Restoring NK Cell Activities in Multiple Myeloma with IL-15 Receptor Agonist NKTR-255

Multiple myeloma (MM) is characterized by an immunosuppressive microenvironment that enables tumor development through the activation of immune cells with a suppressive effect, disruption of antigen presentation and dysregulation of proliferation and functionality of effector cells. NK cells play a major role in antitumor surveillance hindering tumor growth through their potent cytotoxic properties. Nevertheless, MM cells can also induce an inhibition of NK cell effector functions as a mechanism for immune evasion; thus, the restoration of NK cell antitumor activity represents a key goal for new immunotherapeutic approaches, increasing tumor cell recognition, avoiding tumor escape and potentially enhancing the effect of other drugs.

IL-15 promotes proliferation and cytotoxicity of NK and memory CD8 T cells, enhancing innate and adaptive immunity against MM cells in pre-clinical studies, but the unfavorable pharmacokinetic profile hampers its clinical application. In the current study, the ability of the investigational medicine, NKTR-255, an IL-15 receptor agonist, to engage the IL-15 pathway and overcome some of the immune dysfunction was evaluated in MM patients by restoring NK cell activity.

Through a comprehensive flow cytometry approach, we observed that treatment with NKTR-255 was effective to revert the inhibitory status observed in NK cells from MM patients, thereby resulting in improved degranulation and cytokine production in response to tumor targets; and enhanced direct NK cytotoxicity against several MM cell lines and primary MM cells. Since the activation status of NK cells depends on the integration of activating and inhibitory signals, we have evaluated expression of a panel of NK activating and inhibitory receptors and adhesion molecules. While we observed that NKTR-255 treatment significantly increased the expression of activating receptors and adhesion molecules (NKG2D, DNAM-1, NKp30, NKp46, TRAIL, CD57, CD69) with a role on tumor recognition and killing, no significant impact was observed in the expression of inhibitory receptors (PD-1, TIGIT, KIR2DL2/3). This priming effect by NKTR-255 was also observed for normal donor NK cells.

Combination of NKTR255 with current myeloma-targeting antibodies against CD38 and SLAMF7 (daratumumab and elotuzumab respectively) was effective against MM cells in vitro, with significant increase of antibody-dependent cellular cytotoxicity (ADCC) seen compared to single agents.

The efficacy of NKTR-255 in combination with daratumumab against MM cell growth in the context of the immune milieu was confirmed in a fully humanized immunocompetent mouse model of myeloma. While both NKTR-255 and daratumumab delayed tumor growth as single agents (35.4% and 29.6%, respectively), the combination regimen was significantly effective (66.4%) in inhibiting tumor growth. Interestingly, the analysis of immune cells in blood, spleen and tumor tissue from the mice showed that daratumumab depleted, as expected, the total number of NK, CD8+ and CD4+ T cells (mostly at the expense of CD38+ cell subsets); but this depletion was prevented when daratumumab was employed in combination with NKTR-255.

Taken together, our studies show that NKTR-255 restores NK cell activities in MM and provide evidences for clinical use of NKTR-255 as novel immunotherapeutic agent in MM alone or in combination with monoclonal antibodies.