Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease.
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.).
Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ran.reshef@uphs.upenn.edu
Ran
R
Reshef
Selina M
SM
Luger
Elizabeth O
EO
Hexner
Alison W
AW
Loren
Noelle V
NV
Frey
Sunita D
SD
Nasta
Steven C
SC
Goldstein
Edward A
EA
Stadtmauer
Jacqueline
J
Smith
Sarah
S
Bailey
Rosemarie
R
Mick
Daniel F
DF
Heitjan
Stephen G
SG
Emerson
James A
JA
Hoxie
Robert H
RH
Vonderheide
David L
DL
Porter
D000328:Adult; D000368:Aged; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3 / Q000037:antagonists & inhibitors; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003510:Cyclohexanes / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D014184:Transplantation, Homologous; D014230:Triazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D018946:Chemokine CCL5; D003510:Cyclohexanes; D014230:Triazoles; D000077592:Maraviroc