The Experts below are selected from a list of 228 Experts worldwide ranked by ideXlab platform
Kevan C Herold - One of the best experts on this subject based on the ideXlab platform.
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Comparing Beta Cell Preservation Across Clinical Trials in Recent-Onset Type 1 Diabetes.
Diabetes technology & therapeutics, 2020Co-Authors: Laura M. Jacobsen, Stephen E Gitelman, Kevan C Herold, Brian N. Bundy, Madison N. Greco, Desmond A. Schatz, Mark A. Atkinson, Todd M. Brusko, Clayton E. Mathews, Jeffrey P. KrischerAbstract:Several immunotherapies have demonstrated endogenous insulin preservation in recent-onset type 1 diabetes (T1D). We considered the primary results of rituximab, abatacept, Teplizumab, alefacept, hi...
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276-OR: A 2-Dimensional (2D) Analysis of Glucose and C-Peptide Shows a Teplizumab Effect in Individuals at Risk for Type 1 Diabetes (T1D) 3 Months after Treatment
Diabetes, 2020Co-Authors: Emily K. Sims, Kevan C Herold, Megan V. Warnock, Jay M. SosenkoAbstract:We sought to determine whether a measure combining changes in C-peptide and glucose could show efficacy 3 months after Teplizumab treatment among multiple islet autoantibody+ dysglycemic individuals (n=44, age 19.2± 11.9 yrs on Teplizumab and n=32, age 17.5± 11.1 yrs on placebo) in the recent TrialNet Teplizumab prevention trial (Teplizumab delayed T1D onset). In the 2D analysis assessing changes in glucose and C-peptide below (Figure), mean glucose and C-peptide from 30 to 120 minutes are plotted from baseline and 3-month OGTTs. For each OGTT, centroids (central point of OGTT shape) are connected by vectors, showing opposite directionality from baseline to 3 months between groups. Since AUC C-peptide/AUC glucose (AUC Ratio) correlates highly with centroid C-peptide/centroid glucose (r=0.99), to quantify the differences in directionality, we compared AUC Ratio (x1,000; adjusted for baseline) change from baseline to 3 months. The Teplizumab group showed a positive change in AUC Ratio: 1.5±2.9 vs. a negative change in placebo: - 0.78±2.7; p=0.001). This difference was sustained after 6 months of treatment (p=0.004). In summary, a 2D analysis of glucose and C-peptide change provided visual and quantitative evidence of an early treatment effect. As a centroid correlate, the AUC Ratio can be a useful endpoint for performing shorter prevention trials. Disclosure E.K. Sims: None. M.V. Warnock: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. J. Sosenko: None. Funding National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF
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277-OR: Teplizumab Reverses the Loss of C-Peptide in Relatives at Risk for Type 1 Diabetes (T1D)
Diabetes, 2020Co-Authors: Emily K. Sims, Gerald T. Nepom, Brian N. Bundy, Kenneth D. Stier, Elisavet Serti, Noha Lim, Carmella Evans-molina, Kevan C HeroldAbstract:We demonstrated that a 2-week course of Teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) delayed T1D progression by a median of 24 months in high risk relatives of patients with T1D (76 multiple islet autoantibody positive dysglycemic relatives; 912 day median follow-up). Over the study 72% of the placebo-treated and 43% of the Teplizumab-treated participants were diagnosed with T1D. We hypothesized that Teplizumab treatment would also result in a secondary outcome of improved C-peptide responses to oral glucose tolerance tests (OGTT) compared to placebo. The C-peptide, 1 hr insulin secretory rate (early ISR), and glucose area under the curve (AUC) means were calculated for each study timepoint. Results were modeled using ANCOVA, regressing on treatment group, age and the baseline value of the dependent variable. Teplizumab treatment was associated with a greater on-study C-peptide AUC (Teplizumab vs. placebo adjusted means: 1.94 vs. 1.73 nmol/L; p=0.009). For both groups, C-peptide AUC mean slopes over a mean of 7.9 months preceding study entry were similar and significantly less than zero (declining; p=0.03). In the placebo group, this decline continued over the 6 months after study entry. By contrast, the Teplizumab-treated group showed an increased C-peptide AUC over this period (p=0.003 relative to study entry). Insulin secretion during the 1st hr of the OGTT also declined in participants treated with placebo, but increased in those treated with Teplizumab at 6 months (p=0.007). Increases in C-peptide AUC were correlated with increases in partially exhausted KLRG1+TIGIT+ CD8+ T cells (r=0.403; p=0.018). Although rates of diabetes were reduced in Teplizumab-treated participants, OGTTs showed persistent dysglycemia. In conclusion, we found declines in C-peptide responses to OGTTs in high risk individuals prior to study treatment that were abrogated in the 6 month period after immunomodulation with Teplizumab. Disclosure E.K. Sims: None. B.N. Bundy: None. K.D. Stier: None. E. Serti: None. N. Lim: None. G.T. Nepom: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. K.C. Herold: Consultant; Self; Provention Bio, Inc. Funding National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF
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An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes
The New England journal of medicine, 2019Co-Authors: Kevan C Herold, S. Alice Long, Jeffrey A Bluestone, Stephen E Gitelman, Peter A Gottlieb, Matthew J Dufort, Brian N. Bundy, Linda A. Dimeglio, J. Krischer, Peter S LinsleyAbstract:Abstract Background Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions ha...
