Effective Melanoma Immunotherapy in Mice by the Skin-Depigmenting Agent Monobenzone and the Adjuvants Imiquimod and CpG

Jasper G Van Den Boorn,Daisy I Picavet,Jan D Bos,Dmitri V Filippov,Cornelis J M Melief,J P Wietze Van Der Veen,Nico J Meeuwenoord,Debby Konijnenberg,Rosalie M Luiten,Esther P M Tjin

doi:10.1371/journal.pone.0010626

Jasper G Van Den Boorn, Daisy I Picavet + Show 8 more

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https://doi.org/10.1371/journal.pone.0010626

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Abstract

BackgroundPresently melanoma still lacks adequate treatment options for metastatic disease. While melanoma is exceptionally challenging to standard regimens, it is suited for treatment with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of directly inducing vitiligo as a shortcut to effective anti-melanoma immunity.Methodology and Principal FindingsWe developed an effective and simple to use form of immunotherapy by combining the topical skin-bleaching agent monobenzone with immune-stimulatory imiquimod cream and cytosine-guanine oligodeoxynucleotides (CpG) injections (MIC therapy). This powerful new approach promptly induced a melanoma antigen-specific immune response, which abolished subcutaneous B16.F10 melanoma growth in up to 85% of C57BL/6 mice. Importantly, this regimen induced over 100 days of tumor-free survival in up to 60% of the mice, and forcefully suppressed tumor growth upon re-challenge either 65- or 165 days after MIC treatment cessation.ConclusionsMIC therapy is effective in eradicating melanoma, by vigilantly incorporating NK-, B- and T cells in its therapeutic effect. Based on these results, the MIC regimen presents a high-yield, low-cost and simple therapy, readily applicable in the clinic.

Highlights

Melanoma patients could benefit greatly from immunotherapy, since melanoma is one of the most immunogenic tumors [1] and metastatic disease responds poorly to conventional therapy, such as irradiation and chemotherapy [2]
monobenzone with imiquimod and CpG (MIC) therapy is effective in eradicating melanoma, by vigilantly incorporating NK, B- and T cells in its therapeutic effect
To characterize the in vivo immune response induced by monobenzone and the immunostimulatory adjuvants CpG and imiquimod against the highly aggressive and poorly immunogenic B16.F10 melanoma, we inoculated C57BL/6 wildtype mice with 2.56103 B16.F10 cells subcutaneously in the right flank at day 0 (n = 5 mice/group), and from day 2 treated these mice with monobenzone alone, the immunostimulatory adjuvants CpG and imiquimod combined (CI) or monobenzone with imiquimod and CpG (MIC)

Summary

Introduction

Melanoma patients could benefit greatly from immunotherapy, since melanoma is one of the most immunogenic tumors [1] and metastatic disease responds poorly to conventional therapy, such as irradiation and chemotherapy [2]. Recent immunotherapeutic vaccination strategies have appeared moderately effective in achieving superior clinical results than standard interventions [7,8,9]. Successful melanoma immunotherapy can lead to treatment-related vitiligo-like leukoderma as an autoimmune side-effect [18], which is considered an encouraging prognostic sign [19,20]. As a reverse approach, we here investigated the active induction of vitiligo as an immunotherapy approach for melanoma treatment. While melanoma is exceptionally challenging to standard regimens, it is suited for treatment with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of directly inducing vitiligo as a shortcut to effective anti-melanoma immunity

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Conclusion