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

Mikhail Pashenkov, Gerda Goëss, Christine Wagner, Markus Hörmann, Tamara Jandl, Anna Moser, Cedrik M. Britten, Josef Smolle, Silvia Koller, Cornelia Mauch, Iliana Tantcheva-Poor, Stephan Grabbe, Carmen Loquai, Stefan Esser, Tom Franckson, Achim Schneeberger, Cäcilia Haarmann, Arthur M. Krieg, Georg Stingl, Stephan N. Wagner

From the Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, and Department of Radiology, Medical University of Vienna; Center for Molecular Medicine, Austrian Academy of Sciences, Vienna; Department of Dermatology, Medical University of Graz, Graz, Austria; 3rd Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz; Department of Dermatology, University of Cologne, Cologne; Department of Dermatology, University of Muenster, Muenster; Department of Dermatology, University of Duisburg/Essen, Essen, Germany; and Coley Pharmaceutical Group Inc, Wellesley, MA

Address reprint requests to Stephan N. Wagner, Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria; e-mail: stephan.wagner{at}meduniwien.ac.at

PURPOSE: The recent identification of toll-like receptors (TLRs) and respective ligands allows the evaluation of novel dendritic cell (DC) –activating strategies. Stimulation of TLR9 directly activates human plasmacytoid DCs (PDCs) and indirectly induces potent innate immune responses in preclinical tumor models. We performed an open-label, multicenter, single-arm, phase II pilot trial with a TLR9-stimulating oligodeoxynucleotide in melanoma patients.

PATIENTS AND METHODS: Patients with unresectable stage IIIb/c or stage IV melanoma received 6 mg PF-3512676 weekly by subcutaneous injection for 24 weeks or until disease progression to evaluate safety as well as clinical and immunologic activity. Clinical and laboratory safety assessments were performed weekly; blood samples for immunological measurements were taken every 8 weeks. Tumor measurements were performed according to Response Evaluation Criteria in Solid Tumors.

RESULTS: Twenty patients received PF-3512676 for a mean of 10.9 weeks with a mean of 10.7 injections. Laboratory and nonlaboratory adverse events were limited, transient, and did not result in any withdrawals. Two patients experienced a confirmed partial response; one response is ongoing for 140+ weeks. Three patients experienced stable disease. Immunologic measurements revealed induction of an activated phenotype of PDC, elevation of serum levels of 2',5'-oligoadenylate, a surrogate marker of type I interferon production, and significant stimulation of natural killer cell cytotoxicity (the latter was associated with clinical benefit).

CONCLUSION: These results indicate that TLR9-targeted therapy can stimulate innate immune responses in cancer patients, identify biomarkers that may be associated with TLR9-induced tumor regression, and encourage the design of follow-up studies to evaluate the ability of this therapeutic approach to target human cancer.

Supported by the Austrian National Bank (Grant No. 11062), the Medical-Scientific Fund of the Mayor of the City of Vienna (Grant No. 02529), the Deutsche Krebshilfe (Grant No. 70-2427-Hul), and Coley Pharmaceutical Group Inc, Wellesley, MA.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA; the 95th Annual Meeting of the American Association of Cancer Research, March 27-31, 2004, Orlando, FL; and the 31st Annual Meeting of the Arbeitsgemeinschaft Dermatologische Forschung, February 26-28, 2004, Dresden, Germany.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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