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

Abstract

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.

CCR7 Maintains Nonresolving Lymph Node and Adipose Inflammation in Obesity

“…Genetic deficiency of Ccr7 is sufficient to disrupt obesity-induced inflammation and insulin resistance, and therapeutic administration of an anti-CCR7 antibody mimicked these effects. Given that CCR7 is currently being tested as a target for the treatment of metastatic cancer ( 24 ), these studies could inform the development of novel immunotherapies for treating metabolic disease.…”

The role of ZAP70 kinase in acute lymphoblastic leukemia infiltration into the central nervous system

“…Similarly, enforced ZAP70 expression in 697 cells increased the expression of CCR7/CXCR4 and subsequent migration toward their ligand (Figure 2). Importantly, CCR7 blockade resulted in a reduction in homing processes in vivo analogous to B-CLL 42 and, importantly, a reduction in CNS infiltration ( Figure 2E-G), which is an extremely rare event in B-CLL. 43 Stimulating cells with CCL19/CXCL12 increased p-ERK in 697, JURKAT and BCP-ALL primary cells.…”

Monoclonal Antibody Therapies for Hematological Malignancies: Not Just Lineage-Specific Targets

“…Many other CKRs with pathogenic role in hematological malignancies were preclinically validated as good targets for mAb-based therapy. This includes antibodies against CCR7 ( 34 , 250 ) and CCR9 ( 251 ).…”

“…Limited clinical efficacy of some mAbs targeting LSAs and the advent of patients with refractory diseases to therapies directed to LSAs boosted the research on many NLSAs with a relevant role in the pathogenesis of cancer, especially in B-cell malignancies ( 9 , 34 ). Moreover, in some disorders the lack or loss of LSA expression in cell membrane may preclude the use of antibodies, thus prompting research of other potential therapeutic targets.…”