Recombinant Human IL-15 Trans-Presentation by B Leukemic Cells from Chronic Lymphocytic Leukemia Induces Autologous NK Cell Proliferation Leading to Improved Anti-CD20 Immunotherapy

Abstract

Recombinant human IL-15 (rhIL-15) is one of the most promising cytokines for antitumor immunotherapy. In physiology IL-15 trans-presentation by accessory cells leads to pleiotropic activities, including activation of immune cells, such as NK cells. NK cells are largely involved in Ab-dependent cellular cytotoxicity mediated by therapeutic mAbs, such as rituximab, in chronic lymphocytic leukemia (CLL). Nevertheless, in CLL, Ab-dependent cellular cytotoxicity is relatively impaired by the low E:T ratio (NK/B leukemic cells). Thus, any strategy leading to an increase in NK cell number and activation status can offer new strategies for CLL treatment. To this end, we evaluated the effect of rhIL-15 on autologous NK cell stimulation in CLL samples. We show that rhIL-15 induces NK cell activation and proliferation, leading to improved B leukemic cell depletion. This phenomenon is significantly increased in the presence of anti-CD20 mAbs. In addition, the greater effect of obinutuzumab versus rituximab suggests a cooperative role between rhIL-15 signaling and CD16 signaling in the induction of NK cell proliferation. Moreover, rhIL-15–induced proliferation of autologous NK cells is strictly dependent on their interaction with B leukemic cells, identified in this study as new accessory cells for rhIL-15 trans-presentation. Thus, rhIL-15 is able to promote NK cell–based activity in Ab immunotherapy of CLL.

Glycoengineering of Therapeutic Antibodies Enhances Monocyte/Macrophage-Mediated Phagocytosis and Cytotoxicity

“…However, the different experimental conditions used in the two studies (30 min ADCP, E:T ratio of 1:5 in Rafiq et al versus 4 h ADCP, E:T ratio of 3:1 in the current study) and differences in phagocytic effector cells (monocytes and MDMs derived from patients with CLL in Rafiq et al versus CD16 + /CD16 2 monocytes and M1/M2c macrophages in the current study) might have led to different results. Importantly, the elimination of leukemic B cells in whole blood from patients with CLL is consistently superior with GA101 (41,42).…”

Mono- and dual-targeting triplebodies activate natural killer cells and have anti-tumor activityin vitroandin vivoagainst chronic lymphocytic leukemia

“…In CLL patients, high burden of malignant B cells in peripheral blood naturally reduces NK cell proportion and negatively affects the natural and antibody-dependent cytotoxicity of the latter. 3,12 Laprevotte et al reported the median NK:B cells ratio as 0.02:1 in CLL patients and further showed that IL-15 could expand patients' NK cells, which in turn elevated CLL cell depletion by anti-CD20 antibodies (Rituximab and GA101). 12 To check whether increasing NK: B cells ratio also enhances the killing activity of the immunoligand, we purified NK cells from both patients 3 and 4 and incubated with purified CLL cells in autologous setting.…”

“…3,12 Laprevotte et al reported the median NK:B cells ratio as 0.02:1 in CLL patients and further showed that IL-15 could expand patients' NK cells, which in turn elevated CLL cell depletion by anti-CD20 antibodies (Rituximab and GA101). 12 To check whether increasing NK: B cells ratio also enhances the killing activity of the immunoligand, we purified NK cells from both patients 3 and 4 and incubated with purified CLL cells in autologous setting. Within 3 h of co-incubation, ULBP2-aCD19-aCD19 increased NK-cell-dependent killing of CLL cells from both patients in E:T-ratio-dependent manner while bypassing self-inhibition.…”

“…Outgrowth of malignant cells leading to low NK to CLL (effector:target) ratio is one of the main factors accountable for in situ resistance to NK cell effector functions. 12 This is supported by ex vivo expansion of NK cells within the PBMC population from CLL patients, which enhances natural as well as antibodydependent NK cell activity. 3,12 Additionally, shedding of NKcell-activating ligands from the surface of tumor cells is another important immune escape mechanism.…”

“…12 This is supported by ex vivo expansion of NK cells within the PBMC population from CLL patients, which enhances natural as well as antibodydependent NK cell activity. 3,12 Additionally, shedding of NKcell-activating ligands from the surface of tumor cells is another important immune escape mechanism. 1,13 Soluble NKG2D ligands including sMICA, sMICB and sULBP2 are of prognostic relevance in CLL.…”