An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma.
OBJECTIVE
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.


METHODS
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/m(2) and increasing to 0.9 mg/m(2) 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/m(2) than after 0.6 mg/m(2) (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).


CONCLUSIONS
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.
Dummer
Reinhard
R
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. reinhard.dummer@usz.ch
Hauschild
Axel
A
Becker
Juergen C
JC
Grob
Jean-Jacques
JJ
Schadendorf
Dirk
D
Tebbs
Veronica
V
Skalsky
Jeannine
J
Kaehler
Katharina C
KC
Moosbauer
Stephanie
S
Clark
Ruth
R
Meng
Tze-Chiang
TC
Urosevic
Mirjana
M
D000328:Adult; D054357:Chemokine CXCL10 / Q000097:blood; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000097:blood; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D015166:Monitoring, Immunologic; D018579:Patient Selection; D011804:Quinolines / Q000627:therapeutic use* / Q000633:toxicity; D012878:Skin Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides / Q000627:therapeutic use* / Q000633:toxicity; D051199:Toll-Like Receptor 7 / Q000819:agonists*
C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D016207:Cytokines; D007370:Interferon Type I; C523097:N-(4-(4-amino-2-ethyl-1H-imidazo(4,5c)quinolin-1-yl)butyl)methanesulfonamide; D011804:Quinolines; D013449:Sulfonamides; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7