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Elevated T cell levels in peripheral blood predict poor clinical response following rituximab treatment in new-onset type 1 diabetes
Genes & Immunity, 2019Co-Authors: Peter S Linsley, Carla J. Greenbaum, Mario Rosasco, Scott Presnell, Kevan C Herold, Matthew J DufortAbstract:Biologic treatment of type 1 diabetes (T1D) with agents including anti-CD3 (otelixizumab and Teplizumab), anti-CD20 (rituximab), LFA3Ig (alafacept), and CTLA4Ig (abatacept) results in transient stabilization of insulin C-peptide, a surrogate for endogenous insulin secretion. With the goal of inducing more robust immune tolerance, we used systems biology approaches to elucidate mechanisms associated with C-peptide stabilization in clinical trial blood samples from new-onset T1D subjects treated with the B cell-depleting drug, rituximab. RNA sequencing (RNA-seq) analysis of whole-blood samples from this trial revealed a transient increase in heterogeneous T cell populations, which were associated with decreased pharmacodynamic activity of rituximab, increased proliferative responses to islet antigens, and more rapid C-peptide loss. Our findings illustrate complexity in hematopoietic remodeling that accompanies B cell depletion by rituximab, which impacts and predicts therapeutic efficacy in T1D. Our data also suggest that a combination of rituximab with therapy targeting CD4 + T cells may be beneficial for T1D subjects.
William Hagopian - One of the best experts on this subject based on the ideXlab platform.
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Treatment of type 1 diabetes with Teplizumab: clinical and immunological follow-up after 7 years from diagnosis
Diabetologia, 2019Co-Authors: Ana Luisa Perdigoto, S. Alice Long, Kristina M. Harris, Carla J. Greenbaum, Stephen E Gitelman, Peter A Gottlieb, Peter S Linsley, Paula Preston-hurlburt, Pamela Clark, William HagopianAbstract:Aims/hypothesis The long-term effects of successful immune therapies for treatment of type 1 diabetes have not been well studied. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial evaluated Teplizumab, an Fc receptor non-binding humanised anti-CD3 monoclonal antibody in individuals with new-onset type 1 diabetes, and ended in 2011. Clinical drug-treated responders showed an increased frequency of ‘partially exhausted’ CD8^+ T cells. We studied the clinical, immunological and metabolic status of participants after an average follow-up of 7 years. Methods Participants with detectable C-peptide at year 2 of AbATE returned for follow-up. C-peptide responses were assessed by 4 h mixed-meal tolerance test. Autoantibodies and HbA_1c levels were measured and average daily insulin use was obtained from patient logs. Peripheral blood mononuclear cells were analysed by flow cytometry and cytokine release. Results Fifty-six per cent of the original participants returned. Three of the original control group who did not return had lost all detectable C-peptide by the end of the 2 year trial. The C-peptide responses to a mixed-meal tolerance test were similar overall in the drug vs control group of participants but were significantly improved, with less loss of C-peptide, in drug-treated responders identified at 1 year. However, the improvements in C-peptide response were not associated with lower HbA_1c levels or insulin use. Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8^+ T cells at follow-up. Conclusions/interpretation These findings suggest there is reduced decline in C-peptide and persistent immunological responses up to 7 years after diagnosis of diabetes in individuals who respond to Teplizumab. Trial registration ClinicalTrials.gov NCT02067923; the protocol is available at www.immunetolerance.org (ITN027AI).
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Treatment of type 1 diabetes with Teplizumab: clinical and immunological follow-up after 7 years from diagnosis.
Diabetologia, 2018Co-Authors: Ana Luisa Perdigoto, S. Alice Long, Kristina M. Harris, Carla J. Greenbaum, Peter A Gottlieb, Peter S Linsley, Se Gitelman, Paula Preston-hurlburt, Pamela Clark, William HagopianAbstract:The long-term effects of successful immune therapies for treatment of type 1 diabetes have not been well studied. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial evaluated Teplizumab, an Fc receptor non-binding humanised anti-CD3 monoclonal antibody in individuals with new-onset type 1 diabetes, and ended in 2011. Clinical drug-treated responders showed an increased frequency of ‘partially exhausted’ CD8+ T cells. We studied the clinical, immunological and metabolic status of participants after an average follow-up of 7 years. Participants with detectable C-peptide at year 2 of AbATE returned for follow-up. C-peptide responses were assessed by 4 h mixed-meal tolerance test. Autoantibodies and HbA1c levels were measured and average daily insulin use was obtained from patient logs. Peripheral blood mononuclear cells were analysed by flow cytometry and cytokine release. Fifty-six per cent of the original participants returned. Three of the original control group who did not return had lost all detectable C-peptide by the end of the 2 year trial. The C-peptide responses to a mixed-meal tolerance test were similar overall in the drug vs control group of participants but were significantly improved, with less loss of C-peptide, in drug-treated responders identified at 1 year. However, the improvements in C-peptide response were not associated with lower HbA1c levels or insulin use. Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8+ T cells at follow-up. These findings suggest there is reduced decline in C-peptide and persistent immunological responses up to 7 years after diagnosis of diabetes in individuals who respond to Teplizumab. ClinicalTrials.gov NCT02067923; the protocol is available at www.immunetolerance.org (ITN027AI).
