Evaluation of therapeutic targeting of CCR7 in acute graft-versus-host disease.

Graft-versus-host disease (GVHD) is the main complication after allogeneic hematopoietic stem cell transplantation. We previously unveiled a correlation between proportions of C-C motif chemokine receptor 7 (CCR7)+ T cells in the apheresis and the risk of developing GVHD. We wanted to evaluate in vivo whether apheresis with low proportion of CCR7+ cells or treatment with an anti-human CCR7 monoclonal antibody (mAb) were suitable strategies to prevent or treat acute GVHD in preclinical xenogeneic models. Therapeutic anti-CCR7 mAb was the most effective strategy in both prophylactic and therapeutic settings where antibody drastically reduced in vivo lymphoid organ infiltration of donor CCR7+ T cells, extended lifespan and solved clinical signs. The antibody neutralized in vitro migration of naïve and central memory T cells toward CCR7 ligands and depleted target CCR7+ subsets through complement activation. Both mechanisms of action spared CCR7- subsets, including effector memory and effector memory CD45RA+ T cells which may mediate graft versus leukemia effect and immunity against infections. Accordingly, the numbers of donor CCR7+ T cells in the apheresis were not associated to cytomegalovirus reactivation or the recurrence of the underlying disease. These findings provide a promising new strategy to prevent and treat acute GVHD, a condition where new specific, safety and effective treatment is needed.

Immediate Effects of Dasatinib on the Migration and Redistribution of Naïve and Memory Lymphocytes Associated With Lymphocytosis in Chronic Myeloid Leukemia Patients.

Introduction: Dasatinib is a dual SRC/ABL tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML) that is known to have unique immunomodulatory effects. In particular, dasatinib intake typically causes lymphocytosis, which has been linked to better clinical response. Since the underlying mechanisms are unknown and SRC family kinases are involved in many cell motility processes, we hypothesized that the movement and migration of lymphocytes is modulated by dasatinib. Patients, Materials and Methods: Peripheral blood samples from CML patients treated with second-line dasatinib were collected before and 2 h after the first dasatinib intake, and follow-up samples from the same patients 3 and 6 months after the start of therapy. The migratory capacity and phenotype of lymphocytes and differential blood counts before and after drug intake were compared for all study time-points. Results: We report here for the first time that dasatinib intake is associated with inhibition of peripheral blood T-cell migration toward the homeostatic chemokines CCL19 and CCL21, which control the trafficking toward secondary lymphoid organs, mainly the lymph nodes. Accordingly, the proportion of lymphocytes in blood expressing CCR7, the chemokine receptor for both CCL19 and CCL21, decreased after the intake including both naïve CD45RA+ and central memory CD45RO+ T-cells. Similarly, naïve B-cells diminished with dasatinib. Finally, such changes in the migratory patterns did not occur in those patients whose lymphocyte counts remained unchanged after taking the drug. Discussion: We, therefore, conclude that lymphocytosis induced by dasatinib reflects a pronounced redistribution of naïve and memory populations of all lymphocyte subsets including CD4+ and CD8+ T-cells and B-cells.

Preclinical activity of anti-CCR7 immunotherapy in patients with high-risk chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) with deletions of the p53 locus on chromosome 17 and/or refractory to fludarabine chemoimmunotherapy remains a major clinical problem with few therapeutic options. Currently, these types of CLL are treated with approaches that do not target the p53 pathway, such as small molecules and monoclonal antibodies (mAb). We have previously postulated anti-CCR7 mAb therapy as a novel CLL treatment. In the present study, we evaluated the in vitro efficacy of anti-CCR7 mAb as a single agent in CLL patients with high-risk cytogenetics and/or refractory to fludarabine, by measuring CCR7 surface expression and complement-dependent cytotoxicity. Our results demonstrate that CCR7 is highly expressed in challenging and heavily treated CLL patients. In addition, the complement-mediated mechanism of action of this mAb effectively eradicates CLL cells while sparing subsets of T cells in these patients. Moreover, this mAb outperformed the activity of alemtuzumab, the mAb with the highest efficacy in these groups. Finally, in vitro activity was also demonstrated in patients with a disease refractory to both fludarabine and alemtuzumab, and patients harboring 11q22 deletion. Our results propose that anti-CCR7 mAb is an effective and promising future treatment in high-risk CLL.