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enhanced cell surface expression of CCR5 and associates with an increased
rate of HIV progression to AIDS. The study included 1370 donor and recipi-
ent pairs that were matched at 10/10 loci by high-resolution typing. In con-
trast to the report from Bogunia-Kubik, homozygous (H1/H1) recipients
had better disease-free and overall survival but comparable risks for acute
GVHD, whereas HCT using cells from H1/H1 donors resulted in higher
rates of GVHD and lower disease-free survival compared to all other groups
evaluated. In sum, while CCR5 polymorphisms may ultimately play a role
in predicting outcomes for allogeneic HCT recipients, further studies are
required before such data can be proactively utilized to modify approach
to treatment.
These somewhat conflicting reports notwithstanding, investigators at the
University of Pennsylvania evaluated the safety and efficacy of the CCR5
inhibitor Maraviroc as a novel therapy to prevent GVHD
[115]
. Maraviroc is
the first FDA-approved inhibitor of CCR5 that prevents binding of all three of
the receptors' ligands (CCL3, CCL4, and CCL5). Thirty-eight patients under-
going allogeneic peripheral blood stem cell transplant from either matched
related or unrelated donors were included in a phase I/II study. Patients
received a reduced-intensity conditioning using fludarabine and busulfan
and were given methotrexate, tacrolimus and Maraviroc from day -2 until
day 30. Among 35 patients evaluable for GVHD (3 patients treated with low
dose Maraviroc did not reach a pre-determined pharmacokinetic target
were excluded), the cumulative incidence of grade II to IV GVHD was 14.7%
by day 100 and 23.6% by day 180. Of particular note, no patients receiving
Maraviroc developed acute GVHD involving the liver or GI tract within the
first 100 days. Moreover, in 11 patients receiving HLA-matched sibling trans-
plants, there were no cases of acute GVHD before day 100 and no grade II or
IV GVHD before day 180. Additionally, when compared to a control group
of similarly matched and conditioned donor pairs, no difference in the rate
of relapse was observed by day 180. However, 9 patients did require donor
lymphocyte infusions for dropping chimerism levels or relapse between
days 161 and 433. Pharmacadynamic studies showed that sera from patients
receiving Maraviroc blocked T cell chemotaxis to CCR5-binding ligands
in
vitro
suggesting that the drug had
in vivo
effects on its target [115].
417
Early results using Maraviroc are encouraging and suggest that alterna-
tive approaches to regulate chemokine:receptor interactions may also be
successful
[116]
. In line with the importance of Th1-based inflammatory
responses during/following allogeneic HCT and the contribution of CXCR3
receptor:ligand interactions to GVHD target organ inflammation discussed
above, CXCR3 represents another interesting target. While several patents
for CXCR3 antagonists have been disclosed, none are currently approved
for clinical use
[117]
. Likewise, given the critical role of CCR9 in lymphocyte
recruitment to an inflamed intestinal tract, the use of orally bioavailable
inhibitors currently in phase III clinical trials
[117]
may represent a promis-
ing approach for the treatment of intestinal GVHD.
As reviewed in this chapter, CCR5, CXCR3, and CCR9 represent only a few of
the several other potential targets within the chemokine system, for which
selective neutralization (through newly developed antibodies or small mol-
ecules) might be considered for treating or preventing GVHD. However, the
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