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Copyright: American Diabetes Association
2015Co-Authors: William Hagopian, Anastasia G. Daifotis, Scott Koenig, Kevan C Herold, Robert Jr. J Ferry, Nicole Sherry, David Carlin, Ezio Bonvini, Kathryn E. Stein, Post PrintAbstract:Protégé was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous Teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of Teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) re-duced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. resi-dents, patients with C-peptide mean AUC.0.2 nmol/L, those ran-domized #6 weeks after diagnosis, HbA1c,7.5 % (58 mmol/mol), insulin use,0.4 units/kg/day, and 8–17 years of age each had greater Teplizumab-associated C-peptide preservation than thei
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Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial
Diabetes Technology & Therapeutics, 2014Co-Authors: Kevan C Herold, Carla J. Greenbaum, M. R. Ehlers, Karen Boyle, L. Keyes-elstein, Stephen E Gitelman, Peter A Gottlieb, William Hagopian, S. Aggarwal, Deborah PhippardAbstract:DIABETES TECHNOLOGY & THERAPEUTICS Volume 16, Supplement 1, 2014 a Mary Ann Liebert, Inc. DOI: 10.1089/dia.2014.1510 ORIGINAL ARTICLE Immune Intervention for Type 1 Diabetes, 2012–2013 Jay S. Skyler Introduction Results T Teplizumab (14-day full dose) reduced the loss of C-peptide mean area under curve (AUC; a prespecified secondary end- point) at 2 years versus placebo. In analyses of subsets at entry, U.S. residents, patients with C-peptide mean AUC > 0.2 nmol/L, those randomized < 6 weeks after diagnosis, HbA1c < 7.5% (58 mmol/mol), insulin use < 0.4 U/kg/day, and ages 8–17, each had greater Teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be re- duced versus placebo. Antidrug antibodies developed in some patients without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. his chapter of the ATTD 2013 Yearbook reviews the key articles that have appeared between July 2012 and August 2013 in the area of immune intervention in type 1 diabetes. Also included are two studies dealing with beta-cell regen- eration or replacement. The first three studies discussed deal with anti-CD3 monoclonal antibody therapy. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: 2-year results from the randomized, placebo-controlled Protege trial Hagopian W 1 , Ferry RJ Jr 2 , Sherry N 3 , Carlin D 4 , Bonvini E 4 , Johnson S 4 , Stein KE 4 , Koenig S 4 , Daifotis AG 4 , Herold KC 5 , Ludvigsson J 6 ; for the Prote´ge´ Trial Investigators Pacific Northwest Diabetes Research Institute, Seattle, WA; 2 Divi- sion of Pediatric Endocrinology and Metabolism, Le Bonheur Chil- dren’s Hospital and University of Tennessee Health Science Center, Memphis, TN; 3 Massachusetts General Hospital, Boston, MA; MacroGenics, Rockville, MD; 5 Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT; and 6 Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linko¨ping University, Linko¨ping, Sweden Conclusion Anti-CD3 therapy reduced C-peptide loss and thus pre- served b-cell function for 2 years. Diabetes 2013 Jun 25: [Epub ahead of print]; DOI: 10/2337/db13-0236 Background Two years ago we discussed the 1-year results of the Prote´ge´ phase 3 study using Teplizumab. The primary outcome measure—a composite of the percentage of patients with in- sulin use of < 0.5 U/kg per day and HbA1c of < 6.5% at 1 year— was not met. However, exploratory analyses suggested that Teplizumab could help preserve b-cell function—as measured by C-peptide—at 1 year, particularly in subgroups such as children. This report describes the 2-year results from this study. Methods Of the 516 subjects randomized, 462 completed 2 years of follow-up. Treatment was given both at study entry and 6 months later. Comment Previous reports have shown that a short course of hu- manized anti-CD3 monoclonal antibody—either with Teplizumab or otelixizumab—preserved b-cell function as measured by C-peptide. The Prote´ge´ study selected a different primary outcome measure—a composite of the percentage of patients with insulin use of < 0.5 U/kg/ day plus HbA1c of < 6.5% at 1 year. That outcome was not met, and thus many have labeled the Prote´ge´ study a failure. Yet, in the original report, Teplizumab was found to preserve b-cell function at 1 year. The current article demonstrates that this effect was maintained at 2 years. As noted in our earlier discussion of the 1-year results, there was no prior basis for the outcome measure se- lected. Moreover, taking two continuous variables (in- sulin use and HbA1c) and converting them to a single combined dichotomous variable reduces the statistical power of assessment of continuous variables. The C- peptide results, both at 1 year and at 2 years, highlight the problem. Thus, although the original primary outcome was not met, we are still learning from the Prote´ge´ study. Division of Endocrinology, Diabetes, & Metabolism, and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL. S-85
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Teplizumab preserves c peptide in recent onset type 1 diabetes two year results from the randomized placebo controlled protege trial
Diabetes, 2013Co-Authors: William Hagopian, Anastasia G. Daifotis, Scott Koenig, David Carlin, Ezio Bonvini, Kathryn E. Stein, Nicole A. Sherry, Robert J. Ferry, Syd Johnson, Kevan C HeroldAbstract:Protege was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous Teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of Teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized ≤6 weeks after diagnosis, HbA1c <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8–17 years of age each had greater Teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose.
Stephen E Gitelman - One of the best experts on this subject based on the ideXlab platform.
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Comparing Beta Cell Preservation Across Clinical Trials in Recent-Onset Type 1 Diabetes.
Diabetes technology & therapeutics, 2020Co-Authors: Laura M. Jacobsen, Stephen E Gitelman, Kevan C Herold, Brian N. Bundy, Madison N. Greco, Desmond A. Schatz, Mark A. Atkinson, Todd M. Brusko, Clayton E. Mathews, Jeffrey P. KrischerAbstract:Several immunotherapies have demonstrated endogenous insulin preservation in recent-onset type 1 diabetes (T1D). We considered the primary results of rituximab, abatacept, Teplizumab, alefacept, hi...
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An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes
The New England journal of medicine, 2019Co-Authors: Kevan C Herold, S. Alice Long, Jeffrey A Bluestone, Stephen E Gitelman, Peter A Gottlieb, Matthew J Dufort, Brian N. Bundy, Linda A. Dimeglio, J. Krischer, Peter S LinsleyAbstract:Abstract Background Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions ha...
