TLR9-targeted CpG immunostimulatory treatment of metastatic melanoma: A phase II trial with CpG 7909 (ProMune)

Abstract

7513 Background: Malignant melanoma is widely accepted as an immunologically responsive tumor, but large recently reported chemobiotherapy trials have been disappointing and prognosis is poor. The new synthetic oligodeoxynucleotide CpG 7909 activates plasmacytoid dendritic cells (pDC) and B cells through specific interaction with Toll-like receptor 9 (TLR9) and is a strong activator of both innate and specific immunity. CPG 7909 crossreacts with mouse TLR9 and has shown impressive antitumor activity in preclinical tumor models when used as monotherapy. Methods: Patients with confirmed metastatic melanoma (stage IV without CNS metastases) were enrolled into an open-label, multicenter, single arm study. Pts received 6 mg CPG 7909 weekly by SC injection for 24 weeks or until disease progression in an outpatient setting. Disease status was assessed at screening and weeks 8, 16, and 24 according to RECIST. Results: 20 pts (5 female, 15 male, aged between 37 and 74) were enrolled. Two pts achieved a confirmed partial response (PR) and one has maintained this response with continuing therapy for over 13 months. Three pts achieved stable disease (SD). CPG 7909 was well tolerated. Adverse events included transient injection site reactions (erythema, swelling, induration), fever and arthralgias. Hematological and non-hematological toxicities were limited, transient and did not result in any withdrawals. Phenotyping of PBMC revealed activation of pDC under CPG 7909 therapy consistent with the mode of action and pts exhibiting PR or SD could be distinguished from non-R pts by differential dynamics in NK cell-cytotoxicity (1.6-fold increase vs. 1.7-fold decrease in lytic units, p<0.05) during the first 8 weeks of treatment. Conclusions: CPG 7909 exerts anti-tumor activity in pts with metastatic melanoma, can be administered safely and induces a phenotypic signature in PBMC associated with exposure and, possibly, response to therapy. A randomised phase II/III trial has been initiated to compare efficacy and safety of two dose levels of CPG 7909, CPG 7909 in combination with DTIC, and DTIC alone. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Coley Pharmaceutical Group Coley Pharmaceutical Group Coley Pharmaceutical Group Coley Pharmaceutical Group Coley Pharmaceutical Group