Nano‐particle vaccination combined with TLR‐7 and ‐9 ligands triggers memory and effector CD8+ T‐cell responses in melanoma patients

• Published in: European journal of immunology 2012-11, Vol.42 (11), p.3049-3061
• Main Authors: Goldinger, Simone M., Dummer, Reinhard, Baumgaertner, Petra, Mihic‐Probst, Daniela, Schwarz, Katrin, Hammann‐Haenni, Anya, Willers, Joerg, Geldhof, Christine, Prior, John O., Kündig, Thomas M., Michielin, Olivier, Bachmann, Martin F., Speiser, Daniel E.
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - administration & dosage; Aminoquinolines - administration & dosage; Cancer Vaccines - administration & dosage; Cancer Vaccines - adverse effects; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - immunology; Clinical Immunology; Flow Cytometry; Freund's Adjuvant - administration & dosage; Genotype & phenotype; Humans; IFA (Montanide); Imiquimod; Immunization; Immunologic Memory - immunology; Immunology; Ligands; Lipids - administration & dosage; MART-1 Antigen - immunology; Melanoma; Melanoma - immunology; Melanoma - therapy; Melan‐A/MART‐1 antigen; Nanoparticles - administration & dosage; Oligodeoxyribonucleotides - immunology; Peptide‐based vaccination; Skin Neoplasms - immunology; Statistics, Nonparametric; T cell receptors; Toll-Like Receptor 7 - immunology; Toll-Like Receptor 9 - immunology; Vaccines
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201142361

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 peptide16–35 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.