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Treatment of type 1 diabetes with Teplizumab: clinical and immunological follow-up after 7 years from diagnosis
Diabetologia, 2019Co-Authors: Ana Luisa Perdigoto, S. Alice Long, Kristina M. Harris, Carla J. Greenbaum, Stephen E Gitelman, Peter A Gottlieb, Peter S Linsley, Paula Preston-hurlburt, Pamela Clark, William HagopianAbstract:Aims/hypothesis The long-term effects of successful immune therapies for treatment of type 1 diabetes have not been well studied. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial evaluated Teplizumab, an Fc receptor non-binding humanised anti-CD3 monoclonal antibody in individuals with new-onset type 1 diabetes, and ended in 2011. Clinical drug-treated responders showed an increased frequency of ‘partially exhausted’ CD8^+ T cells. We studied the clinical, immunological and metabolic status of participants after an average follow-up of 7 years. Methods Participants with detectable C-peptide at year 2 of AbATE returned for follow-up. C-peptide responses were assessed by 4 h mixed-meal tolerance test. Autoantibodies and HbA_1c levels were measured and average daily insulin use was obtained from patient logs. Peripheral blood mononuclear cells were analysed by flow cytometry and cytokine release. Results Fifty-six per cent of the original participants returned. Three of the original control group who did not return had lost all detectable C-peptide by the end of the 2 year trial. The C-peptide responses to a mixed-meal tolerance test were similar overall in the drug vs control group of participants but were significantly improved, with less loss of C-peptide, in drug-treated responders identified at 1 year. However, the improvements in C-peptide response were not associated with lower HbA_1c levels or insulin use. Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8^+ T cells at follow-up. Conclusions/interpretation These findings suggest there is reduced decline in C-peptide and persistent immunological responses up to 7 years after diagnosis of diabetes in individuals who respond to Teplizumab. Trial registration ClinicalTrials.gov NCT02067923; the protocol is available at www.immunetolerance.org (ITN027AI).
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164-OR: Efficacy of New-Onset Type 1 Diabetes (T1D) Intervention Trials: Variation in 1-Year Outcomes
Diabetes, 2019Co-Authors: Michael J. Haller, Stephen E Gitelman, Kevan C Herold, Laura M. Jacobsen, Madison N. Greco, Desmond A. Schatz, Mark A. Atkinson, Todd M. Brusko, Clayton E. Mathews, Jeffrey P. KrischerAbstract:Mean 2-hour area under the curve (AUC) C-peptide levels at 1 year remain the primary endpoint for most intervention trials in subjects with new onset T1D. Comparisons of efficacy across T1D intervention trials with positive outcomes remain limited. We performed a cross-trial comparison of the NIH TrialNet sponsored new-onset rituximab, abatacept, low-dose anti-thymocyte globulin (ATG) (2.5mg/kg), and ATG/GCSF trials and the NIH ITN sponsored high-dose ATG (6.5mg/kg), alefacept, and Teplizumab trials. One-year study group mean AUC C-peptides were adjusted for baseline C-peptide and age and compared to their internal control to retain individual study effects. To further compare differences in AUC C-peptide across trials, rituximab was used as a reference and percent increase compared to rituximab effect was calculated. Using this methodology, low-dose ATG (164%) and Teplizumab (171%) provided for the largest relative improvements in AUC C-peptide. Percent effects over rituximab of the other studies were: high-dose ATG (-43%), alefacept (33%), abatacept (37%) and ATG/GCSF (45%). Despite the limitations of meta-like analyses and the notable differences in control group AUC C-peptides, these data strongly support the notion that low-dose ATG and Teplizumab provide for the greatest relative preservation of AUC C-peptide amongst recently completed new onset T1D interventions. Disclosure M.J. Haller: Advisory Panel; Self; Pancreum, SAB Biotherapeutics. M.N. Greco: None. D. Schatz: None. M.A. Atkinson: None. T.M. Brusko: Advisory Panel; Self; Caladrius Biosciences, Inc. Board Member; Self; OneVax, LLC. L.M. Jacobsen: None. K.C. Herold: Consultant; Self; Provention Bio, Roche Pharma. S.E. Gitelman: Advisory Panel; Self; Avortes, Intermountain Therapeutics, Lilly Diabetes, Tolerion, Inc. Research Support; Self; Caladrius Biosciences, Inc., Janssen Research & Development. Other Relationship; Self; Novo Nordisk Inc. J. Krischer: None. B.N. Bundy: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust; National Institutes of Health; JDRF; Sanofi; Amgen Inc.; McJunkin Family Charitable Foundation
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antithymocyte globulin treatment for patients with recent onset type 1 diabetes 12 month results of a randomised placebo controlled phase 2 trial
Diabetes Technology & Therapeutics, 2014Co-Authors: Stephen E Gitelman, Mark R Rigby, Steven M Willi, Lynda K Fisher, Michael Gottschalk, Wayne V Moore, Peter A Gottlieb, Antoinette Moran, Eric I Felner, Ashley PinckneyAbstract:DIABETES TECHNOLOGY & THERAPEUTICS Volume 16, Supplement 1, 2014 a Mary Ann Liebert, Inc. DOI: 10.1089/dia.2014.1510 ORIGINAL ARTICLE Immune Intervention for Type 1 Diabetes, 2012–2013 Jay S. Skyler Introduction Results T Teplizumab (14-day full dose) reduced the loss of C-peptide mean area under curve (AUC; a prespecified secondary end- point) at 2 years versus placebo. In analyses of subsets at entry, U.S. residents, patients with C-peptide mean AUC > 0.2 nmol/L, those randomized < 6 weeks after diagnosis, HbA1c < 7.5% (58 mmol/mol), insulin use < 0.4 U/kg/day, and ages 8–17, each had greater Teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be re- duced versus placebo. Antidrug antibodies developed in some patients without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. his chapter of the ATTD 2013 Yearbook reviews the key articles that have appeared between July 2012 and August 2013 in the area of immune intervention in type 1 diabetes. Also included are two studies dealing with beta-cell regen- eration or replacement. The first three studies discussed deal with anti-CD3 monoclonal antibody therapy. