Chemokine receptor blockade in graft-versus-host disease

Abstract

In a phase 1/2 trial, 35 high-risk patients with blood cancer who underwent reduced-intensity allogeneic stem-cell tranplantation who took the CCR5 chemokine receptor blocker maraviroc had lower rates of acute (grade II–IV) graft-versus-host disease (GVHD) than were expected. At 100 days, only 14·7% of patients had developed acute visceral GVHD (no cases were noted in the gut or liver), with few side-eff ects. “The drug prevents lymphocyte traffi cking into organs most aff ected by GVHD—the gut, liver, and skin— without impairing the functionality of T cells or the engraftment of new blood cells”, said lead author Ran Reshef (Abramson Cancer Center, Philadelphia, PA, USA). Maraviroc was developed for a subtype of HIV infection in which CCR5 is used to enter cells, Reshef said. “We hypothesised that CCR5 blockade might decrease lymphocyte recruitment to tissues involved in GVHD if used soon after transplantation because CCR5 is involved in T-cell traffi cking to tissues involved in visceral GVHD”, he added. “We found that the drug did not aff ect other T-cell functionality,” Reshef added. Patients received maraviroc for 2 days before and 30 days after transplantation following standard prophylaxis, and were followed up for a median of 19·6 months. The primary endpoint was incidence of acute GVHD at 100 days. At 6 months, GVHD was seen mostly in skin—grade II–IV disease was noted in 23·6% of patients, of which 2·9% had GVHD in the liver, and 8·8% in the gut. Severe disease (grade III–IV) was noted in 5·9%. By comparison, 38·5% of patients treated at the same hospital without maraviroc had grade II–IV disease, and 21·9% had severe disease. Use of a drug that has already been tested in animal models and is on the market, rather than trying to interest a pharmaceutical company in GVHD—a disease with a small patient population—is an excellent strategy, said Marcel van den Brink (Memorial Sloan-Kettering Cancer Center, New York, NY, USA). “Going after lymphocyte homing to GVHD-specifi c tissues with maraviroc off ers an opportunity to stop GVHD with specifi city, leaving T-cell function intact without interfering with the transplant process”, he added. Maraviroc will next be tested in a multicentre randomised phase 2 trial, comparing it with other interventions such as immune-suppressive drugs, Reshef said.