Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 7, Issue 290, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaa9301
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Funding
- National Health and Medical Research Council (NHMRC) [301244, 351439, 569938]
- AusIndustry Biotechnology Innovation Fund
- Queensland Government Innovation Start-Up Scheme grant
- Princess Alexandra Hospital Foundation
- Arthritis Queensland and an Australian Research Council (ARC) Future Fellowship
- NHMRC Peter Doherty Fellowship
- Queensland Government Smart State Fellowship
- Arthritis Queensland
- De Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) ZonMw Vidi grant
- Therapeutic Innovation Australia
- Australian Cancer Research Foundation for the Diamantina Individualised Oncology Care Centre at The University of Queensland Diamantina Institute
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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 kappa B (NF-kappa B) 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 vimentin(447-455)-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.
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