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

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Abstract

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.

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Abbreviations

12MP:

12 Class I MHC-restricted melanoma peptides

CCL:

C-C motif chemokine ligand (applies to CCL5, CCL21, CCL22)

CCR:

C-C motif chemokine receptor (applies to CCR4, CCR6, CCR7, CCR9)

CV:

Coefficient of variation

CXCL:

C-X-C motif chemokine ligand 9 (applies to CXCL9, CXCL10, CXCL11, CXCL12, and CXCL13)

CXCR3:

Chemokine (C-X-C motif) receptor 3

mcg:

Micrograms

NCI:

National Cancer Institute

Tc17:

T cytotoxic, type 17

Th1:

T helper, type 1

Th17:

T helper, type 17

TME:

Tumor microenvironment

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Acknowledgments

The authors thank the Biorepository and Tissue Research Facility for technical assistance with assays, and Dr. Stefan Bekiranov for advising on gene array analysis. We appreciate the work of Patrice Neese, Carmel Nail, and Kathleen Haden for administering vaccines and managing patient toxicities, and to Cheryl Murphy Chase for RNA preparation from tumor biopsies. Appreciation also goes to clinical research coordinators Kristy Scott, Emily Allred, and Alex Carney, and we thank Eugene Butcher for the ACT-1 alpha4beta7 antibody.

Funding

Support for this work was provided by the University of Virginia Cancer Center Support Grant (NIH/National Cancer Institute P30 CA44579: Clinical Trials Office, Biorepository and Tissue Research Facility, Flow Cytometry Core, Biomolecular Core Facility, Biostatistics Shared Resource and pilot projects funding). Additional philanthropic support was provided by George and Linda Suddock and by Alice and Bill Goodwin and the Commonwealth Foundation for Cancer Research. Support was also provided by the Rebecca Clary Harris Fellowship (Ileana S Mauldin) and the University of Virginia Cancer Training Grant T32 CA009109 (Ileana S Mauldin), a Melanoma Research Alliance Young Investigator Award (David Mullins) and United States Public Health Service R01 CA134799 (David Mullins), and NIH/National Cancer Institute grant K25 CA181638 (Nolan A Wages).

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Correspondence to Craig L. Slingluff Jr..

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Conflict of interest

Craig Slingluff is an inventor of several peptides included in the vaccine that was administered during the clinical trials studied within this paper. The University of Virginia Licensing and Ventures Group holds the patents for those peptides, which have been licensed through the Ludwig Institute for Cancer Research to Glaxo Smith Kline. He also has relationships with several commercial interests related to this work, including Immatics (member, Scientific Advisory Board), Polynoma (principal investigator for MAVIS cancer vaccine trial), Glaxo Smith Kline (recipient of grant support for a clinical trial), but funds from those relationships go to the University of Virginia, not to Dr. Slingluff personally. The remaining authors have nothing to disclose or competing interests in association with this study.

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This paper is published together with doi:10.1007/s00262-016-1881-y.

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Mauldin, I.S., Wages, N.A., Stowman, A.M. et al. Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases. Cancer Immunol Immunother 65, 1201–1212 (2016). https://doi.org/10.1007/s00262-016-1880-z

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