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: 2-year results from the randomized, placebo-controlled Protege trial Hagopian W 1 , Ferry RJ Jr 2 , Sherry N 3 , Carlin D 4 , Bonvini E 4 , Johnson S 4 , Stein KE 4 , Koenig S 4 , Daifotis AG 4 , Herold KC 5 , Ludvigsson J 6 ; for the Prote´ge´ Trial Investigators Pacific Northwest Diabetes Research Institute, Seattle, WA; 2 Divi- sion of Pediatric Endocrinology and Metabolism, Le Bonheur Chil- dren’s Hospital and University of Tennessee Health Science Center, Memphis, TN; 3 Massachusetts General Hospital, Boston, MA; MacroGenics, Rockville, MD; 5 Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT; and 6 Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linko¨ping University, Linko¨ping, Sweden Conclusion Anti-CD3 therapy reduced C-peptide loss and thus pre- served b-cell function for 2 years. Diabetes 2013 Jun 25: [Epub ahead of print]; DOI: 10/2337/db13-0236 Background Two years ago we discussed the 1-year results of the Prote´ge´ phase 3 study using Teplizumab. The primary outcome measure—a composite of the percentage of patients with in- sulin use of < 0.5 U/kg per day and HbA1c of < 6.5% at 1 year— was not met. However, exploratory analyses suggested that Teplizumab could help preserve b-cell function—as measured by C-peptide—at 1 year, particularly in subgroups such as children. This report describes the 2-year results from this study. Methods Of the 516 subjects randomized, 462 completed 2 years of follow-up. Treatment was given both at study entry and 6 months later. Comment Previous reports have shown that a short course of hu- manized anti-CD3 monoclonal antibody—either with Teplizumab or otelixizumab—preserved b-cell function as measured by C-peptide. The Prote´ge´ study selected a different primary outcome measure—a composite of the percentage of patients with insulin use of < 0.5 U/kg/ day plus HbA1c of < 6.5% at 1 year. That outcome was not met, and thus many have labeled the Prote´ge´ study a failure. Yet, in the original report, Teplizumab was found to preserve b-cell function at 1 year. The current article demonstrates that this effect was maintained at 2 years. As noted in our earlier discussion of the 1-year results, there was no prior basis for the outcome measure se- lected. Moreover, taking two continuous variables (in- sulin use and HbA1c) and converting them to a single combined dichotomous variable reduces the statistical power of assessment of continuous variables. The C- peptide results, both at 1 year and at 2 years, highlight the problem. Thus, although the original primary outcome was not met, we are still learning from the Prote´ge´ study. Division of Endocrinology, Diabetes, & Metabolism, and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL. S-85
Peter A Gottlieb - One of the best experts on this subject based on the ideXlab platform.
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An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes
The New England journal of medicine, 2019Co-Authors: Kevan C Herold, S. Alice Long, Jeffrey A Bluestone, Stephen E Gitelman, Peter A Gottlieb, Matthew J Dufort, Brian N. Bundy, Linda A. Dimeglio, J. Krischer, Peter S LinsleyAbstract:Abstract Background Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions ha...
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Treatment of type 1 diabetes with Teplizumab: clinical and immunological follow-up after 7 years from diagnosis
Diabetologia, 2019Co-Authors: Ana Luisa Perdigoto, S. Alice Long, Kristina M. Harris, Carla J. Greenbaum, Stephen E Gitelman, Peter A Gottlieb, Peter S Linsley, Paula Preston-hurlburt, Pamela Clark, William HagopianAbstract:Aims/hypothesis The long-term effects of successful immune therapies for treatment of type 1 diabetes have not been well studied. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial evaluated Teplizumab, an Fc receptor non-binding humanised anti-CD3 monoclonal antibody in individuals with new-onset type 1 diabetes, and ended in 2011. Clinical drug-treated responders showed an increased frequency of ‘partially exhausted’ CD8^+ T cells. We studied the clinical, immunological and metabolic status of participants after an average follow-up of 7 years. Methods Participants with detectable C-peptide at year 2 of AbATE returned for follow-up. C-peptide responses were assessed by 4 h mixed-meal tolerance test. Autoantibodies and HbA_1c levels were measured and average daily insulin use was obtained from patient logs. Peripheral blood mononuclear cells were analysed by flow cytometry and cytokine release. Results Fifty-six per cent of the original participants returned. Three of the original control group who did not return had lost all detectable C-peptide by the end of the 2 year trial. The C-peptide responses to a mixed-meal tolerance test were similar overall in the drug vs control group of participants but were significantly improved, with less loss of C-peptide, in drug-treated responders identified at 1 year. However, the improvements in C-peptide response were not associated with lower HbA_1c levels or insulin use. Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8^+ T cells at follow-up. Conclusions/interpretation These findings suggest there is reduced decline in C-peptide and persistent immunological responses up to 7 years after diagnosis of diabetes in individuals who respond to Teplizumab. Trial registration ClinicalTrials.gov NCT02067923; the protocol is available at www.immunetolerance.org (ITN027AI).
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Treatment of type 1 diabetes with Teplizumab: clinical and immunological follow-up after 7 years from diagnosis.
