Local Adjuvant Treatment with Low-Dose CpG-B Offers Durable Protection against Disease Recurrence in Clinical Stage I–II Melanoma: Data from Two Randomized Phase II Trials

Abstract

Although risk of recurrence after surgical removal of clinical stage I-II melanoma is considerable, there is no adjuvant therapy with proven efficacy. Here, we provide clinical evidence that a local conditioning regimen, aimed at immunologic arming of the tumor-draining lymph nodes, may provide durable protection against disease recurrence (median follow-up, 88.8 months). In two randomized phase II trials, patients, diagnosed with stage I-II melanoma after excision of the primary tumor, received local injections at the primary tumor excision site within 7 days preceding re-excision and sentinel lymph node (SLN) biopsy of either a saline placebo ( = 22) or low-dose CpG type B (CpG-B) with ( = 9) or without ( = 21) low-dose GM-CSF. CpG-B treatment was shown to be safe, to boost locoregional and systemic immunity, to be associated with lower rates of tumor-involved SLN (10% vs. 36% in controls, = 0.04), and, at a median follow-up of 88.8 months, to profoundly improve recurrence-free survival ( = 0.008), even for patients with histologically confirmed (i.e., pathologic) stage I-II disease ( = 0.02). Potentially offering durable protection, local low-dose CpG-B administration in early-stage melanoma provides an adjuvant treatment option for a large group of patients currently going untreated despite being at considerable risk for disease recurrence. Once validated in a larger randomized phase III trial, this nontoxic immunopotentiating regimen may prove clinically transformative. .

Melanoma Sequentially Suppresses Different DC Subsets in the Sentinel Lymph Node, Affecting Disease Spread and Recurrence

“…In line with their reported functional abilities (14), frequencies of in vivo recruited and matured LNresident cDC correlated with increased ex vivo cross-presenting capacity of SLN suspensions (12). We have followed patients participating in these randomized and placebo controlled trials, and have found prolonged melanoma-specific survival and systemic tumor control in groups treated with CpG-B (43).…”

Evaluation of Explant Responses to STING Ligands: Personalized Immunosurgical Therapy for Head and Neck Squamous Cell Carcinoma

“…Our prior studies have demonstrated that immune mechanisms can control minimal residual disease following surgical resection in preclinical models, and that the addition of systemic immunotherapy can enhance local control (3). Moreover, in melanoma we demonstrated clinical immune control of distant metastasis by local injections of CpG after surgical removal of the primary tumor and 1 week prior to the sentinel lymph node procedure (4). Thus, the ability to enhance tumor-specific adaptive immune responses at the time of the initial procedure may be valuable for control of residual microscopic disease, as well as distant tumor deposits (3,5,6).…”

Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy

“…The potential of TDLNs is demonstrated in the clinical study of Koster et al in which stage I and II melanoma patients were treated with immune-stim-ulating TLR9 agonist CpG in the scar of tumor resection, before TDLN resection. Patients displayed stronger tumor-specific immune responses and longer recurrence-free survival than placebo-injected patients (22).…”