CCR7 as a novel therapeutic target in t-cell PROLYMPHOCYTIC leukemia

Abstract

T-cell prolymphocytic leukemia (T-PLL) is a poor prognostic disease with very limited options of efficient therapies. Most patients are refractory to chemotherapies and despite high response rates after alemtuzumab, virtually all patients relapse. Therefore, there is an unmet medical need for novel therapies in T-PLL. As the chemokine receptor CCR7 is a molecule expressed in a wide range of malignancies and relevant in many tumor processes, the present study addressed the biologic role of this receptor in T-PLL. Furthermore, we elucidated the mechanisms of action mediated by an anti-CCR7 monoclonal antibody (mAb) and evaluated whether its anti-tumor activity would warrant development towards clinical applications in T-PLL. Our results demonstrate that CCR7 is a prognostic biomarker for overall survival in T-PLL patients and a functional receptor involved in the migration, invasion, and survival of leukemic cells. Targeting CCR7 with a mAb inhibited ligand-mediated signaling pathways and induced tumor cell killing in primary samples. In addition, directing antibodies against CCR7 was highly effective in T-cell leukemia xenograft models. Together, these findings make CCR7 an attractive molecule for novel mAb-based therapeutic applications in T-PLL, a disease where recent drug screen efforts and studies addressing new compounds have focused on chemotherapy or small molecules.

Combination strategies to maximize the benefits of cancer immunotherapy

“…Sometimes the same chemokines can recruit different immune cells with different and even opposing immune functions. For example, CCL21 and CCL19 recruit CCR7 + dendritic cells and T reg cells, while CCL17 and CCL22 can directly recruit T reg and Th2 lymphocytes [ 137 – 140 ].…”

Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy

“…The silencing of CCR7 gene expression through siRNA or miRNA led to decreased metastasis and tumor growth in models of prostate, breast and colorectal cancer [114][115][116]. Anti-CCR7 mAbs have shown the ability to induce tumor cell death and decrease or avoid central nervous system disease in a T-cell prolymphocytic leukaemia xenograft mice model [113], while single-chain anti-CCR7 antibodies successfully blocked the passage of Tcell acute lymphoblastic leukaemia cells through a blood-brain barrier in vitro model [165].…”

Of Lymph Nodes and CLL Cells: Deciphering the Role of CCR7 in the Pathogenesis of CLL and Understanding Its Potential as Therapeutic Target

“…In several reports, CCR7 expression and/or functionality has been associated with higher LN involvement and staging but no report directly associated this receptor, or its migratory response, with CLL patient survival ( 14 , 42 , 48 , 49 , 51 , 53 , 63 , 78 ). Nonetheless, in other blood cancers such as diffuse large B-cell lymphoma (DLBCL) or T cell prolymphocytic leukemia (T-PLL) a clear correlation was found between CCR7 expression levels at diagnosis and OS ( 79 , 80 ). Moreover, indirect evidence suggests a role of CCR7 in shortening lifespan in CLL.…”