EPIC-LT: Eliminating PGD through Inhibition of CCR5 in Lung Transplantation

Project Summary Lung transplant recipient survival lags other solid organ recipients, with the main early causes of death being primary graft dysfunction (PGD). PGD occurs in up to 1/3 of all recipients, is driven by the innate immune response, and has no known medical therapies for treatment or prevention. Our group has recently shown that Natural Killer (NK) cells, a key innate immune cell, are critical mediators of PGD. Preliminary data show that NK cells traffic to the site of PGD injury dependent upon a chemokine receptor, CCR5. Importantly, we found that Maraviroc, an FDA-approved allosteric inhibitor of CCR5, prevented lung injury in mouse models of PGD. Based on these observations, we hypothesize that CCR5 inhibition can safely prevent early allograft injury after transplantation. However, almost no clinical trials have been conducted and few tools exist to perform definitive clinical trials in the early lung transplant peri-operative period. This proposal seeks to pilot processes to optimize a clinical trial of CCR5 inhibition before transplant. Aim 1 will measure success in enriching a lung transplant population for PGD and will investigate the feasibility of recruitment for a pilot trial of CCR5 inhibition. Aim 2 will assess the safety and tolerability of CCR5 inhibition in lung transplant recipients. We will measure key adverse events and assess for drug-drug interactions. In addition, this Aim will measure Maraviroc drug levels in plasma and bronchoalveolar lavage to determine dosing efficacy. Increasingly, there is awareness that subphenotypes of diseases exist and can be leveraged for targeted therapies. In Aim 3, we seek to develop standard assays for future subphenotyping efforts in a larger multicenter clinical trial. To do this, we will measure donor and recipient biologic endpoints. These include bronchoalveolar lavage NK cells after transplant as a surrogate marker for biologic efficacy. While PGD is a strong clinical phenotype, this proposal is piloting important processes and not primarily investigating efficacy in the intervention arm. However, Aim 3 is well powered to detect differences in biologic efficacy within our constrained sample size and will inform decisions regarding a later phase clinical trial. This proposal is critically important for planning a multi-center clinical trial of CCR5 inhibition during lung transplant induction. This pilot project will test a novel clinical instrument to enrich our study population and will identify key adverse events and biomarkers of treatment success. Finally, a multi-center clinical trial of CCR5 inhibition is feasible as our center is part of the NIH and Cystic Fibrosis Foundation Lung Transplant Consortia.