Although 5-year overall survival rates in patients with Stage I-II melanoma range from 95% to as low as 45%, currently there is no adjuvant treatment available that has been shown to reduce the chances of recurrence after surgical excision of localized melanoma. Between 2004 and 2007 we conducted two randomized and placebo controlled phase II clinical trials in which we treated clinically stage I-II melanoma patients with intradermally injected CpG-B (PF-3512676/CpG7909 at 8 or 2 mg, n=30) or saline (n=22) directly adjacent to the primary melanoma excision scar, seven and two days before re-excision and sentinel lymph node (SLN) biopsy. CpG-B injections were well tolerated by all patients with only transient and mild flu-like symptoms and mild-to-moderate fevers after administration. Immune monitoring revealed recruitment and activation of dendritic cell subsets in the SLN with cross-priming ability upon CpG-B administration as well as increased intra-SLN and systemic rates of melanoma antigen reactive CD8+ T cells. Here, we present clinical follow-up of all 52 patients that participated in these two trials.

Upon pathological examination of the SLN, a remarkable difference in numbers of pathologically stage III patients was revealed, with significantly less tumor positive SLN in the CpG-B administered group (3/30 versus 8/22 in the saline control arm, p=0.037), indicating a rapid CpG-induced antitumor effect. Follow-up further provided evidence of systemic tumor protection: in the CpG-treated group only two recurrences occurred, both within 26 months of SLN biopsy, whereas nine recurrences were observed in the saline group (range 9-99 months). In a post-hoc analysis at a median follow-up of 76.5 months, this translated into a significantly longer recurrence free survival (RFS) in the CpG-treated group (p=0.019). Even for patients with pathologically confirmed and prognostically favorable stage I-II, this difference held true, although at borderline significance (p=0.068). Disease-specific survival rates at this time were 77.2% in the saline vs. 93.3% in the CpG-B group.

We conclude that intradermally administered CpG-B is safe and may prolong RFS. Consistent with findings from immune monitoring, apparent down-staging and prolonged RFS may result from the respective boosting of local and systemic antitumor immunity through local conditioning of the SLN. These exciting findings warrant further clinical exploration of local non-toxic immune potentiation in early-stage melanoma to prevent disease recurrence and metastatic spread.

Citation Format: Tanja D. de Gruijl, Bas D. Koster, Mari F.C.M. van den Hout, Berbel J.R. Sluijter, Barbara G. Molenkamp, Paul A.M. van Leeuwen, Rik J. Scheper, M. Petrousjka van den Tol, Alfons J.M. van den Eertwegh. Local administration of CpG-B increases recurrence-free survival in early-stage melanoma patients: Long-term follow-up of two randomized clinical trials evaluating adjuvant treatment. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A050.