Diabetologia, 2018Co-Authors: Ana Luisa Perdigoto, S. Alice Long, Kristina M. Harris, Carla J. Greenbaum, Peter A Gottlieb, Peter S Linsley, Se Gitelman, Paula Preston-hurlburt, Pamela Clark, William HagopianAbstract:The long-term effects of successful immune therapies for treatment of type 1 diabetes have not been well studied. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial evaluated Teplizumab, an Fc receptor non-binding humanised anti-CD3 monoclonal antibody in individuals with new-onset type 1 diabetes, and ended in 2011. Clinical drug-treated responders showed an increased frequency of ‘partially exhausted’ CD8+ T cells. We studied the clinical, immunological and metabolic status of participants after an average follow-up of 7 years. Participants with detectable C-peptide at year 2 of AbATE returned for follow-up. C-peptide responses were assessed by 4 h mixed-meal tolerance test. Autoantibodies and HbA1c levels were measured and average daily insulin use was obtained from patient logs. Peripheral blood mononuclear cells were analysed by flow cytometry and cytokine release. Fifty-six per cent of the original participants returned. Three of the original control group who did not return had lost all detectable C-peptide by the end of the 2 year trial. The C-peptide responses to a mixed-meal tolerance test were similar overall in the drug vs control group of participants but were significantly improved, with less loss of C-peptide, in drug-treated responders identified at 1 year. However, the improvements in C-peptide response were not associated with lower HbA1c levels or insulin use. Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8+ T cells at follow-up. These findings suggest there is reduced decline in C-peptide and persistent immunological responses up to 7 years after diagnosis of diabetes in individuals who respond to Teplizumab. ClinicalTrials.gov NCT02067923; the protocol is available at www.immunetolerance.org (ITN027AI).
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Teplizumab treatment may improve c peptide responses in participants with type 1 diabetes after the new onset period a randomized controlled trial
Diabetes Technology & Therapeutics, 2014Co-Authors: Kevan C Herold, Steven M Willi, Peter A Gottlieb, Se Gitelman, Lesley Devine, Frank Waldronlynch, Jennifer L Sherr, Stephen M Rosenthal, Saleh Adi, My JalaludinAbstract:DIABETES TECHNOLOGY & THERAPEUTICS Volume 16, Supplement 1, 2014 a Mary Ann Liebert, Inc. DOI: 10.1089/dia.2014.1510 ORIGINAL ARTICLE Immune Intervention for Type 1 Diabetes, 2012–2013 Jay S. Skyler Introduction Results T Teplizumab (14-day full dose) reduced the loss of C-peptide mean area under curve (AUC; a prespecified secondary end- point) at 2 years versus placebo. In analyses of subsets at entry, U.S. residents, patients with C-peptide mean AUC > 0.2 nmol/L, those randomized < 6 weeks after diagnosis, HbA1c < 7.5% (58 mmol/mol), insulin use < 0.4 U/kg/day, and ages 8–17, each had greater Teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be re- duced versus placebo. Antidrug antibodies developed in some patients without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. his chapter of the ATTD 2013 Yearbook reviews the key articles that have appeared between July 2012 and August 2013 in the area of immune intervention in type 1 diabetes. Also included are two studies dealing with beta-cell regen- eration or replacement. The first three studies discussed deal with anti-CD3 monoclonal antibody therapy. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: 2-year results from the randomized, placebo-controlled Protege trial Hagopian W 1 , Ferry RJ Jr 2 , Sherry N 3 , Carlin D 4 , Bonvini E 4 , Johnson S 4 , Stein KE 4 , Koenig S 4 , Daifotis AG 4 , Herold KC 5 , Ludvigsson J 6 ; for the Prote´ge´ Trial Investigators Pacific Northwest Diabetes Research Institute, Seattle, WA; 2 Divi- sion of Pediatric Endocrinology and Metabolism, Le Bonheur Chil- dren’s Hospital and University of Tennessee Health Science Center, Memphis, TN; 3 Massachusetts General Hospital, Boston, MA; MacroGenics, Rockville, MD; 5 Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT; and 6 Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linko¨ping University, Linko¨ping, Sweden Conclusion Anti-CD3 therapy reduced C-peptide loss and thus pre- served b-cell function for 2 years. Diabetes 2013 Jun 25: [Epub ahead of print]; DOI: 10/2337/db13-0236 Background Two years ago we discussed the 1-year results of the Prote´ge´ phase 3 study using Teplizumab. The primary outcome measure—a composite of the percentage of patients with in- sulin use of < 0.5 U/kg per day and HbA1c of < 6.5% at 1 year— was not met. However, exploratory analyses suggested that Teplizumab could help preserve b-cell function—as measured by C-peptide—at 1 year, particularly in subgroups such as children. This report describes the 2-year results from this study. Methods Of the 516 subjects randomized, 462 completed 2 years of follow-up. Treatment was given both at study entry and 6 months later. Comment Previous reports have shown that a short course of hu- manized anti-CD3 monoclonal antibody—either with Teplizumab or otelixizumab—preserved b-cell function as measured by C-peptide. The Prote´ge´ study selected a different primary outcome measure—a composite of the percentage of patients with insulin use of < 0.5 U/kg/ day plus HbA1c of < 6.5% at 1 year. That outcome was not met, and thus many have labeled the Prote´ge´ study a failure. Yet, in the original report, Teplizumab was found to preserve b-cell function at 1 year. The current article demonstrates that this effect was maintained at 2 years. As noted in our earlier discussion of the 1-year results, there was no prior basis for the outcome measure se- lected. Moreover, taking two continuous variables (in- sulin use and HbA1c) and converting them to a single combined dichotomous variable reduces the statistical power of assessment of continuous variables. The C- peptide results, both at 1 year and at 2 years, highlight the problem. Thus, although the original primary outcome was not met, we are still learning from the Prote´ge´ study. Division of Endocrinology, Diabetes, & Metabolism, and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL. S-85
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antithymocyte globulin treatment for patients with recent onset type 1 diabetes 12 month results of a randomised placebo controlled phase 2 trial
