Imiquimod Enhances the Systemic Immunity Attained by Local Cryosurgery Destruction of Melanoma Lesions

• Published in: Journal of investigative dermatology Vol. 127; no. 7; pp. 1673 - 1680
• Main Authors: Redondo, Pedro, del Olmo, Julio, López-Diaz de Cerio, Ascensión, Inoges, Susana, Marquina, Miren, Melero, Ignacio, Bendandi, Maurizio
• Format: Journal Article
• Language: English
• Published: Danvers, MA Elsevier Inc 01-07-2007; Nature Publishing; Elsevier Limited
• Subjects: Adjuvants; Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - pharmacology; Administration, Topical; Aminoquinolines - administration & dosage; Aminoquinolines - pharmacology; Animals; Antigen (tumor-associated); Antigen-presenting cells; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Autografts; Biological and medical sciences; Cancer vaccines; Combined Modality Therapy; Cream; Cryosurgery; Cryosurgery - adverse effects; Cryosurgery - methods; Data processing; Dermatology; Epitopes; Female; gamma -Interferon; Grafting; imiquimod; Immune response; Immunity; Immunity - drug effects; Immunological memory; Inflammation; Interferon Inducers - administration & dosage; Interferon Inducers - pharmacology; Interferon-gamma - metabolism; Internet; Lethal dose; Lymphocytes T; Medical sciences; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - surgery; Membrane Glycoproteins - agonists; Mice; Mice, Inbred C57BL; Nodules; Ovalbumin; Skin Neoplasms - immunology; Skin Neoplasms - surgery; Toll-Like Receptor 7 - agonists; Tumor cells; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Vitiligo; Vitiligo - etiology; Cryosurgery; Destruction; Dermatology; Imiquimod; Systemic; Malignant tumor; Immunomodulator; Local immunity; Treatment; Surgery; Malignant melanoma; Antiviral; Lesion
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/sj.jid.5700777

Melanoma lesions can be frozen in vivo, resulting in necrotic death of malignant cells and in tumor antigen release suitable for cross-presentation by professional antigen-presenting cells. Imiquimod is a small molecule with adjuvant pro-inflammatory effects that can be topically delivered as a cream. Local cryosurgery of B16/ovalbumin (OVA)-derived subcutaneous tumor nodules leads to curative destruction of the lesions. If imiquimod is repeatedly applied on the cryo-treated lesion, a conspicuous, leukocyte-rich inflammatory infiltrate appears during the days following treatment. Mice treated by cryosurgery plus imiquimod rejected rechallenges of B16/OVA in 90% of the cases, whereas cryosurgery alone failed to prevent tumor grafting in 70% of the cases. The combination treatment of B16/OVA tumors was also able to protect 60% of the mice against outgrowth of a lethal dose of non-transfected B16 tumor cells. Addition of imiquimod to cryosurgery results in increases of the cellular immune response against tumor antigens as measured by in vitro IFN-γ production and T-cell proliferation in response to OVA. The potent memory response is not only directed against the OVA epitope, but also toward a broader range of B16 antigens. Our data indicate that these combined treatments turn the treated tumor lesion into an autologous tumor vaccine, which is even able to cause vitiligo in several cases. These preclinical data and the simplicity of the procedures warrant the design of a pilot clinical trial.