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

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 mo...

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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
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0732-183X 1527-7755
DOI:	10.1200/JCO.2006.07.9129