Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial

Abstract

Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation.

The enigma and challenges of vitiligo pathophysiology and treatment

“…Induction F I G U R E 1 Clinical presentation of non-segmental (a) and segmental (b) vitiligo of vitiligo is an indicator of robust anti-melanoma immunity and is associated with reduced risk of disease progression and with improved survival. Interestingly, topical treatment of patients with advanced metastatic melanoma with imiquimod and monobenzone, agents known to cause melanocyte killing, resulted in development of melanoma-specific CD8 + T-cell responses as well as local regression of inoperable metastases (Teulings et al, 2018). This observation suggests that inducing melanocyte death elicits an autoimmune response, possibly due to presentation of neo-antigens.…”

Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma

“…In humans, clinical trials administering IMQ in combination with other therapies or tumor vaccines are ongoing. In detail, a phase II clinical trial combining topical IMQ with monobenzone in twenty-one melanoma patients (stage III-IV) led to the local regression of cutaneous metastases in 52% of the patients [284]. In addition, adjuvant FLT3L administration combined with a peptide-based vaccine and with topically applied IMQ was tested in eight patients with MM [285].…”

Melanoma to Vitiligo: The Melanocyte in Biology & Medicine–Joint Montagna Symposium on the Biology of Skin/PanAmerican Society for Pigment Cell Research Annual Meeting

“…Thus, antimelanocyte responses in vitiligo may present tractable therapeutic strategies in melanoma. Environmental phenolic agents (e.g., monobenzone) can interact with tyrosinase to generate cytotoxic quinones that induce contact vitiligo and subsequently elicit therapeutic immune responses in melanoma (Teulings et al, 2018).…”