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An Exploratory Study of Systemic Administration of the Toll-like Receptor-7 Agonist 852A in Patients with Refractory Metastatic Melanoma

Authors' Affiliations: ¹ Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; ² Clinic for Dermatology, Venereology and Allergy, University Clinic Schleswig-Holstein, Kiel, Germany; ³ University Clinic and Health Center for Skin Diseases, Wurzburg, Germany; ⁴ Service de Dermatologie, Hôpital Ste Marguerite, Marseille, France; ⁵ Skin Cancer Unit, University Hospital Mannheim, Mannheim, Germany; ⁶ Department of Medical and Scientific Affairs, 3M Health Care, Loughborough, United Kingdom; and ⁷ Department of Medical and Scientific Affairs, 3M Pharmaceuticals, Saint Paul, Minnesota

Requests for reprints: Reinhard Dummer, Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zürich, Switzerland. Phone: 41-44-255-2588; Fax: 41-44-255-8988; E-mail: reinhard.dummer{at}usz.ch.

Purpose: A topical Toll-like receptor 7 (TLR7) agonist induces regression of cutaneous melanocytic neoplasms. We explored antitumor activity of a systemically administered TLR7 agonist, 852A, in patients with metastatic melanoma.

Experimental Design: We undertook a phase II, multicenter, open-label study in patients with chemotherapy-refractory metastatic melanoma. Patients received i.v. 852A, starting at 0.6 mg/m² and increasing to 0.9 mg/m² based on tolerance, thrice per week for 12 weeks. Clinical response was determined by Response Evaluation Criteria in Solid Tumors. Immune effects of 852A were monitored by measuring serum type I IFN and IP-10 together with assessment of immune cell markers in peripheral blood.

Results: Twenty-one patients were enrolled. Thirteen patients completed the initial 12-week treatment cycle, with two discontinuing for adverse events considered to be possibly related to study drug. Four (19%) patients had disease stabilization for >100 days. One patient had a partial remission after two treatment cycles, but progressed during the third. Dose-limiting toxicity was observed in two patients. Serum type I IFN and IP-10 increased in most patients on 852A administration. Serum type I IFN increases were greater after dosing with 852A 0.9 mg/m² than after 0.6 mg/m² (P = 0.009). The maximal increase in IP-10 compared with baseline correlated with the maximal increase in type I IFN (P = 0.003). In the eight patients with immune cell marker data, CD86 expression on monocytes increased significantly post-first dose (P = 0.007).

Conclusion: Intravenous 852A was well tolerated and induced systemic immune activation that eventually resulted in prolonged disease stabilization in some patients with stage IV metastatic melanoma who had failed chemotherapy.