The experiments have moved from mice to a clinical trial in humans, and the testing has passed every research milestone ahead of schedule -- an astonishing feat for any clinical research project. The Phase I safety trial in people with Type 1 diabetes is near completion. The next step is to find, in a Phase II study, the possible dose and frequency of administration of BCG vaccinations that will benefit patients with Type 1 diabetes.

What makes these trials unique? First, unlike other immunosuppressive therapies for autoimmune diseases that harm both healthy and disease-causing T-cells, this treatment appears to provide a way to achieve "targeted removal" of only autoimmune disease-causing cells. BCG works by causing the release of a natural protein in the body called tumor necrosis factor, or TNF. In mice, temporarily elevating TNF levels destroys the autoreactive T-cells, allowing the insulin-producing cells of the pancreas to regenerate and produce insulin. TNF in mice also elevates a good population of T-cells, thus restoring the immune system to near normal. In other words, the treatment literally reverses Type 1 diabetes, at least in a mouse model of diabetes. In laboratory experiments, TNF also destroys the autoreactive cells in human blood samples. TNF does not harm the normal, healthy T-cells that help fight infection, leaving the immune system intact.

The human clinical trials seek to expand these findings in human subjects. The BCG trial is also unique since BCG is a generic drug that has been used widely as a vaccine for more than 80 years in humans. Currently, BCG is used in small doses as a vaccine against tuberculosis, and it is used in larger doses as a bladder cancer therapy. Because it has been used for so long and in so many humans, the safety of this vaccine is well-established. This fact allows the trials to move more quickly through safety studies compared to clinical trials that test new drugs.

With a generic drug, it can move BCG to the public rapidly if the drug is indeed found to be safe and effective in patients with Type 1 diabetes. The phase I safety study is following the enrolled patients over months looking for changes in the T-cells and also testing the reliability of the blood tests for tracking disease-causing T-cells.

The BCG trial is one of the few translational studies in human testing where the animal data showed disease reversal in diabetic mice that had hyperglycemia, not just in mice with normal blood sugars and with a predisposition to diabetes. Therefore, this human trial at Mass General is designed to treat people with established Type 1 diabetes unlike most human testing that focuses only on not yet diabetic patients at risk for the disease or newly diagnosed diabetics with a short time period of high blood sugars.

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