Contributions
Abstract: P1646
Type: LB Poster
Abstract Category: Late Breaking News
Background: Teriflunomide, an immunomodulator approved for relapsing-remitting MS (RRMS), selectively inhibits activated T/B-cell proliferation. Differential effects on proliferation of distinct T-cell clones can drive changes in T-cell receptor (TCR) repertoire diversity.
Objective(s): To describe the CD4+ TCR repertoire in RRMS patients prior to and after treatment with teriflunomide, patients receiving other MS therapies, and untreated healthy individuals (HI).
Methods: Peripheral blood mononuclear cells were isolated from RRMS patients receiving once-daily teriflunomide 14 mg (68% with recent prior exposure to another MS therapy) in the Teri-DYNAMIC trial (NCT0186388), non-trial RRMS patients receiving interferon (IFN) B or dimethyl fumarate (DMF; 240 mg, twice-daily), or secondary progressive MS patients receiving mitoxantrone (MTX, 12 mg/m2, 4x yearly), and HI. Deep immunosequencing assessed CD4+ TCR repertoire diversity, including total number of clones, number of unique clones, and clonal entropy (overall diversity). Individual clone tracking was performed.
Results: At baseline, measures of CD4+ TCR repertoire diversity, including the number of unique clones (medians: patients, 219,885; HI, 155,528; P=0.016) and clonal entropy (patients, 16.9; HI, 16.3; P=0.032), were elevated in Teri-DYNAMIC RRMS patients (n=15) vs HI (n=10). Baseline total number of clones was similar for both groups (P=0.302). Teriflunomide treatment “normalized” (i.e. reduced to HI levels) the TCR repertoire diversity in RRMS patients at Week 24 vs baseline: median reductions in the number of unique clones and clonal entropy were 33,886 (P=0.028) and 0.4 (P=0.016). Such changes in TCR repertoire diversity upon treatment were not seen in MS patients receiving IFN B (n=5), MTX (n=3), or DMF (n=5). As expected, TCR repertoire diversity remained unchanged in HI at Week 24 vs baseline. Individual clone tracking showed a high proportion of ablated clones (≥80%) in half of teriflunomide-treated RRMS patients (“TCR repertoire responders”), which correlated with immunological effects, such as reduced absolute number of Th1 cells.
Conclusions: This analysis revealed an enhanced CD4+ TCR repertoire diversity in RRMS patients vs HI, which may reflect underlying MS aetiology. Teriflunomide, but not other MS therapies, appeared to “normalize” TCR repertoire diversity and enhance clonal ablation, potentially suggesting a unique mechanism of action, correlating with key immunological effects.
Disclosure: Study supported by Sanofi Genzyme.
LK: Compensation for serving on scientific advisory boards (Genzyme, Novartis); speaker honoraria/travel support (CSL Behring, Merck Serono, Novartis); research support (Biogen Idec, Novartis).
ML, ME, and AS-M: Nothing to disclose.
CCG: Speaker honoraria and travel support (Bayer HealthCare, Genzyme).
AP-F: Honoraria for consultancy (Genzyme).
SGM: Received honoraria for lecturing and travel expenses for attending meetings, and has received financial research support from Bayer, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi-Aventis, and Teva.
BVW: Financial support/study grants, speaker fees, advisory board membership (Bayer, Biogen, Genzyme/Sanofi, Merck Serono, Novartis, Roche, Teva).
RH: Compensation for lectures, advisory boards, consultancy, research grants (Biogen Idec, Merck Serono, Novartis, Sanofi, Teva).
MM: Compensation for lectures, advisory boards, consultancy (Bayer, Biogen Idec, Bohringer, Merck Serono, Novartis, Roche, Sanofi, Teva).
MS: Received honoraria for scientific lectures or consultancy from Bayer Healthcare, Biogen, Baxter/Baxalta, CSL Behring, Euroimmune, Grifols, Merck-Serono, Novartis, Roche, Sanofi-Aventis, and Teva. His institution received research support from Bayer Healthcare, Biogen Idec, Genzyme, Merck-Serono, Novartis, and Teva.
MLang: Nothing to disclose.
BT: Speaker and consultancy honoraria, travel reimbursements, and unrestricted research grants from Bayer, Biogen, CSL Behring, Grifols, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, Teva.
AL: Educational grants and honoraria as a speaker and member of advisory boards of BAYER, Biogen, TEVA, Novartis, Sanofi Genzyme, Merck.
DD: Nothing to disclose.
MEveslage: Research support by academic partners.
TJT and AJ: Employees of Sanofi Genzyme.
AB-O: Speaking, consultancy fees, and/or grant support (Amplimmune, Biogen Idec, Diogenix, Genentech, Genzyme/Sanofi, GSK, Merck/EMD Serono, Novartis, Ono Pharma, Receptos, Roche, Teva Neuroscience).
HW: Compensation for serving on scientific advisory boards (Bayer HealthCare, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi); speaker honoraria and travel support (Bayer Schering AG, Bayer Vital GmbH, Biogen Idec, CSL Behring, Fresenius Medical Care, Genzyme, GSK, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi); compensation as consultant (Biogen Idec, Merck Serono, Novartis, Sanofi).
