Contributions
Abstract: P464
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Background: There are presently no biomarkers predicting response to fingolimod treatment for relapsing-remitting multiple sclerosis (MS). Here, we prospectively examined fingolimod's effects on a broad range of peripheral blood mononuclear cell (PBMC) subsets in treated patients, and tested for association with clinical and radiological disease activity while on treatment.
Methods: Thirty-six patients initiating fingolimod for MS were followed clinically and with co-registered serial MRI for up to 24 months (mean 23 months, range 8-24 months). Patients were classified as 'active' (n=18) or 'stable' (n=18) based on clinical (relapse) and radiological (new T2 hyperintense lesions) evidence on treatment. 'Active' and 'stable' groups were well matched, including for pre-fingolimod disease activity. Using standardised protocols, detailed multicolour flow cytometric analysis of T-cell subsets, B-cell subsets, NK cells, monocytes and dendritic cells were performed on rigorously collected and cryopreserved PBMC obtained pre-treatment and after at least 6 months on treatment.
Results: Decreased absolute counts of most B-cell and T-cell (CD4+ and CD8+) subsets were seen with fingolimod treatment, including naïve, memory, regulatory and pro-inflammatory cytokine-expressing subsets. Senescent CD8+ T cells (CD8+CD28- and CD8+CD57+), CD56+ T cells, CD56dim NK cells, monocytes and dendritic cells were not reduced in number and hence relatively increased in frequency with treatment. Lower pre-treatment frequencies of CD4+ central memory cells (TCM) (28% vs 37%, p=0.0133) and higher frequencies of CD8+ terminally differentiated effector memory (TEMRA) cells
(22% vs 13%, p=0.038) were noted in patients who remained stable on fingolimod compared with the active cohort. Stable patients were also noted to have significantly lower B-cell counts pre-treatment (p=0.0066), mainly reflecting lower numbers of mature (p=0.0061) but not transitional B cells.
Conclusions: In this prospective and rigorously studied cohort, we document effects of fingolimod treatment on a broad range of peripheral immune cell subsets, including several not previously studied. Early analysis suggests pre-treatment mature B-cell counts, CD4+ TCM and CD8+ TEMRA cell frequencies may have value in predicting fingolimod treatment response and warrant further study. Multiparametric analysis exploring whether interplay between different immune cell types predicts treatment response will also be performed.
Disclosure: This study was funded in part by a grant from Novartis to McGill University.
Dr Mahtab Ghadiri has received a Brain and Mind Research Institute/McGill University Multiple Sclerosis scholarship, funded by Novartis, and has received travel grants and/or speaker fees from Bayer, Novartis, Sanofi-Genzyme, Biogen Idec and Teva Neuroscience.
Dr Rui Li: nothing to disclose.
Ayman Rezk: nothing to disclose.
Dr Paul S. Giacomini has received honoraria for speaking, consulting, and advisory board participation from Allergan, Bayer HealthCare, Biogen Idec, EMD Serono, Genzyme, Merz, Novartis, Roche and Teva Neuroscience, and has acted as a principal investigator or sub-investigator for clinical trials for Alexion, Bayer HealthCare, Biogen Idec, Elan, EMD Serono, GlaxoSmithKline, MedDay, Novartis, Ono, Roche-Genetech, Sanofi-Aventis and Teva Neuroscience.
Dr Jack Antel serves on advisory/safety monitoring boards for Novartis, Sanofi-Genzyme, Biogen Idec, EMD Serono and Medday Pharmaceuticals, and as editor of the Americas, Multiple Sclerosis Journal.
Dr Amit Bar-Or has participated as a speaker at meetings sponsored by, received consulting fees and/or received grant support from: Amplimmune, Bayhill Therapeutics, Berlex/Bayer, Biogen Idec, Diogenix, Eli-Lilly, Genentech, GlaxoSmithKline, Guthy-Jackson/GGF, Merck/EMD Serono, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche, Sanofi-Genzyme, Teva Neuroscience, Wyeth.
