Nano-particle vaccination combined with TLR-7 and -9 ligands triggers memory and effector CD8⁺ T-cell responses in melanoma patients.
Optimal vaccine strategies must be identified for improving T-cell vaccination against infectious and malignant diseases. MelQbG10 is a virus-like nano-particle loaded with A-type CpG-oligonucleotides (CpG-ODN) and coupled to peptide(16-35)  derived from Melan-A/MART-1. In this phase IIa clinical study, four groups of stage III-IV melanoma patients were vaccinated with MelQbG10, given (i) with IFA (Montanide) s.c.; (ii) with IFA s.c. and topical Imiquimod; (iii) i.d. with topical Imiquimod; or (iv) as intralymph node injection. In total, 16/21 (76%) patients generated ex vivo detectable Melan-A/MART-1-specific T-cell responses. T-cell frequencies were significantly higher when IFA was used as adjuvant, resulting in detectable T-cell responses in all (11/11) patients, with predominant generation of effector-memory-phenotype cells. In turn, Imiquimod induced higher proportions of central-memory-phenotype cells and increased percentages of CD127(+)  (IL-7R) T cells. Direct injection of MelQbG10 into lymph nodes resulted in lower T-cell frequencies, associated with lower proportions of memory and effector-phenotype T cells. Swelling of vaccine site draining lymph nodes, and increased glucose uptake at PET/CT was observed in 13/15 (87%) of evaluable patients, reflecting vaccine triggered immune reactions in lymph nodes. We conclude that the simultaneous use of both Imiquimod and CpG-ODN induced combined memory and effector CD8(+)  T-cell responses.
Dermatology and Pathology Departments, University Hospital of Zurich, Zurich, Switzerland.
Simone M
SM
Goldinger
Reinhard
R
Dummer
Petra
P
Baumgaertner
Daniela
D
Mihic-Probst
Katrin
K
Schwarz
Anya
A
Hammann-Haenni
Joerg
J
Willers
Christine
C
Geldhof
John O
JO
Prior
Thomas M
TM
Kündig
Olivier
O
Michielin
Martin F
MF
Bachmann
Daniel E
DE
Speiser
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000634:Aminoquinolines / Q000008:administration & dosage; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D005434:Flow Cytometry; D005620:Freund's Adjuvant / Q000008:administration & dosage; D006801:Humans; D000077271:Imiquimod; D007156:Immunologic Memory / Q000276:immunology*; D008024:Ligands; D008055:Lipids / Q000008:administration & dosage; D058965:MART-1 Antigen / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D053758:Nanoparticles / Q000008:administration & dosage*; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology*; D018709:Statistics, Nonparametric; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D008024:Ligands; D008055:Lipids; D058965:MART-1 Antigen; D009838:Oligodeoxyribonucleotides; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C114843:incomplete Freund's adjuvant; D005620:Freund's Adjuvant; D000077271:Imiquimod