Increase of naïve B cells, M2 macrophages and reduction of memory B/T cells during immune repopulation at 96 weeks in CLARITY assessed by immune cell deconvolution
ECTRIMS Online Library. Giovannoni G. 09/12/19; 279337; P977
Gavin Giovannoni
Gavin Giovannoni
Contributions
Abstract

Abstract: P977

Type: Poster Sessions

Abstract Category: Therapy - Immunomodulation/Immunosuppression

G. Giovannoni1, T. Leist2, P. Soelberg-Sørensen3, I. Kalatskaya4, U. Boschert5, J. DeMartino4, A. Rolfe4

1Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom, 2Division of Clinical Neuroimmunology, Jefferson University, Comprehensive MS Center, Philadelphia, PA, United States, 3Department of Neurology, Danish MS Center, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark, 4EMD Serono Research & Development Institute, Inc., Billerica, MA, United States, 5Ares Trading S.A. an affiliate of Merck Serono S.A., Eysins, Switzerland

Introduction: Cladribine tablets (CT) 10 mg at a cumulative dose of 3.5 mg/kg (CT3.5) are administered as two short oral courses at the beginning of Years 1 and 2. Total lymphocyte counts are transiently reduced following dosing, with median values returning to within normal range within 11 months and B cell median counts returning to within normal range by 6 months. Clinical efficacy of CT is sustained beyond lymphocyte recovery suggesting relevant qualitative immune changes may persist long after the last cladribine dose because of changes in immune cell subtypes and homeostasis. Flow cytometric observations suggest a long-lasting reduction in memory B cells.
Aims: To apply advanced computational algorithms to characterize immune cell transcriptomic signatures in peripheral blood from patients with RRMS during immune repopulation at 96 weeks in the CLARITY study.
Methods: Gene expression data (U133 Plus 2.0 array) in whole blood samples at 96 weeks were available from patients randomised to placebo (n=57), CT3.5 (n=62) or CT 5.25 mg/kg (CT5.25, n=70). These were analysed with the CIBERSORT deconvolution algorithm and the xCell signature-based method for immune cell subsets. CIBERSORT uses support vector regression to estimate absolute fractions of 22 immune cell subtypes and xCell performs cell type enrichment analysis for 43 immune cell types. Comparison between arms were done using a Wilcoxon Rank Sum test and results with p-values less than 0.05 were considered nominally significant.
Results: At 96 weeks, the relative abundance of naïve B-cells in cladribine treated patients was significantly higher in CT vs placebo. Plasma cells and class-switched memory B-cells were significantly reduced in CT vs placebo. No significant difference in mature B cells between placebo and CT was detected. The M2 macrophage signature was significantly enhanced in CT vs placebo. Cell abundance of both naïve and memory CD4+ and CD8+ was significantly reduced in CT vs placebo.
Conclusions: To our knowledge, neither of the bioinformatic computational techniques described in this study have been previously applied to microarray data in an MS clinical study. At this single time point within the reconstitution phase following CT treatment in Year 2, changes in leukocytes suggestive of a shift towards an anti-inflammatory phenotype were detected.
Disclosure: This study was sponsored by EMD Serono Inc, a business of Merck Healthcare KGaA, Darmstadt, Germany.
Gavin Giovannoni has received speaker honoraria and consulting fees from Abbvie, Actelion, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec, FivePrime, GlaxoSmithKline, GW Pharma, Merck & Co., Merck Healthcare KGaA, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec, Merck & Co., Novartis, and Ironwood.
Thomas Leist has received consultancy fees or clinical research grants from EMD Serono, Genentech/Roche, Biogen, Novartis, Teva and Janssen.
Per Soelberg-Sørensen has served on advisory boards for Biogen, Merck Healthcare KGaA, Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck Healthcare KGaA, Teva, GSK, and Novartis; has received speaker honoraria from Biogen Idec, Merck Healthcare KGaA, Teva, Sanofi-Aventis, Genzyme, and Novartis. His department has received research support from Biogen, Merck KGaA, Teva, Novartis, Roche, and Genzyme.
Irina Kalatskaya, Julie DeMartino and Alex Rolfe are employees of EMD Serono Research & Development Institute a business of Merck Healthcare KGaA Darmstadt Germany.
Ursula Boschert is an employee of Ares Trading S.A. an affiliate of Merck Serono S.A., Eysins, Switzerland.

