Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease
Ran Reshef, Selina M Luger, Elizabeth O Hexner, Alison W Loren, Noelle V Frey, Sunita D Nasta, Steven C Goldstein, Edward A Stadtmauer, Jacqueline Smith, Sarah Bailey, Rosemarie Mick, Daniel F Heitjan, Stephen G Emerson, James A Hoxie, Robert H Vonderheide, David L Porter, Ran Reshef, Selina M Luger, Elizabeth O Hexner, Alison W Loren, Noelle V Frey, Sunita D Nasta, Steven C Goldstein, Edward A Stadtmauer, Jacqueline Smith, Sarah Bailey, Rosemarie Mick, Daniel F Heitjan, Stephen G Emerson, James A Hoxie, Robert H Vonderheide, David L Porter
Abstract
Background: Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic stem-cell transplantation (HSCT). The chemokine receptor CCR5 appears to play a role in alloreactivity. We tested whether CCR5 blockade would be safe and limit GVHD in humans.
Methods: We tested the in vitro effect of the CCR5 antagonist maraviroc on lymphocyte function and chemotaxis. We then enrolled 38 high-risk patients in a single-group phase 1 and 2 study of reduced-intensity allogeneic HSCT that combined maraviroc with standard GVHD prophylaxis.
Results: Maraviroc inhibited CCR5 internalization and lymphocyte chemotaxis in vitro without impairing T-cell function or formation of hematopoietic-cell colonies. In 35 patients who could be evaluated, the cumulative incidence rate (±SE) of grade II to IV acute GVHD was low at 14.7±6.2% on day 100 and 23.6±7.4% on day 180. Acute liver and gut GVHD were not observed before day 100 and remained uncommon before day 180, resulting in a low cumulative incidence of grade III or IV GVHD on day 180 (5.9±4.1%). The 1-year rate of death that was not preceded by disease relapse was 11.7±5.6% without excessive rates of relapse or infection. Serum from patients receiving maraviroc prevented CCR5 internalization by CCL5 and blocked T-cell chemotaxis in vitro, providing evidence of antichemotactic activity.
Conclusions: In this study, inhibition of lymphocyte trafficking was a specific and potentially effective new strategy to prevent visceral acute GVHD. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00948753.).
Conflict of interest statement
Dr. Frey reports receiving lecture fees from Pfizer; Dr. Stadt-mauer, consulting fees from Pfizer; Dr. Vonderheide, grant support from Pfizer; and Dr. Porter, consulting fees from Bristol-Myers Squibb and lecture fees from Celgene and Millennium. No other potential conflict of interest relevant to this article was reported.
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Source: PubMed