Combination Therapy of Topical Imiquimod Plus Multipeptide Vaccination for Cutaneous Metastases of Melanoma
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.
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.
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.
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.
1) Toxicity profile of topical imiquimod at sites of melanoma, with or without MELITAC 12.1
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.
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
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
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety: 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.
Craig L Slingluff, M.D.
University of Virginia
United States: Food and Drug Administration
|University of Virginia||Charlottesville, Virginia 22908|