NK cell engagers (NKCE) target tumor antigens and NK-specific receptors to trigger tumor cell killing.
Major finding: NK cell engagers (NKCE) target tumor antigens and NK-specific receptors to trigger tumor cell killing.
Concept: NK cell–based therapies may be more efficacious and less toxic than T cell–based therapies.
Impact: NKCEs represent a safe and specific therapeutic alternative across multiple tumor types.
Immunotherapy targets cancer by activating intrinsic T-cell activity against tumor cells and has been an effective strategy across a number of hematologic malignancies. However, major drawbacks of this approach remain its cytotoxic side effects and its limited ability to target solid tumors. Gauthier and colleagues sought to ascertain whether antibody-based activation of natural killer (NK) cells and tumor cells promotes antibody-dependent cell-mediated cytoxicity with superior potency compared with current immunotherapeutic approaches. Natural killer cytotoxicity triggering receptor 1 (NKp46), an NK stimulatory receptor, was shown to be expressed in tumor-infiltrating NKs. Initially, engineered bispecific NK cell engagers (NKCE) targeting both NKp46 and a tumor antigen (TA)—CD19, CD20, or EGFR—exhibited potent NK-cell activation and antitumor cell activity in vitro. In vivo, treatment of mice bearing Raji cell xenografts with bispecific NKCEs mediated NK-cell infiltration into the tumor bed and limited tumor growth in an NK cell–dependent manner. To increase the activation potential and maintain specificity of NKCEs for NK cells, trifunctional NKCEs were generated to target TA and NKp46 as well as CD16, another NK stimulatory receptor. These trifunctional NKCEs displayed superior NK-cell activation and specific antitumor cell activity in vitro compared with bispecific NKCEs, the anti-CD20 antibodies rituximab and obinutuzumab, or the anti-EGFR antibody cetuximab. In vivo, the trifunctional NKCE more effectively limited the growth of Raji cell xenografts and prolonged survival compared with obinutuzumab. Taken together, these results demonstrate the superior efficacy and reduced cytotoxicity of activating the antitumor potential of NK cells versus effector T cells. Moreover, these NKCEs represent a safe and versatile therapeutic option to target both liquid and solid cancer types expressing various TAs.
Gauthier L, Morel A, Anceriz N, Rossi B, Blanchard-Alvarez A, Grondin G, et al. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell 2019 May 30 [Epub ahead of print].
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