Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia

Abstract

Natural killer (NK)-cell count is predictive of chronic lymphoid leukemia (CLL) disease progression and their dysfunction is well documented, but the etiology of this is currently lacking. CLL cells have been shown to over-express HLA-E, the natural ligand for NKG2A expressed on NK-cells that generates a distinct negative signal relative to direct NK-cell cytotoxicity in other disease models. Utilizing a novel anti-NKG2A monoclonal blocking antibody (mAb), monalizumab, we explored the in vitro preclinical activity of targeting the NKG2A receptor, and the NKG2A/HLA-E interaction as a mechanism of tumor evasion in CLL patients. Our work confirmed overexpression of HLA-E on CLL B-cells and demonstrated NKG2A expression on CD56C/16C NK-cells from CLL patients. We also demonstrate that blocking NKG2A on CLL NK-cells was sufficient to restore direct cytotoxicity ability of NK-cells against HLA-E-expressing targets without impacting NK-cell mediated antibody-dependent cellular cytotoxicity. Additionally, we proved the specificity of monalizumab in blocking NKG2A through Fc-blocking mechanisms. This paper provides justification for the potential clinical utility of monalizumab in the treatment of patients with CLL.

NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors

“…Although not assessed in our study, a recent report found no differences in expression of the NKG2A/CD94 inhibitory receptor on NK cells when comparing CLL patients and healthy controls, but demonstrated upregulation of its ligand, HLA-E, on CLL tumor cells as a potential NK cell evasion mechanism. 58 Our data suggest that immunotherapies that promote NK cell survival and function could improve immune responses toward CLL, especially treatments that enhance function or improve viability of the mature KIR C NK cells. NK cell boosting therapies may be especially beneficial to combat minimal residual disease after tumor-depleting therapies, or perhaps to prevent progression of indolent disease.…”

Dysregulated Expression of Tim-3 and NKp30 Receptors on NK Cells of Patients with Chronic Lymphocytic Leukemia

“…Similarly to T cells, NK cell exhaustion has also been described in numerous cancers and chronic viral infections [47, 48]. McWilliams et al[49] showed that therapeutic blockade of CD94/NKG2A, defined as an inhibitory signaling receptor, can restore the functional activities of NK cells in CLL patients. However, expression of other co-inhibitory receptors like Tim-3 on NK cells of CLL patients had not yet been addressed.…”

Challenges of NK cell-based immunotherapy in the new era

“…This effect may be reversed by optimizing the clinical scheme and combination therapy [39]. Furthermore, several blocking antibodies, such as the anti-NKG2A blocking antibody monalizumab and the antiTim-3 blocking antibody MBG453 [40][41][42], target immune checkpoints on NK and T cells and can reverse NK-cell dysfunction in preclinical studies. However, the safety and efficacy of these inhibitors or combination therapies require further investigation.…”