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Novel CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL.

ABSTRACT: Chronic lymphocytic leukemia (CLL) is characterized by chronic clonal expansion of mature CD19-expressing B lymphocytes and global dysfunction of immune effectors, including natural killer (NK) cells. CLL remains incurable, and novel approaches to refractory CLL are needed. Our group has previously described trispecific killer engager (TriKE) molecules that redirect NK cell function against tumor cells. TriKE reagents simultaneously bind an activating receptor on NK cells, CD16, and a tumor antigen while also providing an NK cell expansion signal via an interleukin-15 moiety. Here we developed the novel CD19-targeting 161519 TriKE. We demonstrate that 161519 TriKE induced killing of a CD19-expressing Burkitt's lymphoma cell line and examined the impact on primary CLL targets using healthy donor and patient NK cells. 161519 TriKE induced potent healthy donor NK cell activation, proliferation, and directed killing. Furthermore, 161519 TriKE rescued the inflammatory function of NK cells obtained from CLL patient peripheral blood samples. Finally, we show that 161519 TriKE induced better directed killing of CLL in vitro when compared with rituximab. In conclusion, 161519 TriKE drives a potent activating and proliferative signal on NK cells, resulting in enhanced NK cell expansion and CLL target killing. Our findings indicate the potential immunotherapeutic value of 161519 TriKE in CLL.

SUBMITTER: Felices M

PROVIDER: S-EPMC6436008 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Novel CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL.

Felices Martin M Kodal Behiye B Hinderlie Peter P Kaminski Michael F MF Cooley Sarah S Weisdorf Daniel J DJ Vallera Daniel A DA Miller Jeffrey S JS Bachanova Veronika V

Blood advances 20190301 6

Chronic lymphocytic leukemia (CLL) is characterized by chronic clonal expansion of mature CD19-expressing B lymphocytes and global dysfunction of immune effectors, including natural killer (NK) cells. CLL remains incurable, and novel approaches to refractory CLL are needed. Our group has previously described trispecific killer engager (TriKE) molecules that redirect NK cell function against tumor cells. TriKE reagents simultaneously bind an activating receptor on NK cells, CD16, and a tumor anti ...[more]

PMID: 30890546

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Project description:RATIONALE:Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function. OBJECTIVES:To determine the effects of PD-1 pathway blockade on sarcoidosis CD4(+) T-cell proliferative capacity. METHODS:Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage-derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens. MEASUREMENTS AND MAIN RESULTS:Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1(+) CD4(+) T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1(+) CD4(+) T cells with spontaneous clinical resolution but not with disease progression. CONCLUSIONS:Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4(+) T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.

Dataset Information

Novel CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL.

Publications

Novel CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL.

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