Combination Therapy of Topical Imiquimod Plus Multipeptide Vaccination for Cutaneous Metastases of Melanoma

The purpose of the study is to determine 1) the safety of administration of topical 5% imiquimod cream with or without administration of a peptide-based vaccine in patients with cutaneous metastases of melanoma and 2) evaluate whether topical imiquimod at sites of melanoma metastasis, with or without vaccine, increases a) endothelial expression of E-selectin and b) T cell infiltration.

Primary goals: Safety: 1\) To determine the safety of administration of topical 5% imiquimod cream with or without administration of a peptide-based vaccine in patients with cutaneous metastases of melanoma. Biologic effect: 1\) To evaluate whether topical imiquimod at sites of melanoma metastasis, with or without vaccine, increases a) endothelial expression of E-selectin and b) T cell infiltration. Secondary goals: 1. To assess whether T cells infiltrating melanoma metastases after imiquimod, with and without vaccination, are reactive to peptides in the vaccine. 2. To evaluate whether topical imiquimod decreases the proportion of FoxP3+ CD25hi CD4+ cells (putative regulatory T cells, Tregs) among tumor infiltrating T cells. 3. To estimate the effects of vaccine on CXCR3, CLA, and activation marker expression by circulating and tumor-infiltrating antigen-experienced CD4 and CD8 T cells. 4. To obtain preliminary data on the clinical response of cutaneous metastases of melanoma to the proposed combination regimen. 5. To determine the expression of TLR7 by immune cells and/or melanoma cells in the metastatic melanoma microenvironment. 6. To obtain preliminary data on associations between metastatic melanoma T cell infiltration patterns (immunotypes) and molecular and clinical responses to imiquimod. Design: The present proposal is for a clinical trial and associated correlative studies that bring together several observations and unmet scientific and clinical needs that have promise for a new effective immunotherapy for melanoma metastases. This is an open-label two-cohort, nonrandomized, pilot study of a combination of topical imiquimod plus systemic vaccination with MELITAC 12.1 vaccine, an emulsion of a mixture of 12 class I MHC-restricted melanoma peptides (12-MP) and a class II MHC-restricted tetanus toxoid helper peptide (tet). Cohort 1 will receive the combination of imiquimod + vaccine; Cohort 2 will receive imiquimod only. Patients will be eligible for cohort 1 if they are eligible for the vaccine based on HLA type and clinical factors. Cohort 2 is for patients who are not eligible for the vaccine. Primary Endpoints: Safety: 1\) Toxicity profile of topical imiquimod at sites of melanoma, with or without MELITAC 12.1 vaccine. Biologic effect: 1\) Change in levels of intratumoral E-selectin and infiltrating TCD4 and TCD8 lymphocytes: 1. pretreatment vs after vaccine + imiquimod; 2. with vaccine vs. without vaccine (cohorts 1 vs 2); 3. lesions with imiquimod vs. without imiquimod. Secondary Endpoints: The following will be evaluated by comparing pretreatment to after vaccine + imiquimod, and comparing findings from patients with and without vaccine (cohorts 1 and 2), as well as lesions with and without imiquimod. 1. Change in the number of vaccine-reactive T cells in the melanoma metastases, as determined by ELIspot and tetramer analyses. 2. Change in the percentage of FoxP3+ CD25hi CD4+ (putative regulatory T cells, Tregs) among tumor infiltrating T cells as determined by immunohistochemistry and flow cytometry. 3. Expression of CXCR3, CLA, and activation markers (CD69, CD137, HLA-DR, CD27 and CD28) on vaccine-reactive cells in the blood and within the melanoma metastases by immunohistochemistry and flow cytometric analyses. 4. TLR7 expression by cells in the metastatic melanoma microenvironment. 5. Changes in T cell infiltration patterns of metastases (immunotype) The following will be evaluated post-treatment 6. Clinical regression of individual imiquimod-treated and untreated metastases