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Imiquimod

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Interferons

Peptide Vaccine: Days 1, 8, 15, 36, 57, 78 Imiquimod: Applied daily on days 1-85.

Vaccine regimen: The vaccines will be administered in two treatment cycles. During cycle one, three vaccines will be administered over a 3-week period on days 1, 8, and 15. During cycle two, three vaccines will be administered over a 9-week period on days 36, 57, 78. Participants in cohort 1 will receive MELITAC 12.1 (100 mcg each of the12-MP and 200 mcg of Peptide-tet) administered subcutaneously (1 ml) and intradermally (1 ml) in Montanide ISA-51 VG adjuvant at a single vaccination site.

MELITAC 12.1

Topical Imiquimod regimen: Beginning on day 1, patients in cohorts 1 and 2 will have one or more cutaneous melanoma metastases treated topically with 5% imiquimod cream, with a dose of 1 to 3 packets of imiquimod daily, (depending on the extent of cutaneous metastases). Each packet contains 250 mg of cream and may be used for a surface area of up to 20 cm2. The number of lesions that are treated will be dependent on the availability and size of the lesions. In addition, if available, at least two lesions will be followed without treatment with the plan that they will be excised at week 3 (day 22) and week 6 (day 43), respectively, as controls. Imiquimod will be applied daily for seven days each week for 12 weeks. One course of treatment will be three weeks in duration, with evaluation by a clinician after every treatment course.

Craig L Slingluff, M.D.

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

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

University of Virginia

Professor of Surgery, Principal Investigator, University of Virginia Health System, Department of Surgery, Human Immune Therapy Center

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