Cancer Immunity 4:4 (2004)

Ex vivo detectable activation of Melan-A-specific T cells correlating with inflammatory skin reactions in melanoma patients vaccinated with peptides in IFA

Danielle Liénard^1,2, Donata Rimoldi³, Marie Marchand^4,5, Pierre-Yves Dietrich⁶, Nicolas van Baren⁴, Christine Geldhof¹, Pascal Batard^1*, Philippe Guillaume³, Maha Ayyoub¹, Mikaël J. Pittet¹, Alfred Zippelius¹, Katharina Fleischhauer⁷, Ferdy Lejeune², Jean-Charles Cerottini^1,3, Pedro Romero^1,3, and Daniel E. Speiser¹

¹Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
²Multidisciplinary Oncology Center, CHUV, Lausanne, Switzerland
³Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland
⁴Ludwig Institute for Cancer Research, Brussels Branch, Belgium
⁵Medical Oncology, Cliniques Universitaires St. Luc, Université de Louvain, Brussels, Belgium
⁶Medical Oncology, University Hospital, Geneva, Switzerland
⁷Division of Immunohematology and Blood Bank, Telethon Institute for Gene Therapy, Istituto Scientifico H.S. Raffaele, Milan, Italy
^*Deceased

Keywords: clinical trial, melanoma, vaccination, Melan-A peptide, immunological adjuvants, immunological monitoring

Abstract

The purpose of this study was to test melanoma vaccines consisting of peptides and immunological adjuvants for optimal immunogenicity and to evaluate laboratory immune monitoring for in vivo relevance. Forty-nine HLA-A2 positive patients with Melan-A positive melanoma were repeatedly vaccinated with Melan-A peptide, with or without immune adjuvant AS02B (QS21 and MPL) or IFA. Peptide-specific CD8 T cells in PBLs were analyzed ex vivo using fluorescent HLA-A2/Melan-A multimers and IFN-gamma ELISPOT assays. The vaccines were well tolerated. In vivo expansion of Melan-A-specific CD8 T cells was observed in 13 patients (1/12 after vaccination with peptide in AS02B and 12/17 after vaccination with peptide in IFA). The T cells produced IFN-gamma and downregulated CD45RA and CD28. T-cell responses correlated with inflammatory skin reactions at vaccine injection sites (P < 0.001) and with DTH reaction to Melan-A peptide (P < 0.01). Twenty-six of 32 evaluable patients showed progressive disease, whereas 4 patients had stable disease. The two patients with the strongest Melan-A-specific T-cell responses experienced regression of metastases in skin, lymph nodes, and lung. We conclude that repeated vaccination with Melan-A peptide in IFA frequently leads to sustained responses of specific CD8 T cells that are detectable ex vivo and correlate with inflammatory skin reactions.