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AACR 2023: Checkpoint Blockade and Multiple Myeloma–Specific Targeting May Enhance NK Cell Responses

By: Julia Fiederlein Cipriano
Posted: Friday, May 12, 2023

Alice Y. Zhou, MD, PhD, of Washington University, St. Louis, and colleagues conducted a study to evaluate the preclinical significance of memory-like natural killer (NK) cell differentiation in combination with other approaches in the treatment of multiple myeloma. Their findings, which were presented during the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 2897/2), highlighted the potential of adding inhibitory NKG2A/HLA-E checkpoint blockade or multiple myeloma–specific targeting strategies in the clinical setting.

Compared with conventional NK cells, healthy donor–derived, memory-like NK cells demonstrated similar interferon-gamma (IFN-γ) responses and “modestly” increased cytotoxicity against the MM1.s and OPM2 cell lines. Both multiple myeloma cell lines and primary cells were found to express high levels of HLA-E. Mass cytometry analyses of patients with multiple myeloma versus healthy controls revealed enrichment of an NK cell population expressing high levels of NKG2A, as well as high levels of both activation and cytotoxic markers.

Compared with isotype monoclonal antibody therapy, using the monoclonal antibody monalizumab to disrupt HLA-E binding to NKG2A was found to significantly increase the healthy donor–derived, memory-like NK cell IFN-γ response, degranulation, and killing of MM1.s cells. NK cells isolated from patients with multiple myeloma exhibited similarly enhanced functionality after memory-like differentiation and NKG2A blockade. In MM.1s cell–implanted mouse models, healthy donor–derived, memory-like NK cells plus monalizumab demonstrated improved control of tumor growth compared with treatment with memory-like NK cells alone and conventional NK cells, as well as versus untreated control mice.

Furthermore, the anti-SLAMF7 antibody elotuzumab appeared to increase the functionality of memory-like NK cells against multiple myeloma cell lines with and without the addition of monalizumab. NK cells engineered to express B-cell maturation antigen chimeric antigen receptors demonstrated increased IFN-γ production and degranulation against MM1.s cells versus their nontransduced counterparts. According to the investigators, these functional responses were further enhanced with memory-like differentiation.

Disclosure: For full disclosures of the study authors, visit

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