Abstract: P464
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Background: There are presently no biomarkers predicting response to fingolimod treatment for relapsing-remitting multiple sclerosis (MS). Here, we prospectively examined fingolimod's effects on a broad range of peripheral blood mononuclear cell (PBMC) subsets in treated patients, and tested for association with clinical and radiological disease activity while on treatment.
Methods: Thirty-six patients initiating fingolimod for MS were followed clinically and with co-registered serial MRI for up to 24 months (mean 23 months, range 8-24 months). Patients were classified as 'active' (n=18) or 'stable' (n=18) based on clinical (relapse) and radiological (new T2 hyperintense lesions) evidence on treatment. 'Active' and 'stable' groups were well matched, including for pre-fingolimod disease activity. Using standardised protocols, detailed multicolour flow cytometric analysis of T-cell subsets, B-cell subsets, NK cells, monocytes and dendritic cells were performed on rigorously collected and cryopreserved PBMC obtained pre-treatment and after at least 6 months on treatment.
Results: Decreased absolute counts of most B-cell and T-cell (CD4+ and CD8+) subsets were seen with fingolimod treatment, including naïve, memory, regulatory and pro-inflammatory cytokine-expressing subsets. Senescent CD8+ T cells (CD8+CD28- and CD8+CD57+), CD56+ T cells, CD56dim NK cells, monocytes and dendritic cells were not reduced in number and hence relatively increased in frequency with treatment. Lower pre-treatment frequencies of CD4+ central memory cells (TCM) (28% vs 37%, p=0.0133) and higher frequencies of CD8+ terminally differentiated effector memory (TEMRA) cells
(22% vs 13%, p=0.038) were noted in patients who remained stable on fingolimod compared with the active cohort. Stable patients were also noted to have significantly lower B-cell counts pre-treatment (p=0.0066), mainly reflecting lower numbers of mature (p=0.0061) but not transitional B cells.
Conclusions: In this prospective and rigorously studied cohort, we document effects of fingolimod treatment on a broad range of peripheral immune cell subsets, including several not previously studied. Early analysis suggests pre-treatment mature B-cell counts, CD4+ TCM and CD8+ TEMRA cell frequencies may have value in predicting fingolimod treatment response and warrant further study. Multiparametric analysis exploring whether interplay between different immune cell types predicts treatment response will also be performed.
Disclosure: This study was funded in part by a grant from Novartis to McGill University.
Dr Mahtab Ghadiri has received a Brain and Mind Research Institute/McGill University Multiple Sclerosis scholarship, funded by Novartis, and has received travel grants and/or speaker fees from Bayer, Novartis, Sanofi-Genzyme, Biogen Idec and Teva Neuroscience.
Dr Rui Li: nothing to disclose.
Ayman Rezk: nothing to disclose.
Dr Paul S. Giacomini has received honoraria for speaking, consulting, and advisory board participation from Allergan, Bayer HealthCare, Biogen Idec, EMD Serono, Genzyme, Merz, Novartis, Roche and Teva Neuroscience, and has acted as a principal investigator or sub-investigator for clinical trials for Alexion, Bayer HealthCare, Biogen Idec, Elan, EMD Serono, GlaxoSmithKline, MedDay, Novartis, Ono, Roche-Genetech, Sanofi-Aventis and Teva Neuroscience.
Dr Jack Antel serves on advisory/safety monitoring boards for Novartis, Sanofi-Genzyme, Biogen Idec, EMD Serono and Medday Pharmaceuticals, and as editor of the Americas, Multiple Sclerosis Journal.
Dr Amit Bar-Or has participated as a speaker at meetings sponsored by, received consulting fees and/or received grant support from: Amplimmune, Bayhill Therapeutics, Berlex/Bayer, Biogen Idec, Diogenix, Eli-Lilly, Genentech, GlaxoSmithKline, Guthy-Jackson/GGF, Merck/EMD Serono, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche, Sanofi-Genzyme, Teva Neuroscience, Wyeth.