• February 2021

    Studies show small molecule successfully blocks inflammation after auto islet cell transplant

Patients with chronic pancreatitis often experience intractable pain. Patients make frequent trips to the emergency department and may have numerous hospital admissions. They also can experience significant lifestyle disruptions and a greatly diminished quality of life.

Patients who have failed other therapies may be evaluated for total pancreatectomy followed by autologous islet cell transplantation. In North Texas, this innovative procedure is available only at Baylor University Medical Center in Dallas. Baylor Dallas is among the top five centers in the United States to offer the procedure in terms of the number of cases.

In this procedure, the pancreas is surgically removed and taken to the laboratory where the patient’s own islet cells are extracted. Islet cells produce insulin that helps the body to control blood glucose level. The isolated islet cells are then infused into the patient’s liver through the portal vein, where they take hold and ideally begin to produce insulin again on their own. This may allow the patient to become less dependent on insulin or not dependent on insulin at all, thus avoiding the diagnosis of brittle diabetes. Importantly, the patient is relieved of much or all of the pain they had experienced. 

“Auto islet cell transplantation is an important treatment option for patients,” says Bashoo Naziruddin, PhD, director of the Islet Cell Laboratory at Baylor Dallas and adjunct professor at Baylor University in Waco. “Yet despite improvements made in the past two decades, early graft loss and sustained islet function remain a challenge. During the isolation procedure and immediately after infusion into the patient, we have discovered that up to 50 percent of islet cells are lost due to inflammation. Therefore, reducing inflammation pretransplant may be an important step for improving transplant outcomes.

Recent evidence has identified the role of toll-like receptors (TLRs) – a class of proteins that play a key role in immune response –  in poor transplant outcomes. Of particular interest is TLR4. Activation of TLR4 triggers a robust inflammatory cascade that ultimately results in the production of inflammatory cytokines and possibly islet cell death.

The Baylor islet cell team designed two studies to evaluate the efficacy of TAK-242, a small molecular inhibitor of TLR4, in reducing inflammation. TAK-242 was identified as an ideal candidate due to its specificity for TLR4 and its safety as demonstrated by a phase II clinical trial.

The first study used a small mouse model to incorporate soluble TAK-242 with collagenase enzyme to inhibit sterile inflammation sustained during and after isolation. TAK-242 was shown to be safe to the islet cells, but, more importantly, the quality of the islet cells were better, and they were resistant to damage by inflammation.

“The results are very exciting and important for the field of islet cell transplantation,” says Dr. Naziruddin. “We were encouraged by the good results of this first study, so we came up with a very novel design to release the drug locally.”

In the second study, TAK-242 was attached to the islet surface using a chemical method, again in a small mouse model. When the islet cells are infused intraportally, the team found that TAK-242 was released slowly from the islets and offered protection from inflammation damage.

“Localized drug delivery has the potential to improve transplant outcomes by providing sustained exposure to efficacious drug concentrations while avoiding systemic immunosuppression and off-target effects,” Dr. Naziruddin says.  “The second study has given us hope that we do not need to treat the whole patient with the drug, but simply treat in the local environment.”

Both studies were published and have received great interest, Dr. Naziruddin continues. The Baylor team presented the studies in 2018 at the International Pancreas and Islet Transplant Association meeting, where the studies were recognized as the best studies in the entire conference. The Baylor team is now working to design some clinical trials to show the efficacy of these studies. Baylor Dallas is also involved in multicenter studies designed to improve outcomes of total pancreatectomy and auto islet transplantation.