Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant.
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.
Department of Medicine, Division of Medical Oncology, New York University Cancer Institute, School of Medicine, New York, NY 10016, USA.
Sylvia
S
Adams
David W
DW
O'Neill
Daisuke
D
Nonaka
Elizabeth
E
Hardin
Luis
L
Chiriboga
Kimberly
K
Siu
Crystal M
CM
Cruz
Angelica
A
Angiulli
Francesca
F
Angiulli
Erika
E
Ritter
Rose Marie
RM
Holman
Richard L
RL
Shapiro
Russell S
RS
Berman
Natalie
N
Berner
Yongzhao
Y
Shao
Olivier
O
Manches
Linda
L
Pan
Ralph R
RR
Venhaus
Eric W
EW
Hoffman
Achim
A
Jungbluth
Sacha
S
Gnjatic
Lloyd
L
Old
Anna C
AC
Pavlick
Nina
N
Bhardwaj
D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000009:adverse effects / Q000494:pharmacology*; D000917:Antibody Formation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D001706:Biopsy; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology*; D018604:Epitope Mapping; D004890:Erythema / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D000077271:Imiquimod; D007114:Immunization; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008565:Membrane Proteins / Q000276:immunology*; D008875:Middle Aged; D010865:Pilot Projects; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D008565:Membrane Proteins; D051199:Toll-Like Receptor 7; D000077271:Imiquimod