Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways

Abstract

Elotuzumab is a humanized monoclonal antibody specific for signaling lymphocytic activation molecule-F7 (SLAMF7, also known as CS1, CD319, or CRACC) that enhances natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of SLAMF7-expressing myeloma cells. This study explored the mechanisms underlying enhanced myeloma cell killing with elotuzumab as a single agent and in combination with lenalidomide, to support ongoing phase III trials in patients with relapsed/refractory or newly-diagnosed multiple myeloma (MM). An in vitro peripheral blood lymphocyte (PBL)/myeloma cell co-culture model was developed to evaluate the combination of elotuzumab and lenalidomide. Expression of activation markers and adhesion receptors was evaluated by flow cytometry, cytokine expression by Luminex and ELISPOT assays, and cytotoxicity by myeloma cell counts. Elotuzumab activated NK cells and promoted myeloma cell death in PBL/myeloma cell co-cultures. The combination of elotuzumab plus lenalidomide demonstrated superior anti-myeloma activity on established MM xenografts in vivo and in PBL/myeloma cell co-cultures in vitro than either agent alone. The combination enhanced myeloma cell killing by modulating NK cell function that coincided with the upregulation of adhesion and activation markers, including interleukin (IL)-2Rα expression, IL-2 production by CD3+CD56+ lymphocytes, and tumor necrosis factor (TNF)-α production. In co-culture assays, TNF-α directly increased NK cell activation and myeloma cell death with elotuzumab or elotuzumab plus lenalidomide, and neutralizing TNF-α decreased NK cell activation and myeloma cell death with elotuzumab. These results demonstrate that elotuzumab activates NK cells and induces myeloma cell death via NK cell-mediated ADCC, which is further enhanced when combined with lenalidomide.

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma

“…18 Elotuzumab also demonstrates immunostimulatory activity on NK cells, including upregulation of interleukin 2 and tumor necrosis factor a. 19 The effects of elotuzumab on NK cells in the phase 3 ELOQUENT-2 study were not reported. 20 However, unlike daratumumab, elotuzumab was associated with high rates of grade 3 and 4 lymphopenia (77% vs 49% for the control group).…”

A phase 2 safety study of accelerated elotuzumab infusion, over less than 1 h, in combination with lenalidomide and dexamethasone, in patients with multiple myeloma

“…Binding of elotuzumab to SLAMF7 on natural killer cells both directly activates these immune cells and indirectly enhances their antimyeloma activity through antibody-dependent cell-mediated cytotoxicity (ADCC) via the CD16 pathway, resulting in increased targeted cell death of elotuzumab-bound myeloma cells that also express SLAMF7 and undergo apoptosis. 14 In preclinical myeloma xenograft models involving mice, elotuzumab demonstrated dose-dependent antitumor activity via ADCC. 15 Furthermore, elotuzumab in combination with lenalidomide (an IMiD) and bortezomib (a PI) enhanced ADCC in vitro, potentially mediated through enhancement of natural killer cell activity.…”

Elotuzumab for Treatment of Multiple Myeloma (Literature Review)

“…Предполагают, что есть и другие механизмы целена-правленного воздействия элотузумаба на миеломные клетки [29,31,32]. В исследовании in vitro на линиях миеломных клеток было показано, что элотузумаб может ингибировать адгезию миеломных клеток, экспрессирующих SLAMF7, к стромальным клеткам костного мозга [28].…”