A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study of the Safety and Efficacy of Autologous Immunoregulatory Dendritic Cells in Patients With Type 1 Diabetes

This is a double-blind, placebo-controlled cross study designed to evaluate the safety and efficacy of autologous immunoregulatory dendritic cells (iDC) in patients with type 1 diabetes. To do this, a total of 24 subjects with recent onset (<100 days from diagnosis) type 1 diabetes will have circulating dendritic cells harvested via leukapheresis. The harvested dendritic cells will then be incubated in vitro with antisense DNA oligonucleotides targeting the primary transcripts of cluster of differentiation antigen 40 (CD40), cluster of differentiation antigen 80 (CD80) and cluster of differentiation antigen 86 (CD86). These engineered dendritic cells will then be given as autologous intradermal injections (4 injections administered at 2 week intervals) in the subject' peri-umbilical region. The hypothesis is that the injected cells will generate immunoregulatory cells that suppress the autoimmune process responsible for the development of type 1 diabetes via destruction of the subject's pancreatic beta cells.

Employing a cross-over design, all subjects will undergo leukapheresis at the outset. Twelve subjects will be randomly assigned to receive cell injections at the outset while the other 12 subjects will receive sham injections and serve as controls. At the end of 12 months, all subjects will cross-over to the alternative treatment and continue to be followed for an additional 12 months. (Note: The subjects assigned to receive the cell therapy for this segment will receive injections of their autologous cells harvested and engineered at the time of the leukapheresis performed at study entry. The engineered cells will be stored frozen until needed for administration. This design will test whether treatment later (>1 year after diagnosis) is as effective as immediate treatment (<100 days from the diagnosis of type 1 diabetes).

As an added safety measure, the first 6 subjects randomized will all be over the age of 18. When the last of these 6 subjects complete 3 months of observation following the initiation of therapy, the age for enrollment will be lowered to age 16 for the next 6 subjects unless safety observations dictate otherwise. When all subjects in this cohort have been enrolled, the age for enrollment will be lowered to age 14 unless advised otherwise by the independent Data Safety Monitoring Board. When all subjects in this cohort have completed observation for 3 months, the age for enrollment will be lowered to age 12 following clearance by the Data Safety Monitoring Board.

If this therapy is successful, the subjects' remaining beta cell mass will be preserved and hopefully expanded once the autoimmune process is slowed or stopped. This outcome will be assessed indirectly using plasma c-peptide concentrations following ingestion of a standardized mixed meal at the end of 12 and 24 months of therapy. If the treatment is successful, glucose control should improve and be detectable via measurement of hemoglobin A1c (measure of long-term control), fasting plasma glucose concentrations and the plasma glucose concentrations following ingestion of the standardized mixed meal. In addition, the total daily insulin requirements should decrease. These measures of glucose control will be assessed at baseline and then at 3, 6, 9, 12, 15, 18, 21 and 24 months.

Immune markers will also be profiled at 3 month intervals to assess potential tolerogenic effects of the therapy. To this end, numbers of potentially tolerogenic/regulatory T-cells, B-cells and dendritic cells in the circulating peripheral blood monocyte population will be assessed. In addition, analysis of selected populations of T-cells, B-cells and dendritic cells will be conducted over the entire study period in an attempt to identify molecular signatures correlated with the clinical response.