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Immunization of Malignant Melanoma Patients with Full-Length NY-ESO-1 Protein Using TLR7 Agonist Imiquimod as Vaccine Adjuvant¹

Sylvia Adams^2,*, David W. O'Neill^2,, Daisuke Nonaka, Elizabeth Hardin^*, Luis Chiriboga, Kimberly Siu, Crystal M. Cruz, Angelica Angiulli, Francesca Angiulli, Erika Ritter^||, Rose Marie Holman^*, Richard L. Shapiro, Russell S. Berman, Natalie Berner^*, Yongzhao Shao^¶, Olivier Manches, Linda Pan^||, Ralph R. Venhaus^||, Eric W. Hoffman^||, Achim Jungbluth^||, Sacha Gnjatic^||, Lloyd Old^||, Anna C. Pavlick^*, and Nina Bhardwaj^3,*,

^* Department of Medicine, Division of Medical Oncology, Department of Pathology, Department of Surgery, Department of Dermatology, and ^¶ Department of Environmental Medicine, Division of Biostatistics, New York University Cancer Institute, New York University School of Medicine, New York, NY 10016; and ^|| Ludwig Institute for Cancer Research, New York, NY 10021

T cell-mediated immunity to microbes and to cancer can be enhanced by the activation of dendritic cells (DCs) via TLRs. In this study, we evaluated the safety and feasibility of topical imiquimod, a TLR7 agonist, in a series of vaccinations against the cancer/testis Ag NY-ESO-1 in patients with malignant melanoma. Recombinant, full-length NY-ESO-1 protein was administered intradermally into imiquimod preconditioned sites followed by additional topical applications of imiquimod. The regimen was very well tolerated with only mild and transient local reactions and constitutional symptoms. Secondarily, we examined the systemic immune response induced by the imiquimod/NY-ESO-1 combination, and show that it elicited both humoral and cellular responses in a significant fraction of patients. Skin biopsies were assessed for imiquimod’s in situ immunomodulatory effects. Compared with untreated skin, topical imiquimod induced dermal mononuclear cell infiltrates in all patients composed primarily of T cells, monocytes, macrophages, myeloid DCs, NK cells, and, to a lesser extent, plasmacytoid DCs. DC activation was evident. This study demonstrates the feasibility and excellent safety profile of a topically applied TLR7 agonist used as a vaccine adjuvant in cancer patients. Imiquimod’s adjuvant effects require further evaluation and likely need optimization of parameters such as formulation, dose, and timing relative to Ag exposure for maximal immunogenicity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Ludwig Institute for Cancer Research, the Cancer Vaccine Collaborative, and the Cancer Research Institute. S.A. was supported in part by an American Society of Clinical Oncology Career Development Award and National Institutes of Health Grant 5P30CA016087. Y.S. was supported in part by National Institutes of Health Grant 5P30CA016087. N.B. was supported in part by National Institutes of Health Grant 5R01AIO61684, the Emerald Foundation, Center for AIDS-HIV Vaccine Immunology, the Gates Foundation, and is a recipient of the Burroughs Wellcome Fund Clinical Scientist Award and a Doris Duke Distinguished Clinical Scientist Award.

² S.A. and D.W.O. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Nina Bhardwaj, New York University Cancer Institute, Smilow 1304, 522 First Avenue, New York, NY 10016. E-mail address: Nina.Bhardwaj{at}nyumc.org

⁴ Abbreviations used in this paper: DC, dendritic cell; DTH, delayed-type hypersensitivity; ICS, Intracellular cytokine staining; IVS, in vitro T cell presensitization; LAMP, lysosome-associated membrane protein; NED, no evidence of disease; FSC, forward scatter.

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