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

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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.)

Original languageEnglish (US)
Pages (from-to)135-145
Number of pages11
JournalNew England Journal of Medicine
Volume367
Issue number2
DOIs
StatePublished - Jul 12 2012

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Graft vs Host Disease
Chemotaxis
Lymphocytes
Hematopoietic Stem Cell Transplantation
T-Lymphocytes
Recurrence
Chemokine Receptors
Incidence
Mortality
maraviroc
Liver
Infection
Serum
In Vitro Techniques

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Reshef, R., Luger, S. M., Hexner, E. O., Loren, A. W., Frey, N. V., Nasta, S. D., ... Porter, D. L. (2012). Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. New England Journal of Medicine, 367(2), 135-145. https://doi.org/10.1056/NEJMoa1201248

Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. / Reshef, Ran; Luger, Selina M.; Hexner, Elizabeth O.; Loren, Alison W.; Frey, Noelle V.; Nasta, Sunita D.; Goldstein, Steven C.; Stadtmauer, Edward A.; Smith, Jacqueline; Bailey, Sarah; Mick, Rosemarie; Heitjan, Daniel F.; Emerson, Stephen G.; Hoxie, James A.; Vonderheide, Robert H.; Porter, David L.

In: New England Journal of Medicine, Vol. 367, No. 2, 12.07.2012, p. 135-145.

Research output: Contribution to journalArticle

Reshef, R, Luger, SM, Hexner, EO, Loren, AW, Frey, NV, Nasta, SD, Goldstein, SC, Stadtmauer, EA, Smith, J, Bailey, S, Mick, R, Heitjan, DF, Emerson, SG, Hoxie, JA, Vonderheide, RH & Porter, DL 2012, 'Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease', New England Journal of Medicine, vol. 367, no. 2, pp. 135-145. https://doi.org/10.1056/NEJMoa1201248
Reshef R, Luger SM, Hexner EO, Loren AW, Frey NV, Nasta SD et al. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. New England Journal of Medicine. 2012 Jul 12;367(2):135-145. https://doi.org/10.1056/NEJMoa1201248
Reshef, Ran ; Luger, Selina M. ; Hexner, Elizabeth O. ; Loren, Alison W. ; Frey, Noelle V. ; Nasta, Sunita D. ; Goldstein, Steven C. ; Stadtmauer, Edward A. ; Smith, Jacqueline ; Bailey, Sarah ; Mick, Rosemarie ; Heitjan, Daniel F. ; Emerson, Stephen G. ; Hoxie, James A. ; Vonderheide, Robert H. ; Porter, David L. / Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. In: New England Journal of Medicine. 2012 ; Vol. 367, No. 2. pp. 135-145.
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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.)",
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AU - Reshef, Ran

AU - Luger, Selina M.

AU - Hexner, Elizabeth O.

AU - Loren, Alison W.

AU - Frey, Noelle V.

AU - Nasta, Sunita D.

AU - Goldstein, Steven C.

AU - Stadtmauer, Edward A.

AU - Smith, Jacqueline

AU - Bailey, Sarah

AU - Mick, Rosemarie

AU - Heitjan, Daniel F.

AU - Emerson, Stephen G.

AU - Hoxie, James A.

AU - Vonderheide, Robert H.

AU - Porter, David L.

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N2 - 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.)

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