Synthetic
oligodeoxynucleotides (ODNs), such as
PF-3512676, that contain unmethylated
cytosine-
guanine motifs (
CpG ODN) have been identified as highly potent immune activators by in vitro examinations and in murine models. CpG ODNs induce innate and adaptive immune responses by triggering
Toll-like receptor 9 expressed by human B cells and plasmacytoid dendritic cells. A phase 1 study was initiated to investigate safety, tolerability, serum
cytokine levels, cellular immune responses, and clinical activity of intralesional treatment with
PF-3512676 in patients with
basal cell carcinoma (BCC) or cutaneous or subcutaneous
melanoma metastases. Intrapatient escalating doses of
PF-3512676 (up to 10 mg) were injected intralesionally every 14 days in 5 patients with BCC and in cutaneous or subcutaneous
metastases of 5 patients with
melanoma.
PF-3512676 was well tolerated. Local swelling and
erythema occurred at the injection site in 9/10 patients. There was only 1 incidence of a grade III hematologic adverse event (
lymphocytopenia). Local
tumor regressions were observed in patients with BCC (1 complete regression, 4 partial regressions) and metastatic
melanoma (1 complete regression).
After treatment with
PF-3512676,
interleukin-6 was increased in all patients,
interferon-gamma induced protein-10 in 8/10 patients, interleukin-12p40 in 7/10 patients, and
tumor necrosis factor-alpha levels in 6/10 patients. All patients had biopsies; moderate to abundant cellular infiltrates of lymphocytes were found posttreatment in most lesions of both histologic types. Intralesional treatment of skin
tumors with
PF-3512676 was safe and well tolerated. Despite the relatively low dosage, clinical activity was demonstrated both in patients with BCC and with cutaneous or subcutaneous metastatic
melanoma lesions.