In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 24, No. 36 ( 2006-12-20), p. 5716-5724
Abstract:
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 and Methods 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. Results 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). Conclusion 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.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2006.07.9129
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2006
detail.hit.zdb_id:
2005181-5
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