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

Research output: Contribution to journalArticleResearchpeer-review

139 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

Cite this

Benham, H., Nel, H. J., Law, S. C. C., Mehd, A. M., Street, S. E. A., Ramnoruth, N., ... Thomas, R. (2015). Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Science Translational Medicine, 7(290), 1 - 12. https://doi.org/10.1126/scitranslmed.aaa9301
Benham, Helen ; Nel, Hendrik J ; Law, Soi Cheng Cheng ; Mehd, Ahmed M ; Street, Shayna E A ; Ramnoruth, Nishta ; Pahau, Helen ; Lee, Bernett T ; Ng, Jennifer ; Brunck, Marion E G ; Hyde, Claire ; Trouw, Leendert A ; Dudek, Nadine L ; Purcell, Anthony W ; O'Sullivan, Brendan J ; Connolly, John E ; Paul, Sanjoy K ; Cao, Kim-Anh L ; Thomas, Ranjeny. / Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. In: Science Translational Medicine. 2015 ; Vol. 7, No. 290. pp. 1 - 12.
@article{32ff673e87774faeafa83e859d331f8e,
title = "Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients",
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.",
author = "Helen Benham and Nel, {Hendrik J} and Law, {Soi Cheng Cheng} and Mehd, {Ahmed M} and Street, {Shayna E A} and Nishta Ramnoruth and Helen Pahau and Lee, {Bernett T} and Jennifer Ng and Brunck, {Marion E G} and Claire Hyde and Trouw, {Leendert A} and Dudek, {Nadine L} and Purcell, {Anthony W} and O'Sullivan, {Brendan J} and Connolly, {John E} and Paul, {Sanjoy K} and Cao, {Kim-Anh L} and Ranjeny Thomas",
year = "2015",
doi = "10.1126/scitranslmed.aaa9301",
language = "English",
volume = "7",
pages = "1 -- 12",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science (AAAS)",
number = "290",

}

Benham, H, Nel, HJ, Law, SCC, Mehd, AM, Street, SEA, Ramnoruth, N, Pahau, H, Lee, BT, Ng, J, Brunck, MEG, Hyde, C, Trouw, LA, Dudek, NL, Purcell, AW, O'Sullivan, BJ, Connolly, JE, Paul, SK, Cao, K-AL & Thomas, R 2015, 'Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients', Science Translational Medicine, vol. 7, no. 290, pp. 1 - 12. https://doi.org/10.1126/scitranslmed.aaa9301

Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. / Benham, Helen; Nel, Hendrik J; Law, Soi Cheng Cheng; Mehd, Ahmed M; Street, Shayna E A; Ramnoruth, Nishta; Pahau, Helen; Lee, Bernett T; Ng, Jennifer; Brunck, Marion E G; Hyde, Claire; Trouw, Leendert A; Dudek, Nadine L; Purcell, Anthony W; O'Sullivan, Brendan J; Connolly, John E; Paul, Sanjoy K; Cao, Kim-Anh L; Thomas, Ranjeny.

In: Science Translational Medicine, Vol. 7, No. 290, 2015, p. 1 - 12.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients

AU - Benham, Helen

AU - Nel, Hendrik J

AU - Law, Soi Cheng Cheng

AU - Mehd, Ahmed M

AU - Street, Shayna E A

AU - Ramnoruth, Nishta

AU - Pahau, Helen

AU - Lee, Bernett T

AU - Ng, Jennifer

AU - Brunck, Marion E G

AU - Hyde, Claire

AU - Trouw, Leendert A

AU - Dudek, Nadine L

AU - Purcell, Anthony W

AU - O'Sullivan, Brendan J

AU - Connolly, John E

AU - Paul, Sanjoy K

AU - Cao, Kim-Anh L

AU - Thomas, Ranjeny

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/26041704

U2 - 10.1126/scitranslmed.aaa9301

DO - 10.1126/scitranslmed.aaa9301

M3 - Article

VL - 7

SP - 1

EP - 12

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 290

ER -