Prevention of Graft-Versus-Host Disease by Inhibition of Lymphocyte Trafficking Using a CCR5 Antagonist

• Published in: Blood 2010-11, Vol.116 (21), p.673-673
• Main Authors: Reshef, Ran, Luger, Selina M., Loren, Alison W., Frey, Noelle V., Goldstein, Steven C., Hexner, Elizabeth O., Stadtmauer, Edward A., Smith, Jacqueline, Mick, Rosemarie, Heitjan, Daniel F., Shetzline, Susan E., Danet-Desnoyers, Gwenn-ael H., Emerson, Stephen G., Hoxie, James A., Vonderheide, Robert H., Porter, David L.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V116.21.673.673

Abstract 673 Inhibition of lymphocyte trafficking early after allogeneic stem cell transplantation (SCT) could limit T cell interactions with antigen-presenting cells and migration to target tissues. This represents a novel strategy to prevent GvHD without interfering with GvL activity. CCR5 is a chemokine receptor expressed on effector T-cells and immature dendritic cells and binds 3 ligands - CCL3, CCL4 and RANTES (CCL5). Accumulating evidence from animal models and clinical observations implicates CCR5 as pivotal in the pathogenesis of GvHD. Genomic analyses suggest that the same CCR5 polymorphisms that confer resistance to HIV infection also correlate with a lower susceptibility to acute GvHD. Maraviroc (MVC; Selzentry®, Pfizer) is the first oral CCR5 antagonist in clinical use. We hypothesized that modulating T-cell trafficking early after allogeneic SCT via CCR5 blockade would limit GvHD. We therefore performed preclinical and clinical testing of MVC as GvHD prophylaxis. Our goals were to 1) determine in vitro activity of MVC on chemotaxis, 2) determine the feasibility, safety and appropriate dose of MVC as part of GvHD prophylaxis, and 3) demonstrate biological activity of MVC through immune pharmacodynamic assays. In vitro, MVC fully inhibited CCR5 internalization by CCL3 and RANTES even at concentrations as low as 1 μM. Using RANTES as a chemotactic trigger, MVC caused dose-dependent inhibition of lymphocyte chemotaxis by up to 53% at MVC 1mM. To address concerns that MVC might impair hematopoiesis, we demonstrated that CCR5 was not expressed on the surface of bone marrow- and peripheral blood-derived CD34+ cells. Moreover, when CD34+ cells were plated in methylcellulose, formation of CFU-GEMM and CFU-GM was not affected by the presence of MVC 1μM; CFU-E and BFU-E were slightly decreased compared to controls. Based on these and other data, we enrolled 19 pts in a phase I/II study of reduced intensity conditioned allogeneic SCT with MVC GvHD prophylaxis. Pts received fludarabine 120mg/m2 and IV busulfan 6.4 mg/kg followed by peripheral blood stem cells from matched related (n=6), matched unrelated (n=10) and 1-antigen mismatched unrelated (n=3) donors. In addition to standard GvHD prophylaxis with tacrolimus and methotrexate, MVC at escalating dose levels was given from day -2 to +30. Median age was 63 (range 21–74). Indications for SCT were AML/MDS (9), NHL (4), myelofibrosis (2), CLL, aplastic anemia, Hodgkin lymphoma and myeloma (1 each). Pharma