A Pharmacokinetic and Pharmacodynamic Study of Maraviroc as Acute Graft-versus-Host Disease Prophylaxis in Pediatric Allogeneic Stem Cell Transplant Recipients with Nonmalignant Diagnoses.

Maraviroc is an allosteric small molecule antagonist of chemokine receptor type 5 (CCR5) and has been used in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients to prevent acute graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract and liver. The goal of this study was to establish feasibility and pharmacokinetic and pharmacodynamic profiles of maraviroc in pediatric HSCT recipients. Children ages 2 to 12 years were enrolled and maraviroc was added to standard GVHD prophylaxis, which included a calcineurin inhibitor and either steroids or mycophenolate mofetil. Maraviroc was started on day -3 and administered at a dose of approximately 300 mg/m(2) orally twice daily until day +30 after stem cell infusion. On days 0 and day +10, samples for pharmacokinetic analysis were collected before the dose and 1, 2, 4, 6, 8, and 12 hours after maraviroc administration. Additional trough concentrations were collected on days +7, 14, and 21. Patients were followed until day +100 for acute GVHD. Functional blockade of CCR5 was assessed in a pharmacodynamic assay by flow cytometry. Thirteen patients, median age of 4 years (range, 2 to 11 years), were prospectively enrolled. Underlying diagnoses included a primary immune deficiency (n = 6), hemoglobinopathy (n = 4), metabolic disorder (n = 1), and bone marrow failure syndrome (n = 2). Patients received either a myeloablative preparative regimen (n = 7) or a reduced-intensity conditioning regimen (n = 6). Cyclosporine and methylprednisolone (n = 7) was the predominant GVHD prophylactic regimen, followed by tacrolimus and mycophenolate mofetil (n = 4) and tacrolimus and steroids (n = 2). Two formulations of maraviroc (150-mg tablets and 20-mg/mL solution) were used on study. Mean (± SD) area under the concentration-time curve from 0 to 12 hours was 4805 ± 3265 hour * ng/mL on day 0 and 5917 ± 4048 hour * ng/mL on day +10. Four patients developed grade 1 or 2 acute skin GVHD before day +100 and were successfully treated. Two patients developed grade 3 acute GI GVHD on days +23 and +24 after HSCT and both had discontinued maraviroc before development of GI GVHD. No adverse effects attributable to maraviroc were observed and administration by enteral tubes was well tolerated by children and accepted by parents. All evaluable patients demonstrated functional CCR5 blockade on day 0. Administration of maraviroc is feasible in most pediatric HSCT recipients with good safety and tolerability profile.

Antineoplastic effects of targeting CCR5 and its therapeutic potential for colorectal cancer liver metastasis.

PURPOSE: Liver metastasis is observed in up to 50% of colorectal cancer (CRC) patients. Available treatment options are limited and disease recurrence is often. Chemokine receptor 5 (CCR5) has attracted attention as novel therapeutic target for treating cancers. In this study, we reinforced the importance of CCR5 as therapeutic target in CRC and its liver metastasis by applying in vitro, in vivo and clinical investigations. METHODS: By targeting CCR5 via siRNAs or an FDA approved antagonist (maraviroc), we investigated the ensuing antineoplastic effects in three CRC cell lines. An animal model for CRC liver metastasis was used to evaluate time-dependent expressional modulation of the CCR5 axis by cDNA microarray. The model was also used to evaluate the in vivo efficacy of targeting CCR5 by maraviroc. Circulatory and tumor associated levels of CCR5 and its cognate ligands (CCL3, CCL4, CCL5) were analyzed by ELISA, qRT-PCR and immunohistochemistry. RESULTS: Targeting the CCR5 inhibited proliferative, migratory and clonogenic properties and interfered with cell cycle-related signaling cascades. In vivo findings showed significant induction of the CCR5 axis during the early liver colonization phase. Treatment with maraviroc significantly inhibited CRC liver metastasis in the animal model. Differential expression profiles of circulatory and tumor associated CCR5/ligands were observed in CRC patients and healthy controls. CONCLUSION: The findings indicate that targeting the CCR5 axis can be an effective strategy for treating CRC liver metastasis.

Differential Analyses of Peripheral Blood Parameters in CCR5 Inhibition-treated Colorectal Cancer Patients Reveal Dynamic Changes Linked to Clinical Outcomes.

BACKGROUND/AIM: Chemokine receptor inhibition is an immunotherapy that modulates the innate arm of the immune system. Previous work in microsatellite-stable metastatic colorectal cancer showed an exploitive loop that could be successfully targeted via C-C-motive-chemokine-receptor 5 (CCR5) specific blocking, resulting in a selective anti-tumoral activation of macrophages. In the respective trial (MARACON trial, NCT01736813) the peripheral blood laboratory markers and cytokine values were measured over time. Little is known on their role as biomarkers or stratification parameters in immunotherapy trials. PATIENTS AND METHODS: Systematic analyses of key laboratory parameters are presented, highlighting specific dynamics of lymphocyte and monocyte percentages, lactate dehydrogenase as well as interleukin-6 and interleukin-8 levels as parameters of a systemic inflammatory readout. RESULTS: Specific dynamical changes of lymphocyte and monocyte compositions were noted between different patients, showing a stabilization (or increase) versus decreased numbers over time for monocytes. While lactate dehydrogenase, interleukin-6 and interleukin-8 showed almost uniformly rising levels over time, the systemic monocyte patterns prompted a further evaluation. Stabilized or increasing monocyte percentages were associated with improved overall survival (Kaplan Meier analysis, p=0.025) and with induced overt radiologic necrosis in patients. CONCLUSION: The observed association between monocyte dynamics and imaging findings as well as overall survival suggests that analyses of dynamical parameters in the peripheral blood should be implemented in immunotherapy trials.