Stem cell treatment study yields promising results for type 1 diabetes

Most patients in Brazilian study achieved prolonged insulin independence.

Issue: May 2007

In a small pilot study, treatment with immunosuppression followed by autologous hematopoietic stem cell transplantation was well tolerated and resulted in prolonged insulin independence in almost all patients with diabetes.

Julio C. Voltarelli, MD, PhD, of the Regional Blood Center at the University of Sao Paulo in Brazil, and colleagues conducted the first prospective trial using stem cell therapy in humans to treat diabetes. The pilot study analyzed the safety, metabolic effects and ability of autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) to preserve beta cell function in patients with newly diagnosed type 1 diabetes.

“Since 1996, organ-threatening systemic lupus erythematosus and other autoimmune diseases have been successfully treated with high-dose immunosuppression followed by autologous nonmyeloablative hematopoietic stem cell transplantation,” the researchers wrote in the Journal of the American Medical Association. “In animal models, allogeneic bone marrow transplantation prevents both insulitis and the development of type 1 diabetes mellitus in susceptible strains of mice.”

Study methods

The researchers enrolled 15 patients aged 14 to 31 (mean 19.2) between November 2003 and July 2006. All patients had been diagnosed with type 1 diabetes mellitus within the prior six weeks.

All patients were first given an immune ablative conditioning regimen. This consisted of cyclophosphamide, which was given intravenously (50 mg/kg per day over one hour; five, four, three and two days prior to stem cell infusion), and antithymocyte globulin (0.5 mg/kg per day five days before, 1.0 mg/kg per day four, three, two and one day before infusion).

The first patient enrolled was diagnosed with diabetic ketoacidosis and was given hydrocortisone and methylprednisolone to prevent reactions with the antithymocyte globulin. This patient’s continued insulin dependence following stem cell transplantation and increasing insulin requirements (up to 250% higher than initial requirement at 12 months) led the investigators to change the study protocol. Ketoacidosis was considered an exclusion criterion, and glucocorticoid use was avoided in later patients; instead, dexchlorpheniramine (6 mg by mouth) was administered as prophylaxis of antithymocyte globulin reactions.

Peripheral hematopoietic stem cells were first mobilized with cyclophosphamide and granulocyte colony-stimulating factor. Using leukapheresis, the cells were harvested and stored in liquid nitrogen until infusion. The mean number of infused cells was 11 kg × 10⁶/kg. Although most patients experienced what the investigators called “common transplantation-related complications” such as febrile neutropenia, nausea, vomiting and alopecia, only one severe acute complication of AHST occurred. This was a case of bilateral pneumonia that required supplementary oxygen therapy; the patient responded completely to broad-spectrum antibiotics.

Exogenous insulin

Because the study protocol was changed after the first patient’s treatment, those data were excluded from the final analyses. Among the other patients, all patients required exogenous insulin at baseline (mean, 0.38 IU/kg per day). As of February 2007, 13 patients were free from exogenous insulin for a mean of 16.2 months (range, one to 35 months). One patient resumed insulin use 360 days after transplantation following a viral upper respiratory tract infection.

At baseline, 11 of the 14 patients had HbA1c values >7%. There was a statistically significant reduction in HbA1c (P<.05) after transplantation, and all patients achieved the treatment goal of HbA1c <7% and maintained this throughout the follow-up period (with the exception of the one patient who resumed insulin treatment).

The researchers also analyzed C-peptide levels as a measure of beta cell function. Mean peak stimulated C-peptide levels were 1.3 ng/mL at pretreatment; this average rose to 4.0 ng/mL after six months, 3.7 ng/mL after 12 months and 4.5 ng/mL after 24 months ( P<.05 vs. all other time points). At six months after transplantation, the peak stimulated C-peptide levels had increased in 11 of 13 patients studied; at 12 months it increased in eight of 10 patients studied; at 24 months it increased in four of four patients studied; at 36 months it increased in the one patient studied.

Study limitations

Although the mechanism involved in the effects seen in this study remains unknown, Voltarelli hypothesized that “the infused stem cells build up the immune system’s tolerance to pancreatic beta cells.” Whether this tolerance is an active or passive tolerance (characterized by T-regulatory cell suppression and clonal deletion, respectively) has yet to be determined.

Jay S. Skyler, MD, a professor in the division of endocrinology, diabetes and metabolism at the University of Miami School of Medicine, wrote an accompanying editorial in the journal about cellular therapies for type 1 diabetes and elaborated on possible mechanisms.

“Although the goal of AHST for patients with autoimmune diseases is to generate new self-tolerant lymphocytes after elimination of self-reactive or autoreactive lymphocytes, other mechanisms have not been excluded, such as generation of relatively larger numbers of regulatory lymphocytes or stem cell differentiation to new healthier cells within the organs being damaged by the autoimmune disease process.”

Skyler said in an interview with Endocrine Today that although these current results may be promising, the limitations of the study should lead to caution when interpreting the study. “To me, this study indicates that more research is needed before any conclusions can be drawn about clinical applicability,” he said. “I’d like to see complete two- to four-year data in an adequately powered randomized controlled study.” Voltarelli noted that his group is starting a new trial using the same therapy in children aged younger than 12 years.

Skyler’s editorial also outlined some of the other possible approaches currently under consideration as treatments for type 1 diabetes: infusion of dendritic cells, T-regulatory lymphocytes, umbilical cord cells, embryonic or adult stem cells and allogenic bone marrow transplantation.

“There is going to be much experimentation with cellular therapies during the next few years,” he told Endocrine Today. “But we are a long way from general usage.” – by Dave Levitan

For more information:
Voltarelli JC, Couri CEB, Stracieri ABPL, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2007;297:1568-1576.
Skyler JS. Cellular therapy for type 1 diabetes: has the time come? JAMA. 2007;297:1599-1600.