Improving NK cell function in multiple myeloma with NKTR-255, a novel polymer-conjugated human IL-15

• Published in: Blood advances 2023-01, Vol.7 (1), p.9-19
• Main Authors: Fernandez, Rafael Alonso, Mayoral, Jessica Encinas, Pierre-Louis, Laetitia, Yao, Yao, Xu, Yan, Mu, Shidai, Martinez-Lopez, Joaquin, Primo, Daniel, Miyazaki, Takahiro, Prabhala, Rao, Anderson, Kenneth C., Overwijk, Willem W., Munshi, Nikhil C., Fulciniti, Mariateresa
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Humans; Immunologic Factors - therapeutic use; Interleukin-15 - metabolism; Killer Cells, Natural; Leukocytes, Mononuclear; Mice; Multiple Myeloma - therapy; Polymers - metabolism; Polymers - pharmacology; Polymers - therapeutic use; Regular; Tumor Microenvironment
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2022007985

•The induction of an activated profile in NK cells by NKTR-255 correlates with an effective enhancement of the anti-MM effector functions.•NKTR-255 increases NK-mediated ADCC against MM cells and partially overcomes daratumumab-induced NK cell depletion in vivo. [Display omitted] Multiple myeloma (MM) is characterized by an immunosuppressive microenvironment that enables tumor development. One of the mechanisms of immune evasion used by MM cells is the inhibition of natural killer (NK) cell effector functions; thus, the restoration of NK cell antitumor activity represents a key goal to increase tumor cell recognition, avoid tumor escape and potentially enhancing the effect of other drugs. In this study, we evaluated the ability of the investigational medicine NKTR-255, an IL-15 receptor agonist, to engage the IL-15 pathway and stimulate NK cells against MM cells. We observed that incubation with NKTR-255 was able to tilt the balance toward an activated phenotype in NK cells isolated from peripheral blood mononuclear cells of patients with MM, with increased expression of activating receptors on the surface of treated NK cells. This resulted in an enhanced degranulation, cytokine release, and anti-tumor cytotoxicity when the NK cells were exposed to both MM cell lines and primary MM cells. We further evaluated the in vivo effect of NKTR-255 in fully humanized immunocompetent mice subcutaneously engrafted with H929 MM cells. Compared with placebo, weekly injection of the mice with NKTR-255 increased the number of circulating NK cells in peripheral blood and delayed tumor growth. Finally, we observed that combination of NKTR-255 with the anti-CD38 antibody, daratumumab, was effective against MM cells in vitro and in vivo. Taken together, our data suggest a significant impact of NKTR-255 in inducing NK cell function against MM cells with important translational implications.