Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients

Helen Benham, Hendrik J Nel, Soi Cheng Cheng Law, Ahmed M Mehd, Shayna E A Street, Nishta Ramnoruth, Helen Pahau, Bernett T Lee, Jennifer Ng, Marion E G Brunck, Claire Hyde, Leendert A Trouw, Nadine L Dudek, Anthony W Purcell, Brendan J O'Sullivan, John E Connolly, Sanjoy K Paul, Kim-Anh L Cao, Ranjeny Thomas

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183 Citations (Scopus)

Abstract

In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experimental arthritis in an antigen-specific manner. In rheumatoid arthritis (RA), disease-specific anti-citrullinated peptide autoantibodies (ACPA or anti-CCP) are found in the serum of about 70 of RA patients and are strongly associated with HLA-DRB1 risk alleles. This study aimed to explore the safety and biological and clinical effects of autologous DCs modified with a nuclear factor kappaB (NF-kappaB) inhibitor exposed to four citrullinated peptide antigens, designated Rheumavax, in a single-center, open-labeled, first-in-human phase 1 trial. Rheumavax was administered once intradermally at two progressive dose levels to 18 human leukocyte antigen (HLA) risk genotype-positive RA patients with citrullinated peptide-specific autoimmunity. Sixteen RA patients served as controls. Rheumavax was well tolerated: adverse events were grade 1 (of 4) severity. At 1 month after treatment, we observed a reduction in effector T cells and an increased ratio of regulatory to effector T cells; a reduction in serum interleukin-15 (IL-15), IL-29, CX3CL1, and CXCL11; and reduced T cell IL-6 responses to vimentin447-455-Cit450 relative to controls. Rheumavax did not induce disease flares in patients recruited with minimal disease activity, and DAS28 decreased within 1 month in Rheumavax-treated patients with active disease. This exploratory study demonstrates safety and biological activity of a single intradermal injection of autologous modified DCs exposed to citrullinated peptides, and provides rationale for further studies to assess clinical efficacy and antigen-specific effects of autoantigen immunomodulatory therapy in RA.
Original languageEnglish
Pages (from-to)1 - 12
Number of pages12
JournalScience Translational Medicine
Volume7
Issue number290
DOIs
Publication statusPublished - 2015

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