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

• Published in: Journal of clinical oncology Vol. 24; no. 36; pp. 5716 - 5724
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 20-12-2006; Lippincott Williams & Wilkins
• Subjects: Adult; Aged; Biological and medical sciences; Biomarkers, Tumor; Dermatology; Female; Humans; Interferon Type I - metabolism; Killer Cells, Natural - immunology; Male; Medical sciences; Melanoma - immunology; Melanoma - therapy; Middle Aged; Neoplasm Metastasis; Oligonucleotides - therapeutic use; Skin Neoplasms - immunology; Skin Neoplasms - therapy; Toll-Like Receptor 9 - genetics; Treatment Outcome; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Human; Cancerology; Phase II trial; Malignant melanoma; Advanced stage; Oligonucleotide; Malignant tumor; Metastasis; Toll like receptor 9
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2006.07.9129

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.