess the safety and efficacy of the Toll-like receptor 2/6 agonist MALP-2 in combination with gemcitabine in patients with incompletely resectable pancreatic carcinoma.…”

Section: Tlrs In Clinical Trials Against Human Malignanciesmentioning

confidence: 99%

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Wolska

Lech‐Marańda

Robak

2009

Cellular and Molecular Biology Letters

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Toll-like receptors (TLRs) have been described as major components of the innate immune system, recognizing the conserved molecular structures found in the large groups of pathogens called pathogen-associated molecular patterns (PAMPs). TLR expression is ubiquitous, from epithelial to immunocompetent cells. TLR ligation triggers several adapter proteins and downstream kinases, leading to the induction of key pro-inflammatory mediators but also anti-inflammatory and anti-tumor cytokines. The result of this activation goes beyond innate immunity to shape the adaptive responses against pathogens and tumor cells, and maintains host homeostasis via cell debris utilization. TLRs have already become potent targets in infectious disease treatment and vaccine therapy and in neoplastic disease treatment, due to their ability to enhance antigen presentation. However, some studies show the dual effect of TLR stimulation on malignant cells: they can be proapoptotic or promote survival under different conditions. It is therefore crucial to design further studies assessing the biology of these receptors in normal and transformed cells. The established role of TLRs in human disease therapy is based on TLR7 and TLR4 agonists, respectively for the novel treatment of some types of skin cancer and for the anti-hepatitis B virus vaccine. Some clinical trials involving TLR agonists as potent enhancers of the anti-tumor response in solid tumors have begun.

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Phase II Trial of a Toll-Like Receptor 9–Activating Oligonucleotide in Patients With Metastatic Melanoma

Cited by 198 publications

References 28 publications

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

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