Abstract: P977

Type: Poster Sessions

Abstract Category: Therapy - Immunomodulation/Immunosuppression

G. Giovannoni1, T. Leist2, P. Soelberg-Sørensen3, I. Kalatskaya4, U. Boschert5, J. DeMartino4, A. Rolfe4

1Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom, 2Division of Clinical Neuroimmunology, Jefferson University, Comprehensive MS Center, Philadelphia, PA, United States, 3Department of Neurology, Danish MS Center, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark, 4EMD Serono Research & Development Institute, Inc., Billerica, MA, United States, 5Ares Trading S.A. an affiliate of Merck Serono S.A., Eysins, Switzerland

Introduction: Cladribine tablets (CT) 10 mg at a cumulative dose of 3.5 mg/kg (CT3.5) are administered as two short oral courses at the beginning of Years 1 and 2. Total lymphocyte counts are transiently reduced following dosing, with median values returning to within normal range within 11 months and B cell median counts returning to within normal range by 6 months. Clinical efficacy of CT is sustained beyond lymphocyte recovery suggesting relevant qualitative immune changes may persist long after the last cladribine dose because of changes in immune cell subtypes and homeostasis. Flow cytometric observations suggest a long-lasting reduction in memory B cells.
Aims: To apply advanced computational algorithms to characterize immune cell transcriptomic signatures in peripheral blood from patients with RRMS during immune repopulation at 96 weeks in the CLARITY study.
Methods: Gene expression data (U133 Plus 2.0 array) in whole blood samples at 96 weeks were available from patients randomised to placebo (n=57), CT3.5 (n=62) or CT 5.25 mg/kg (CT5.25, n=70). These were analysed with the CIBERSORT deconvolution algorithm and the xCell signature-based method for immune cell subsets. CIBERSORT uses support vector regression to estimate absolute fractions of 22 immune cell subtypes and xCell performs cell type enrichment analysis for 43 immune cell types. Comparison between arms were done using a Wilcoxon Rank Sum test and results with p-values less than 0.05 were considered nominally significant.
Results: At 96 weeks, the relative abundance of naïve B-cells in cladribine treated patients was significantly higher in CT vs placebo. Plasma cells and class-switched memory B-cells were significantly reduced in CT vs placebo. No significant difference in mature B cells between placebo and CT was detected. The M2 macrophage signature was significantly enhanced in CT vs placebo. Cell abundance of both naïve and memory CD4+ and CD8+ was significantly reduced in CT vs placebo.
Conclusions: To our knowledge, neither of the bioinformatic computational techniques described in this study have been previously applied to microarray data in an MS clinical study. At this single time point within the reconstitution phase following CT treatment in Year 2, changes in leukocytes suggestive of a shift towards an anti-inflammatory phenotype were detected.
Disclosure: This study was sponsored by EMD Serono Inc, a business of Merck Healthcare KGaA, Darmstadt, Germany.
Gavin Giovannoni has received speaker honoraria and consulting fees from Abbvie, Actelion, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec, FivePrime, GlaxoSmithKline, GW Pharma, Merck & Co., Merck Healthcare KGaA, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec, Merck & Co., Novartis, and Ironwood.
Thomas Leist has received consultancy fees or clinical research grants from EMD Serono, Genentech/Roche, Biogen, Novartis, Teva and Janssen.
Per Soelberg-Sørensen has served on advisory boards for Biogen, Merck Healthcare KGaA, Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck Healthcare KGaA, Teva, GSK, and Novartis; has received speaker honoraria from Biogen Idec, Merck Healthcare KGaA, Teva, Sanofi-Aventis, Genzyme, and Novartis. His department has received research support from Biogen, Merck KGaA, Teva, Novartis, Roche, and Genzyme.
Irina Kalatskaya, Julie DeMartino and Alex Rolfe are employees of EMD Serono Research & Development Institute a business of Merck Healthcare KGaA Darmstadt Germany.
Ursula Boschert is an employee of Ares Trading S.A. an affiliate of Merck Serono S.A., Eysins, Switzerland.

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