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

Simone M Goldinger,Daniela Mihic‐Probst,Anya Hammann‐Haenni,Thomas M Kündig,Olivier Michielin,Martin F Bachmann,John O Prior,Reinhard Dummer,Christine Geldhof,Daniel E Speiser,Joerg Willers,Petra Baumgaertner,Katrin Schwarz

doi:10.1002/eji.201142361

Simone M Goldinger, Daniela Mihic‐Probst + Show 11 more

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https://doi.org/10.1002/eji.201142361

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Abstract

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.

Highlights

Melanoma is associated with frequent spontaneous CD8+ T-cell responses that may improve the clinical outcome of the disease
The 21 patients experienced a total of 187 adverse events (AEs)
We analyzed the T-cell induction properties and the safety profile of MelQbG10 when combined with different adjuvants (IFA, Imiquimod 5%) and/or administered by different routes (s.c., i.d., and i.n.)

Summary

Introduction

Melanoma is associated with frequent spontaneous CD8+ T-cell responses that may improve the clinical outcome of the disease. CD8+ cytotoxic T cells recognize a wide variety of tumor-associated antigens including melanocytic differentiation antigens, shared tumor-specific antigens, and mutated antigens, as listed in the T cell-defined tumor antigen database at http://cancerimmunity.org/peptide/. These antigens are presented as peptides by human leucocyte antigen (HLA) molecules on the surface of tumor cells and antigen presenting cells (APCs). Improvement of cancer vaccines depends on continued investments in research and development, and a better understanding of innate and specific immune activation pathways [6, 7]. Cancer vaccines are still relatively inefficient in the generation of therapeutic T-cell responses; this is the case for vaccines against infectious diseases, where efficient and protective memory and effector T-cell responses are rarely induced

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