Abstract: P1646
Type: LB Poster
Abstract Category: Late Breaking News
Background: Teriflunomide, an immunomodulator approved for relapsing-remitting MS (RRMS), selectively inhibits activated T/B-cell proliferation. Differential effects on proliferation of distinct T-cell clones can drive changes in T-cell receptor (TCR) repertoire diversity.
Objective(s): To describe the CD4+ TCR repertoire in RRMS patients prior to and after treatment with teriflunomide, patients receiving other MS therapies, and untreated healthy individuals (HI).
Methods: Peripheral blood mononuclear cells were isolated from RRMS patients receiving once-daily teriflunomide 14 mg (68% with recent prior exposure to another MS therapy) in the Teri-DYNAMIC trial (NCT0186388), non-trial RRMS patients receiving interferon (IFN) B or dimethyl fumarate (DMF; 240 mg, twice-daily), or secondary progressive MS patients receiving mitoxantrone (MTX, 12 mg/m2, 4x yearly), and HI. Deep immunosequencing assessed CD4+ TCR repertoire diversity, including total number of clones, number of unique clones, and clonal entropy (overall diversity). Individual clone tracking was performed.
Results: At baseline, measures of CD4+ TCR repertoire diversity, including the number of unique clones (medians: patients, 219,885; HI, 155,528; P=0.016) and clonal entropy (patients, 16.9; HI, 16.3; P=0.032), were elevated in Teri-DYNAMIC RRMS patients (n=15) vs HI (n=10). Baseline total number of clones was similar for both groups (P=0.302). Teriflunomide treatment “normalized” (i.e. reduced to HI levels) the TCR repertoire diversity in RRMS patients at Week 24 vs baseline: median reductions in the number of unique clones and clonal entropy were 33,886 (P=0.028) and 0.4 (P=0.016). Such changes in TCR repertoire diversity upon treatment were not seen in MS patients receiving IFN B (n=5), MTX (n=3), or DMF (n=5). As expected, TCR repertoire diversity remained unchanged in HI at Week 24 vs baseline. Individual clone tracking showed a high proportion of ablated clones (≥80%) in half of teriflunomide-treated RRMS patients (“TCR repertoire responders”), which correlated with immunological effects, such as reduced absolute number of Th1 cells.
Conclusions: This analysis revealed an enhanced CD4+ TCR repertoire diversity in RRMS patients vs HI, which may reflect underlying MS aetiology. Teriflunomide, but not other MS therapies, appeared to “normalize” TCR repertoire diversity and enhance clonal ablation, potentially suggesting a unique mechanism of action, correlating with key immunological effects.
Disclosure: Study supported by Sanofi Genzyme.
LK: Compensation for serving on scientific advisory boards (Genzyme, Novartis); speaker honoraria/travel support (CSL Behring, Merck Serono, Novartis); research support (Biogen Idec, Novartis).
ML, ME, and AS-M: Nothing to disclose.
CCG: Speaker honoraria and travel support (Bayer HealthCare, Genzyme).
AP-F: Honoraria for consultancy (Genzyme).
SGM: Received honoraria for lecturing and travel expenses for attending meetings, and has received financial research support from Bayer, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi-Aventis, and Teva.
BVW: Financial support/study grants, speaker fees, advisory board membership (Bayer, Biogen, Genzyme/Sanofi, Merck Serono, Novartis, Roche, Teva).
RH: Compensation for lectures, advisory boards, consultancy, research grants (Biogen Idec, Merck Serono, Novartis, Sanofi, Teva).
MM: Compensation for lectures, advisory boards, consultancy (Bayer, Biogen Idec, Bohringer, Merck Serono, Novartis, Roche, Sanofi, Teva).
MS: Received honoraria for scientific lectures or consultancy from Bayer Healthcare, Biogen, Baxter/Baxalta, CSL Behring, Euroimmune, Grifols, Merck-Serono, Novartis, Roche, Sanofi-Aventis, and Teva. His institution received research support from Bayer Healthcare, Biogen Idec, Genzyme, Merck-Serono, Novartis, and Teva.
MLang: Nothing to disclose.
BT: Speaker and consultancy honoraria, travel reimbursements, and unrestricted research grants from Bayer, Biogen, CSL Behring, Grifols, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, Teva.
AL: Educational grants and honoraria as a speaker and member of advisory boards of BAYER, Biogen, TEVA, Novartis, Sanofi Genzyme, Merck.
DD: Nothing to disclose.
MEveslage: Research support by academic partners.
TJT and AJ: Employees of Sanofi Genzyme.
AB-O: Speaking, consultancy fees, and/or grant support (Amplimmune, Biogen Idec, Diogenix, Genentech, Genzyme/Sanofi, GSK, Merck/EMD Serono, Novartis, Ono Pharma, Receptos, Roche, Teva Neuroscience).
HW: Compensation for serving on scientific advisory boards (Bayer HealthCare, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi); speaker honoraria and travel support (Bayer Schering AG, Bayer Vital GmbH, Biogen Idec, CSL Behring, Fresenius Medical Care, Genzyme, GSK, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi); compensation as consultant (Biogen Idec, Merck Serono, Novartis, Sanofi).