Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Pashenkov, M; Goëss, G; Wagner, C; Hörmann, M; Jandl, T; Moser, A; Britten, CM; Smolle, J; Koller, S; Mauch, C; Tantcheva-Poor, I; Grabbe, S; Loquai, C; Esser, S; Franckson, T; Schneeberger, A; Haarmann, C; Krieg, AM; Stingl, G; Wagner, SN.
Phase II trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma.
J CLIN ONCOL. 2006; 24(36): 5716-5724.
Doi: 10.1200/JCO.2006.07.9129
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- Co-Autor*innen der Med Uni Graz
- Koller Silvia Eleonore
- Smolle Josef
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Adult -
- Aged -
- Female -
- Humans -
- Interferon Type I - metabolism
- Killer Cells, Natural - immunology
- Male - immunology
- Melanoma - immunology
- Middle Aged - immunology
- Neoplasm Metastasis - immunology
- Oligonucleotides - therapeutic use
- Skin Neoplasms - immunology
- Toll-Like Receptor 9 - genetics
- Treatment Outcome - genetics
- Tumor Markers, Biological - genetics