Natural killer (NK) cells are attractive candidates for allogeneic cell-based immunotherapy due to their potent antitumor effector function and good safety profile. NK cells express killer immunoglobulin-like receptors (KIRs) and the NKG2A receptor important for NK cells education as well as providing inhibitory signals upon encountering HLA-expressing target cells. Multiple myelomas (MM) is an example of a tumor expressing relatively high levels of HLA molecules.

NK cells can sense self vs. missing-self via receptors belonging to the killer immunoglobulin-like receptor (KIR) family and NKG2A. In this review, we will provide an overview of the functional relevance of KIR and NKG2A for the anti-tumor response of NK cells in an allogeneic setting.

The researcher will specifically address the role of allogeneic NK cells in multiple myeloma (MM), a hematological malignancy characterized by the expansion of malignant plasma cells in the bone marrow.

To date, MM remains incurable despite the greatly improved clinical perspective due to novel immunomodulatory agents like lenalidomide and pomalidomide and highly promising antibodies like daratumumab (anti-CD38) and elotuzumab (anti-CS-1/SLAMF7).

Given their excellent safety and feasibility profiles, NK cells are interesting candidates to combine with these novel agents to enhance clinical efficacy and to ultimate achieve curative treatment for MM patients.

One way to improve clinical responses of IPH2101 may be by combinational therapies with drugs providing strong activating signals to the NK cells. In a phase, I clinical trial with relapsed/refractory MM patients, the combination of the anti-KIR antibody with lenalidomide, an immunomodulatory agent, augmented NK cell function and resulted in an objective response.

Inhibitory NK cell signaling

Moreover, the combination of IPH2101 and the ADCC-triggering antibody daratumumab could also enhance NK cell cytotoxicity against MM cell lines and against primary myeloma cells in vitro while IPH2101 alone did not induce a significant antitumor effect in this setting.

Blocking NKG2A is another option to reduce inhibitory NK cell signaling aiming to improve the effector function of either endogenous NK cells or of donor NK cell in allo-SCT or adoptive transfer settings.

In a preclinical mouse study, infusion of NKG2A+ NK cells mediated anti-leukemia effects when NK cells were pre-treated with an anti-NKG2A antibody and rescued the mice from developing leukemia.

In another in vitro preclinical study, blocking NKG2A with the anti-NKG2A antibody monalizumab could restore the cytotoxic potential of NK cells derived from patients with chronic lymphocytic leukemia. However, thus far completed clinical trials testing the safety and efficacy of monalizumab in MM patients are not available.