Diabetes Technology & Therapeutics, 2014Co-Authors: Stephen E Gitelman, Mark R Rigby, Steven M Willi, Lynda K Fisher, Michael Gottschalk, Wayne V Moore, Peter A Gottlieb, Antoinette Moran, Eric I Felner, Ashley PinckneyAbstract:DIABETES TECHNOLOGY & THERAPEUTICS Volume 16, Supplement 1, 2014 a Mary Ann Liebert, Inc. DOI: 10.1089/dia.2014.1510 ORIGINAL ARTICLE Immune Intervention for Type 1 Diabetes, 2012–2013 Jay S. Skyler Introduction Results T Teplizumab (14-day full dose) reduced the loss of C-peptide mean area under curve (AUC; a prespecified secondary end- point) at 2 years versus placebo. In analyses of subsets at entry, U.S. residents, patients with C-peptide mean AUC > 0.2 nmol/L, those randomized < 6 weeks after diagnosis, HbA1c < 7.5% (58 mmol/mol), insulin use < 0.4 U/kg/day, and ages 8–17, each had greater Teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be re- duced versus placebo. Antidrug antibodies developed in some patients without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. his chapter of the ATTD 2013 Yearbook reviews the key articles that have appeared between July 2012 and August 2013 in the area of immune intervention in type 1 diabetes. Also included are two studies dealing with beta-cell regen- eration or replacement. The first three studies discussed deal with anti-CD3 monoclonal antibody therapy. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: 2-year results from the randomized, placebo-controlled Protege trial Hagopian W 1 , Ferry RJ Jr 2 , Sherry N 3 , Carlin D 4 , Bonvini E 4 , Johnson S 4 , Stein KE 4 , Koenig S 4 , Daifotis AG 4 , Herold KC 5 , Ludvigsson J 6 ; for the Prote´ge´ Trial Investigators Pacific Northwest Diabetes Research Institute, Seattle, WA; 2 Divi- sion of Pediatric Endocrinology and Metabolism, Le Bonheur Chil- dren’s Hospital and University of Tennessee Health Science Center, Memphis, TN; 3 Massachusetts General Hospital, Boston, MA; MacroGenics, Rockville, MD; 5 Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT; and 6 Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linko¨ping University, Linko¨ping, Sweden Conclusion Anti-CD3 therapy reduced C-peptide loss and thus pre- served b-cell function for 2 years. Diabetes 2013 Jun 25: [Epub ahead of print]; DOI: 10/2337/db13-0236 Background Two years ago we discussed the 1-year results of the Prote´ge´ phase 3 study using Teplizumab. The primary outcome measure—a composite of the percentage of patients with in- sulin use of < 0.5 U/kg per day and HbA1c of < 6.5% at 1 year— was not met. However, exploratory analyses suggested that Teplizumab could help preserve b-cell function—as measured by C-peptide—at 1 year, particularly in subgroups such as children. This report describes the 2-year results from this study. Methods Of the 516 subjects randomized, 462 completed 2 years of follow-up. Treatment was given both at study entry and 6 months later. Comment Previous reports have shown that a short course of hu- manized anti-CD3 monoclonal antibody—either with Teplizumab or otelixizumab—preserved b-cell function as measured by C-peptide. The Prote´ge´ study selected a different primary outcome measure—a composite of the percentage of patients with insulin use of < 0.5 U/kg/ day plus HbA1c of < 6.5% at 1 year. That outcome was not met, and thus many have labeled the Prote´ge´ study a failure. Yet, in the original report, Teplizumab was found to preserve b-cell function at 1 year. The current article demonstrates that this effect was maintained at 2 years. As noted in our earlier discussion of the 1-year results, there was no prior basis for the outcome measure se- lected. Moreover, taking two continuous variables (in- sulin use and HbA1c) and converting them to a single combined dichotomous variable reduces the statistical power of assessment of continuous variables. The C- peptide results, both at 1 year and at 2 years, highlight the problem. Thus, although the original primary outcome was not met, we are still learning from the Prote´ge´ study. Division of Endocrinology, Diabetes, & Metabolism, and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL. S-85
Peter S Linsley - One of the best experts on this subject based on the ideXlab platform.
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250 or hypoproliferative cd8 effector memory em subsets are linked to preservation of c peptide in alefacept treated recent onset type 1 diabetes t1d subjects
Diabetes, 2020Co-Authors: Elisavet Serti, Gerald T. Nepom, Kirsten E Diggins, Virginia S Muir, Elisa Balmas, Alice S Long, Peter S LinsleyAbstract:In the ITN T1DAL trial, alefacept (LFA3-Ig fusion protein) preserved endogenous insulin production in 30% of recent onset T1D patients for two years after therapy. Although patients experienced immune alterations following treatment, including depletion of CD2hi effector T-cells and preservation of CD2lo regulatory T-cells, these effects were not predictive of overall response or outcome. However, using an unbiased approach and a combination of flow cytometry, RNA-sequencing, and CyTOF, we were able to identify a CD8 T-cell signature of response at ∼two years following treatment. Preservation of C-peptide was associated with a large transcriptional module (n= 738 genes; R= 0.4, p= 0.023) including activation and exhaustion-associated genes identified at two years following treatment using WGCNA. This module was further dissected into two distinct CD8 EM populations through correlation with hierarchically gated and clustered cytometry data. While both populations expressed multiple inhibitory receptors (IR) (TIGIT, KLRG1, T-bet, EOMES) and were hypo-responsive in in vitro proliferation assays, they were distinguished by higher expression either of markers seen in cytotoxic and terminally differentiated effector T cells (CD57+ Granzyme B+) or of PD-1. Gene expression signatures of both the CD57 and PD-1 subsets significantly overlapped with a previously identified partial exhaustion signature (p= 0.005, for both subsets). Our findings demonstrate an association of partially exhausted memory CD8 T-cells with beneficial clinical response to alefacept as we observed previously with Teplizumab (anti-CD3) treatment. Our findings also demonstrate linkage of two phenotypically distinct IR-high, hypo-proliferative CD8 EM T-cell subsets with beneficial response. Together, our findings suggest that pathways regulating proliferation of EM CD8 cells may lead to successful immune interventions for T1D. Disclosure E. Serti: None. K.E. Diggins: None. V.S. Muir: None. T. Lu: None. E. Balmas: None. G.T. Nepom: None. S. Long: None. P. Linsley: Consultant; Self; Bristol-Myers Squibb. Funding National Institute of Diabetes and Digestive and Kidney Diseases/National Institute of Allergy and Infectious Diseases (UM1AI109565)
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An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes
The New England journal of medicine, 2019Co-Authors: Kevan C Herold, S. Alice Long, Jeffrey A Bluestone, Stephen E Gitelman, Peter A Gottlieb, Matthew J Dufort, Brian N. Bundy, Linda A. Dimeglio, J. Krischer, Peter S LinsleyAbstract:Abstract Background Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions ha...
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Elevated T cell levels in peripheral blood predict poor clinical response following rituximab treatment in new-onset type 1 diabetes
Genes & Immunity, 2019Co-Authors: Peter S Linsley, Carla J. Greenbaum, Mario Rosasco, Scott Presnell, Kevan C Herold, Matthew J DufortAbstract:Biologic treatment of type 1 diabetes (T1D) with agents including anti-CD3 (otelixizumab and Teplizumab), anti-CD20 (rituximab), LFA3Ig (alafacept), and CTLA4Ig (abatacept) results in transient stabilization of insulin C-peptide, a surrogate for endogenous insulin secretion. With the goal of inducing more robust immune tolerance, we used systems biology approaches to elucidate mechanisms associated with C-peptide stabilization in clinical trial blood samples from new-onset T1D subjects treated with the B cell-depleting drug, rituximab. RNA sequencing (RNA-seq) analysis of whole-blood samples from this trial revealed a transient increase in heterogeneous T cell populations, which were associated with decreased pharmacodynamic activity of rituximab, increased proliferative responses to islet antigens, and more rapid C-peptide loss. Our findings illustrate complexity in hematopoietic remodeling that accompanies B cell depletion by rituximab, which impacts and predicts therapeutic efficacy in T1D. Our data also suggest that a combination of rituximab with therapy targeting CD4 + T cells may be beneficial for T1D subjects.
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Treatment of type 1 diabetes with Teplizumab: clinical and immunological follow-up after 7 years from diagnosis
Diabetologia, 2019Co-Authors: Ana Luisa Perdigoto, S. Alice Long, Kristina M. Harris, Carla J. Greenbaum, Stephen E Gitelman, Peter A Gottlieb, Peter S Linsley, Paula Preston-hurlburt, Pamela Clark, William HagopianAbstract:Aims/hypothesis The long-term effects of successful immune therapies for treatment of type 1 diabetes have not been well studied. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial evaluated Teplizumab, an Fc receptor non-binding humanised anti-CD3 monoclonal antibody in individuals with new-onset type 1 diabetes, and ended in 2011. Clinical drug-treated responders showed an increased frequency of ‘partially exhausted’ CD8^+ T cells. We studied the clinical, immunological and metabolic status of participants after an average follow-up of 7 years. Methods Participants with detectable C-peptide at year 2 of AbATE returned for follow-up. C-peptide responses were assessed by 4 h mixed-meal tolerance test. Autoantibodies and HbA_1c levels were measured and average daily insulin use was obtained from patient logs. Peripheral blood mononuclear cells were analysed by flow cytometry and cytokine release. Results Fifty-six per cent of the original participants returned. Three of the original control group who did not return had lost all detectable C-peptide by the end of the 2 year trial. The C-peptide responses to a mixed-meal tolerance test were similar overall in the drug vs control group of participants but were significantly improved, with less loss of C-peptide, in drug-treated responders identified at 1 year. However, the improvements in C-peptide response were not associated with lower HbA_1c levels or insulin use. Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8^+ T cells at follow-up. Conclusions/interpretation These findings suggest there is reduced decline in C-peptide and persistent immunological responses up to 7 years after diagnosis of diabetes in individuals who respond to Teplizumab. Trial registration ClinicalTrials.gov NCT02067923; the protocol is available at www.immunetolerance.org (ITN027AI).
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Treatment of type 1 diabetes with Teplizumab: clinical and immunological follow-up after 7 years from diagnosis.
Diabetologia, 2018Co-Authors: Ana Luisa Perdigoto, S. Alice Long, Kristina M. Harris, Carla J. Greenbaum, Peter A Gottlieb, Peter S Linsley, Se Gitelman, Paula Preston-hurlburt, Pamela Clark, William HagopianAbstract:The long-term effects of successful immune therapies for treatment of type 1 diabetes have not been well studied. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial evaluated Teplizumab, an Fc receptor non-binding humanised anti-CD3 monoclonal antibody in individuals with new-onset type 1 diabetes, and ended in 2011. Clinical drug-treated responders showed an increased frequency of ‘partially exhausted’ CD8+ T cells. We studied the clinical, immunological and metabolic status of participants after an average follow-up of 7 years. Participants with detectable C-peptide at year 2 of AbATE returned for follow-up. C-peptide responses were assessed by 4 h mixed-meal tolerance test. Autoantibodies and HbA1c levels were measured and average daily insulin use was obtained from patient logs. Peripheral blood mononuclear cells were analysed by flow cytometry and cytokine release. Fifty-six per cent of the original participants returned. Three of the original control group who did not return had lost all detectable C-peptide by the end of the 2 year trial. The C-peptide responses to a mixed-meal tolerance test were similar overall in the drug vs control group of participants but were significantly improved, with less loss of C-peptide, in drug-treated responders identified at 1 year. However, the improvements in C-peptide response were not associated with lower HbA1c levels or insulin use. Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8+ T cells at follow-up. These findings suggest there is reduced decline in C-peptide and persistent immunological responses up to 7 years after diagnosis of diabetes in individuals who respond to Teplizumab. ClinicalTrials.gov NCT02067923; the protocol is available at www.immunetolerance.org (ITN027AI).