Reducing lung transplant rejection aim of clinical trial funded with $22 million grant

Physicians at Washington University School of Medicine in St. Louis and Massachusetts General Hospital/Harvard Medical School in Boston have received a seven-year, $22 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) to help lead a multicenter clinical trial evaluating whether a novel immunosuppressant can reduce the risk of organ rejection after a lung transplant.

Immune-suppressing drugs temper the immune system, and people who have undergone an organ transplant typically take such drugs for the remainder of their lives to reduce the risk of organ rejection. But for lung transplant recipients, the chance of organ rejection is particularly high. Unlike other organs, lungs constantly are exposed to whatever is in the environment, including bacteria, viruses and air pollution. These characteristics contribute to the increased risk of chronic rejection and tissue failure in lung recipients.

NIAID will oversee the phase 2 clinical trial through its  Clinical Trials in Organ Transplantation in Children and Adults (CTOT-CA) consortium, which conducts studies designed to improve short- and long-term survival of both transplanted organs and transplant recipients. The new trial will evaluate an immune-suppressing antibody and involve 16 medical institutions in North America. It will be one of the largest such studies conducted in the lung transplant field, according to the lead researchers from Washington University and Harvard Medical School.

The double-blind randomized controlled study will test the drug clazakizumab, a monoclonal antibody against interleukin-6, in 330 patients.

“Of all the organs that we transplant, the outcomes generally are worse with a lung for a variety of immunological and biological reasons,” said one of the grant’s three principal investigators, Daniel Kreisel, MD, PhD, the surgical director of lung transplantation at Washington University School of Medicine and Barnes-Jewish Hospital, and the G. Alexander Patterson, MD/Mid-America Transplant Endowed Distinguished Chair in Lung Transplantation. “This clinical trial is an attempt to address the problem using a different strategy that broadens our immunosuppressive capabilities across different parts of the immune system.”

In general, most research on organ transplants has focused on the immune system’s T-cells, white blood cells that attack foreign invaders such as viruses or bacteria. However, the researchers’ past studies in animals have found that focusing on cytokines — small proteins secreted by cells that direct the immune system’s reactions — can help the body tolerate a newly transplanted lung. Specifically, the researchers have found success using drugs that block the inflammatory signaling pathway of a key cytokine called interleukin-6 (IL-6).

Only about half of transplanted lungs are still functioning five years after transplantation, according to the U.S. Organ Procurement and Transplantation Network. This compares with five-year organ survival rates of about 70% in heart, liver and kidney transplants. “Improving health outcomes would be a game-changer in the lives of thousands of lung transplant patients, as well as in the organ transplantation field,” said Ramsey Hachem, MD, one of the principal investigators and the medical director of the lung transplant program at the School of Medicine and Barnes-Jewish Hospital, and the Tracey C. Marshall – Dr. Elbert P. Trulock Distinguished Professor of Medicine. Often, lung transplant remains the only option for patients with end-stage lung disease, a condition that can be brought on by emphysema, pulmonary fibrosis, cystic fibrosis and other lung disorders.

“The results from the ALL IN LUNG study could potentially shift current clinical practice paradigms not only for lung transplantation but potentially for all solid organ transplantation,” said principal investigator Joren C. Madsen, MD, DPhil. He is the Paul S. Russell/Warner-Lambert Professor of Surgery at Harvard Medical School and director of the Massachusetts General Hospital Transplant Center.