Novel trispecific killer engager targeting B7-H3 enhances natural killer cell antitumor activity against head and neck cancer

BACKGROUND: ) subset, have a dismal prognosis. Furthermore, patients with Fanconi anemia (FA) have a genetic predisposition with a 500-fold to 700-fold higher incidence of HNSCC. Thus, novel and more efficacious therapies are needed. As current immunotherapies often fail due to suppressive elements in the tumor microenvironment (TME), we developed a trispecific killer engager (TriKE) to direct multiple signals to natural killer (NK) cells to overcome the hypoxic TME. This TriKE is comprised of a camelid nanobody that binds to CD16 on NK cells, an interleukin (IL)-15 moiety, and another novel camelid nanobody that binds to the B7-H3 antigen, which is highly and specifically expressed on the tumor cell surface. METHODS: (NSG) mice engrafted with human HNSCC. RESULTS: , the B7H3 TriKE-treated mice demonstrated substantial antitumor activity and prolonged survival. CONCLUSIONS: The B7H3 TriKE is a novel immunotherapeutic approach that can overcome hypoxic suppression of NK cells in the HNSCC TME. These highly translational studies present an innovative therapy for patients with HNSCC and will be developed further for clinical application.