Direct and antibody-dependent cell-mediated cytotoxicity of head and neck squamous cell carcinoma cells by high-affinity natural killer cells

Abstract

High affinity natural killer cells (haNKs) are a cell therapy product capable of mediating both direct and antibody-dependent cell-mediated cytotoxicity (ADCC). These cells may be particularly useful in tumors that escape T-cell anti-tumor immunity by harboring antigen processing and presentation defects. Here, we demonstrated that haNKs directly kill both HPV-positive and negative head and neck squamous cell carcinoma cells. Variable tumor cell sensitivity to haNK direct cytotoxicity did not correlated with MHC class I chain-related protein A or B (MICA or MICB) expression. Importantly, haNK killing was significantly enhanced via ADCC mediated by cetuximab or avelumab in cells with higher baseline EGFR or PD-L1 expression, respectively. The ability of IFNγ to induce tumor cell PD-L1 expression correlated with enhanced PD-L1-specific ADCC. IFNγ induced neither tumor cell EGFR expression nor EGFR-specific ADCC. Although a single dose of 8Gy IR did not appear to directly enhance susceptibility to haNK killing alone, enhanced PD-L1-and EGFR-mediated ADCC after IR correlated with increased PD-L1 and EGFR expression in one of four models. This pre-clinical evidence supports the investigation of haNK cellular therapy in combination with ADCC-mediating mAbs, with or without IR, in the clinical trial setting for patients with advanced HNSCCs. Given the MHC-unrestricted nature of this treatment, it may represent an opportunity to treat patients with non-T-cell inflamed tumors.

Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells

“…To overcome this requirement, haNKs, or high-affinity NK cells, are NK-92 cells engineered to express endoplasmic reticulum-retained IL-2(11). haNKs have demonstrated the ability to efficiently kill carcinoma cells at low effector-to-target ratios(12, 13). Irradiation of haNKs and haNK-derived cell products ensures short life span of these cells and allows for repeat administration with no risk of cellular engraftment and low risk of cytopenias in treated hosts(14, 27).…”

“…NK-92 cells, derived from a Non-Hodgkin’s lymphoma patient, can be continuously expanded in culture and following irradiation, can be safely administered in high doses to patients with cancer(8-10). High-affinity NK (haNK) cells are NK-92 cells engineered to express endoplasmic reticulum-retained IL-2(11), have demonstrated potent effector function in numerous pre-clinical models(12, 13), and following irradiation, can also be safely administered in high doses to patients(14). haNKs represent an “off the shelf” NK cellular therapy available for pre-clinical and clinical study.…”

Overcoming hypoxia-induced functional suppression of NK cells

“…16 We have previously extensively described the clinical potential of high affinity NK (haNK) cells. [17][18][19][20][21] These cells are based on NK-92 (non-Hodgkin's lymphoma) engineered to express high avidity CD16 (V158) for increased ADCC activity and IL-2 for an internal autocrine loop. In addition, these cells do not express the inhibitor molecule Open access killer immunoglobulin receptor.…”

Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells

“…To overcome this requirement, haNKs, or high-affinity NK cells, are NK-92 cells engineered to express endoplasmic reticulum-retained IL-2(11). haNKs have demonstrated the ability to efficiently kill carcinoma cells at low effector-to-target ratios ( Friedman et al, 2019 ; Friedman et al, 2018 ). Irradiation of haNKs and haNK-derived cell products ensures short life span of these cells and allows for repeat administration with no risk of cellular engraftment and low risk of cytopenias in treated hosts ( Seery et al, 2019 ; Brudno and Kochenderfer, 2016 ).…”

“…NK-92 cells, derived from a Non-Hodgkin’s lymphoma patient, can be continuously expanded in culture and following irradiation, can be safely administered in high doses to patients with cancer ( Gong et al, 1994 ; Williams et al, 2017 ; Tonn et al, 2013 ). High-affinity NK (haNK) cells are NK-92 cells engineered to express endoplasmic reticulum-retained IL-2(11), have demonstrated potent effector function in numerous pre-clinical models ( Friedman et al, 2019 ; Friedman et al, 2018 ), and following irradiation, can also be safely administered in high doses to patients ( Seery et al, 2019 ). haNKs represent an ‘off the shelf’ NK cellular therapy available for pre-clinical and clinical study.…”