Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2016-10, Vol.65 (10), p.1201-1212
• Main Authors: Mauldin, Ileana S., Wages, Nolan A., Stowman, Anne M., Wang, Ena, Olson, Walter C., Deacon, Donna H., Smith, Kelly T., Galeassi, Nadedja, Teague, Jessica E., Smolkin, Mark E., Chianese‐Bullock, Kimberly A., Clark, Rachael A., Petroni, Gina R., Marincola, Francesco M., Mullins, David W., Slingluff, Craig L.
• Format: Article
• Language: English
• Subjects: Administration, Topical; Aged; Aminoquinolines - therapeutic use; Antigens, Neoplasm - immunology; Antineoplastic Agents - therapeutic use; Antiviral drugs; Biopsy; Cancer Research; Cancer vaccines; Cancer Vaccines - immunology; Cell Movement - drug effects; Cells, Cultured; Chemokines; Combined Modality Therapy; Combined vaccines; Cytokines; Cytokines - genetics; Cytokines - metabolism; Enzyme-linked immunosorbent assay; Enzyme-Linked Immunospot Assay; Female; Gene expression; Humans; Imiquimod; Immunology; Immunotherapy; Infiltration; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - pathology; Male; Medicine; Medicine & Public Health; Melanoma; Melanoma - secondary; Melanoma - therapy; Metastases; Metastasis; Middle Aged; Neoplasm Staging; Oncology; Original Article; Patients; Peptide Fragments - immunology; Skin Neoplasms - secondary; Skin Neoplasms - therapy; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tetanus; TLR7 protein; Toll-Like Receptor 7 - agonists; Toll-like receptors; Transcriptome - immunology; Tumor microenvironment; Tumors; Vaccination; Vaccines; Vaccines, Subunit - immunology; γ-Interferon
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-016-1880-z

Introduction Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases. Patients and methods Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression. Results and conclusions Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma.