Nicole A. Sherry, MD
Instructor in Pediatrics, Harvard Medical School; Physician, Pediatric Endocrinology, Mass General Hospital for Children; Director, Diabetes Program, Pediatric Endocrinology, MassGeneral Hospital for Children
My focus is to develop a better understanding of type 1 diabetes by conducting current trials in immune therapy for type 1 diabetes (TIDM) and leading the development of new approaches to clinical trials in this field.
I started in this field, studying the effect of anti-CD3 antibody immune therapy in NOD mice (a mouse model of T1DM) to determine the effect of anti-CD3 and the immune disease on beta cell dynamics and determine methods of strengthening this effect.
I have been more recently involved in clinical trials in immune therapy in early onset T1DM. I recently authored the report of the 1 year results of the Protégé study, a Phase 3 immune therapy trial of anti-CD3 antibody (teplizumab) for which I was the investigator at MGH. This was a double-blind, placebo-controlled, multicenter, international trial of about 500 patients with new-onset type 1 diabetes. The primary objective of this trial was to show that there was preservation of beta cells using 2 short courses of immune therapy (14 days of IV infusions at 0 and 6 months). This objective was tested by comparing the number of patients who met a composite endpoint of an HbA1c of <6.5% and an insulin use of <0.5 U/kg per day– signifying remission- in the control and study groups at 1 year. The study did not show a difference in this parameter. However despite this negative finding the study did suggest that there was a biological effect of teplizumab on beta cells which was consistent with prior smaller studies of this drug. In post-hoc analyses in the overall population and in pre-specified subgroup analyses, there was a greater preservation of C-peptide at 1 year in patients who received the drug. This effect was most pronounced in young patients and patients in the US (see figure). Strikingly, 5% of patients in the teplizumab-treated groups were off insulin at 1 year with maintenance of metabolic control compared to none in the placebo group. The majority of the patients in this study were followed for 2 years and analysis of these results is ongoing.
From this data as well as several other studies of immune therapy that have been published in the past several years it is clear that a single drug treatment of type 1 diabetes will not reverse the immune process. As such there has been the development of a handful of different approaches that target antigens, B cells, T cells and cytokines that all work together to cause the autoimmune process in T1DM. I am currently the lead investigator at MGH for 2 such trials which are in Phase 1, the RETAIN study, which is studying alpha-1 antitrypsin and the T1DAL study, which is studying alefacept.
In the near future, I will be involved in looking at some of these modalities in patients at risk for but who have not yet developed T1DM as well as looking at combination therapies in patients recently diagnosed with type 1 diabetes.
Sherry NA, Kushner JA, Glandt M, Kitamura T, Brillantes A-M, and Herold KC. Effects of autoimmunity and immune therapy on beta cell turnover in Type 1 diabetes. Diabetes 2006:55(12)3238-45.
Sherry NA, Chen W, Kushner JA, Glandt M, Tang Q, Tsai S, Santamaria P, Bluestone JA, Brillantes AM, Herold KC. Exendin-4 improves reversal of diabetes in NOD mice treated with anti-CD3 mAb by enhancing recovery of beta cells. Endocrinology 2007;148(11):5136-44.
Sherry N, Hagopian W, Ludvigsson J, Jain SM, Wahlen J, Ferry RJ Jr, Bode B, Aronoff S, Holland C, Carlin D, King KL, Wilder RL, Pillemer S, Bonvini E, Johnson S, Stein KE, Koenig S, Herold KC, Daifotis AG; for the Protégé Trial Investigators. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet 2011;378(9790):487-97.