Details

Autor(en) / Beteiligte

• PASHENKOV, Mikhail
• GOËSS, Gerda
• TANTCHEVA-POOR, Iliana
• GRABBE, Stephan
• LOQUAI, Carmen
• ESSER, Stefan
• FRANCKSON, Tom
• SCHNEEBERGER, Achim
• HAARMANN, Cäcilia
• KRIEG, Arthur M
• STINGL, Georg
• WAGNER, Stephan N
• WAGNER, Christine
• HÖRMANN, Markus
• JANDL, Tamara
• MOSER, Anna
• BRITTEN, Cedrik M
• SMOLLE, Josef
• KOLLER, Silvia
• MAUCH, Cornelia

Titel

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

Ist Teil von

• Journal of clinical oncology, 2006-12, Vol.24 (36), p.5716-5724

Ort / Verlag

Baltimore, MD: American Society of Clinical Oncology

Erscheinungsjahr

2006

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 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. 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). 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.