Background: NKTR-255 is a polymer-conjugated IL-15 receptor agonist that accesses the IL-15 signaling pathway, and enhances the function and numbers of natural killer (NK) cells and CD8 memory T cell populations. Many hematological malignancies are treated with targeted antibodies that utilize effector mechanisms to recruit NK cells and macrophages. Most patients with hematological malignancies experience a progressive decline of NK cell immunity, a phenomenon termed as an “immunological desert”. We evaluated the hypothesis that a combination of NKTR-255 with a targeted antibody such as an anti-CD38 monoclonal antibody (mAb) or an anti-CD20 mAb, when evaluated in a preclinical hematological tumor model, would provide enhanced efficacy. Methods: Human PBMCs were stimulated with NKTR-255 and/or daratumumab for in vitro NK cell characterization. Using a B cell lymphoma model, SCID mice were inoculated i.v. with 10⁷ Daudi cells and treated with a single dose of daratumumab or rituximab two weeks after tumor cell injection. NKTR-255 was administered s.c. concurrently on a q7dx3 dosing schedule. Survival of treated animals was measured using hind limb paralysis and morbidity as surrogate endpoints. Tumor cell depletion and phenotyping of immune cells in bone marrow were conducted by flow cytometry. Results: NKTR-255, when combined with daratumumab, enhanced NK cell degranulation and decreased NK cell death, leading to enhanced antibody-dependent cellular cytotoxicity (ADCC) activity for the daratumumab - NKTR-255 combination over the single agents. NKTR-255 demonstrated synergistic activity and provided a long-term survival benefit when combined with daratumumab or rituximab in the CD38 and CD20-expressing lymphoma mouse models. Mechanistic studies conducted in tumor-bearing mice treated with a combination of NKTR-255 and daratumumab showed effective clearance of lymphoma cells from the bone marrow and increased expansion of effector NK cells and other immune cells. Depletion experiments confirmed the role of NK, CD8 and other monocyte lineage immune cells in the observed anti-myeloma activity. Conclusions: These studies indicate that administration of NKTR-255, when combined with a monoclonal antibody such as daratumumab and rituximab, significantly increases NK cell numbers and activates their tumor killing capacity by virtue of an enhanced ADCC effect. Combinatorial approaches of NKTR-255 with these targeting agents could lead to novel and effective clinical applications in hematology.